PRODEKS SASE

INSTRUCTIONS FOR MEDICAL USE OF MIRAPEX MEDICINE

MIRAPEX (MIRAPEX)

Composition:

active substance: pramipexole; 1 tablet contains pramipexole dihydrochloride monohydrate 0.25 mg, which corresponds to 0.18 mg of pramipexole, or 1 mg, which corresponds to 0.7 mg of pramipexole; excipients: mannitol (E 421), corn starch, colloidal anhydrous silicon dioxide, povidone, magnesium stearate.

Pharmaceutical form.

Tablets.

Main physical and chemical properties:

0.25 mg tablets - white, oval, flat on both sides of the tablet with beveled edges and marking: R7 / deep score line / R7 on one side, Boehringer Ingelheim company logo / score line / Boehringer Ingelheim company logo on the other side. Tablets can be divided into equal halves; 1 mg tablets - white, round, flat tablets with beveled edges and marking: R9 / deep score line / R9 on one side, Boehringer Ingelheim company logo / score line / Boehringer Ingelheim company logo on the other side. Tablets can be divided into equal halves.

Pharmacotherapeutic group.

Antiparkinsonian agents. Dopaminergic agents. Dopamine agonists.

ATC code N04B C05.

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 them has a predominant affinity for D3 receptors, as well as full inherent activity.

Pramipexole facilitates parkinsonian motor disorders by stimulating dopamine receptors in the striatum (striated body). Animal studies have shown that pramipexole inhibits the synthesis, release, and reuptake of dopamine.

The exact mechanism of action of MIRAPEX in the treatment of restless legs syndrome is unknown. Neuropharmacological data indicate the involvement of the primary dopaminergic system.

Pharmacodynamic effects

In volunteers, a dose-dependent decrease in prolactin was observed. In a clinical study involving healthy volunteers, with faster titration of the MIRAPEX dose (every 3 days) to 4.5 mg of pramipexole as a salt (3.15 mg of pramipexole) per day, an increase in arterial pressure and heart rate was observed. This effect was not observed in patient studies.

Pharmacokinetics.

Absorption

Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability exceeds 90%. The maximum plasma concentration is reached between 1 and 3 hours after administration. The rate of absorption is not reduced when taken with food, but the overall level of absorption is reduced. Pramipexole demonstrates linear kinetics and minimal variability in plasma levels in different patients.

Distribution

In humans, the ability of pramipexole to bind to plasma proteins is very low (<20%), and the volume of distribution is large (400 liters). High concentrations were observed in brain tissue of rats (approximately 8 times higher compared to plasma).

Metabolism

Pramipexole is metabolized in humans to a negligible extent only.

Excretion

Renal excretion of unchanged pramipexole is the main route of excretion. Approximately 90% of the labeled dose of 14C is excreted by the kidneys, while less than 2% is found in the feces. The total clearance of pramipexole is approximately 500 ml/h, and renal clearance is approximately 400 ml/h. The half-life (t 1/2) varies from 8 hours in young people to 12 hours in the elderly.

Clinical characteristics.

Indications.

MIRAPEX is indicated for adults for the treatment of signs and symptoms of idiopathic Parkinson's disease, as monotherapy (without levodopa) or in combination with levodopa, i.e. throughout the entire disease, from early to late stages, when the effect of levodopa decreases or becomes unstable and fluctuations in therapeutic effect occur (cessation of action of the dose or fluctuations according to the "on-off" principle).

MIRAPEX is indicated for adults for the symptomatic treatment of idiopathic restless legs syndrome of moderate to severe severity with doses not exceeding 0.75 mg of pramipexole dihydrochloride monohydrate (0.54 mg of pramipexole) (see "Method of administration and doses").

Contraindications.

Hypersensitivity to the active substance or to any other component of the drug.

Interaction with other medicinal products and other types of interactions.

Binding to plasma proteins.

Pramipexole binds to plasma proteins to a very small extent (<20%), and minimal biotransformation is observed in humans. Therefore, interaction with other medicinal products that affect the binding of the drug to plasma proteins or its excretion through biotransformation is unlikely. Since anticholinergic agents are excreted mainly through biotransformation, potential interaction is unlikely, although interaction with anticholinergic agents has 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%, probably by inhibiting the cationic secretory transport system of renal tubules. Therefore, medicinal products that are inhibitors of this pathway of active excretion of the drug by the kidneys or that are excreted by this pathway, such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine, and procainamide, may interact with pramipexole, leading to a decrease in the clearance of pramipexole. When these medicinal products are used in combination with MIRAPEX, a reduction in the dose of pramipexole should be considered.

Combination with levodopa

When increasing the dose of MIRAPEX in combination with levodopa, it is recommended to reduce the dose of levodopa, and the dose 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 "Special instructions", "Ability to affect reaction rate when driving or operating other mechanisms", and "Side effects").

Antipsychotic medicinal products.

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

Special instructions.

When prescribing MIRAPEX to patients with Parkinson's disease and impaired renal function, the dose should be reduced according to the "Method of administration and doses" section.

Hallucinations. Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients must be informed that (mostly visual) hallucinations may occur.

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

Dystonia

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

If dystonia occurs, it is necessary to review the scheme of treatment with dopaminergic drugs and adjust the dose of pramipexole.

Sudden onset of sleep and sleepiness. The use of pramipexole has been associated with sleepiness and sudden onset of sleep, particularly in patients with Parkinson's disease. Sudden onset of sleep during daytime activities, which in some cases occurs without awareness of it or without warning signs, has been rarely reported. Patients need to be informed about this. They should be advised to exercise caution when driving or operating other mechanisms during treatment with MIRAPEX. Patients who experience sleepiness and/or sudden onset of sleep should refrain from driving or operating other mechanisms. Additionally, it may be necessary to reduce the dose or discontinue treatment. Due to possible additive effects, caution is recommended if patients take other sedative medicinal products in combination with pramipexole or consume alcohol (see "Interaction with other medicinal products and other types of interactions", "Ability to affect reaction rate when driving or operating other mechanisms", and "Side effects").

Impulse control disorders. Patients should be carefully monitored for the development of impulse control disorders. Patients and caregivers should be aware that treatment with dopamine agonists, including MIRAPEX, may be associated with symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating. If such symptoms develop, it is necessary to consider reducing the dose/discontinuing the drug.

Mania and delirium. Patients should be carefully 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, it is necessary to consider reducing the dose/discontinuing the drug.

Patients with psychotic disorders. Patients with psychotic 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 "Interaction with other medicinal products and other types of interactions").

Ophthalmological monitoring. Ophthalmological monitoring is recommended at regular intervals or when visual disturbances occur.

Severe cardiovascular disease. Caution should be exercised in severe cardiovascular disease. It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the general risk of postural arterial hypotension associated with dopaminergic therapy.

Malignant neuroleptic syndrome. Symptoms suggesting the presence of malignant neuroleptic syndrome have been observed after abrupt withdrawal of dopaminergic treatment (see "Method of administration and doses").

Dopamine agonist withdrawal syndrome.

Dopamine agonist withdrawal syndrome has been observed with the use of dopamine agonists, including pramipexole (see "Side effects"). To discontinue treatment, the dose of pramipexole should be gradually reduced in patients with Parkinson's disease (see "Method of administration and doses"). Limited data suggest that patients with impulse control disorders and patients who receive high daily doses and/or high cumulative doses of dopamine agonists may have a higher risk of developing dopamine agonist withdrawal syndrome. The syndrome may include apathy, anxiety, depression, fatigue, sweating, and pain. Before reducing the dose and discontinuing pramipexole, patients should be informed about the possible symptoms of withdrawal syndrome. Patients should be closely monitored during dose reduction and withdrawal of pramipexole. In case of pronounced and/or persistent symptoms of dopamine agonist withdrawal syndrome, temporary re-appointment of pramipexole at the lowest effective dose may be considered.

Augmentation of restless legs syndrome. Treatment of restless legs syndrome with pramipexole may cause augmentation. Augmentation is characterized by early onset of symptoms in the evening (or even during the day), increased severity of symptoms, and spread of symptoms to other limbs.

The risk of augmentation may increase with increasing dose. Before starting treatment, patients should be informed about the risk of augmentation and should consult a doctor if symptoms of augmentation occur. If augmentation is suspected, it is necessary to consider adjusting the dose to the lowest effective dose or consider discontinuing pramipexole (see "Method of administration and doses" and "Side effects").

Pregnancy and lactation.

Pregnancy. The effect on pregnancy and lactation in humans has not been studied. Pramipexole did not have a teratogenic effect in studies on rats and rabbits, but it had an embryotoxic effect on rats at doses that had a toxic effect on pregnant females. MIRAPEX should not be used during pregnancy unless absolutely necessary, i.e. when the potential benefit outweighs the potential risk to the fetus.

Lactation. Since treatment with pramipexole suppresses prolactin secretion in humans, suppression of lactation is expected. The penetration of pramipexole into breast milk in women 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 relevant data in humans, MIRAPEX is not recommended during breastfeeding. However, if it is unavoidable to use this drug, 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 is expected for a dopamine agonist. However, these studies did not reveal any direct or indirect harmful effects on male fertility.

Ability to affect reaction rate when driving or operating other mechanisms.

MIRAPEX may have a significant impact on the ability to drive or operate other mechanisms. Hallucinations or sleepiness may occur.

Patients who are treated with MIRAPEX and experience sleepiness and/or sudden onset of sleep during such treatment should be informed that they should refrain from driving or operating other mechanisms that may pose a risk to themselves or others due to decreased alertness (see "Special instructions", "Interaction with other medicinal products and other types of interactions", and "Side effects").

Method of administration and doses.

Parkinson's disease.

The daily dose is administered in 3 divided doses.

Initial treatment.

The dose of the drug should be gradually increased, starting from 0.375 mg of pramipexole dihydrochloride monohydrate (0.264 mg of pramipexole) per day, and then increased every 5-7 days. If patients do not experience intolerable side effects, the dose should be titrated to achieve the maximum therapeutic effect (see Table 1).

In case of further dose increase, the daily dose should be increased by 0.75 mg of pramipexole dihydrochloride monohydrate (0.54 mg of pramipexole) per week up to a maximum of 4.5 mg of pramipexole dihydrochloride monohydrate (3.3 mg of pramipexole) per day. However, it should be noted that the frequency of occurrence of sleepiness increases when using doses higher than 1.5 mg of pramipexole dihydrochloride monohydrate (1.1 mg of pramipexole) per day (see "Side effects").

Maintenance therapy.

The individual dose varies from 0.375 mg of pramipexole dihydrochloride monohydrate (0.264 mg of pramipexole) to a maximum of 4.5 mg of pramipexole dihydrochloride monohydrate (3.3 mg of pramipexole) per day. During dose increase in pilot studies, the effectiveness of treatment was observed, starting from a daily dose of 1.5 mg of pramipexole dihydrochloride monohydrate (1.1 mg of pramipexole). Further dose adjustment should be made taking into account the clinical response and the occurrence of side effects. During clinical studies, approximately 5% of patients were treated with doses that were less than 1.5 mg of pramipexole dihydrochloride monohydrate (1.1 mg of pramipexole) per day. In progressive Parkinson's disease, doses of pramipexole higher than 1.5 mg of pramipexole dihydrochloride monohydrate (1.1 mg of pramipexole) per day may be beneficial for patients, especially if levodopa dose reduction is planned. It is recommended to reduce the dose of levodopa when increasing the dose of MIRAPEX and during maintenance therapy with this drug, depending on the response in individual patients (see "Interaction with other medicinal products and other types of interactions").

Discontinuation of treatment.

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

Dosing for patients with impaired renal function.

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

- Patients with a creatinine clearance of more than 50 ml/min do not need to reduce the daily dose or frequency of administration;

- Patients with a creatinine clearance of 20-50 ml/min should start with an initial daily dose of MIRAPEX, administered in 2 divided doses, starting with 0.125 mg of pramipexole dihydrochloride monohydrate (0.088 mg of pramipexole) twice a day (0.25 mg/day of pramipexole dihydrochloride monohydrate/0.176 mg/day of pramipexole). The maximum daily dose should not exceed 2.25 mg of pramipexole dihydrochloride monohydrate (1.57 mg of pramipexole);

- Patients with a creatinine clearance of less than 20 ml/min should start with an initial daily dose of MIRAPEX, administered in 1 divided dose, starting with 0.125 mg/day of pramipexole dihydrochloride monohydrate (0.088 mg/day of pramipexole). The maximum daily dose should not exceed 1.5 mg of pramipexole dihydrochloride monohydrate (1.1 mg of pramipexole);

- In case of deterioration of renal function during maintenance therapy, the daily dose of MIRAPEX should be reduced by the same percentage as the reduction in creatinine clearance. For example, if creatinine clearance decreases by 30%, the daily dose of MIRAPEX should be reduced by 30%. The daily dose can be administered in 2 divided doses if creatinine clearance is between 20-50 ml/min and in 1 divided dose if creatinine clearance is less than 20 ml/min.

Dosing for patients with impaired liver function.

It is likely that there is no need to adjust the dose for patients with impaired liver function, since approximately 90% of the absorbed active substance is excreted by the kidneys. However, the potential impact of impaired liver function on the pharmacokinetics of MIRAPEX has not been studied.

Restless legs syndrome.

The recommended initial dose of MIRAPEX is 0.125 mg of pramipexole dihydrochloride monohydrate (0.088 mg of pramipexole) once daily, 2-3 hours before bedtime. For patients who require additional relief of symptoms, the dose can be increased every 4-7 days up to a maximum dose of 0.75 mg of pramipexole dihydrochloride monohydrate (0.54 mg of pramipexole) per day (see Table 2). The lowest effective dose should be used (see "Special instructions, Restless legs syndrome").

* If necessary

It is necessary to evaluate the patient's response to treatment after 3 months and review the need to continue therapy. If treatment is interrupted for more than a few days, it is necessary to restart titration as described above.

Discontinuation of treatment.

Since the daily dose for the treatment of restless legs syndrome does not exceed 0.75 mg of pramipexole dihydrochloride monohydrate (0.54 mg of pramipexole), the use of MIRAPEX can be discontinued without gradual dose reduction. In a 26-week placebo-controlled clinical trial, a recurrence of restless legs syndrome symptoms (increase in severity of symptoms compared to the initial level) was observed in 10% of patients (14 out of 135 patients) after abrupt discontinuation of pramipexole. This effect was similar at all doses.

Dosing for patients with impaired renal function.

The excretion of MIRAPEX from the body depends on renal function. Patients with a creatinine clearance of more than 20 ml/min do not need to reduce the daily dose.

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

Dosing for patients with impaired liver function.

For patients with impaired liver function, dose reduction is not considered necessary, since almost 90% of the absorbed active substance is excreted by the kidneys.

Method of administration.

Tablets should be taken orally, with water, during or after meals.

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 the unfavorable benefit/risk ratio for this disease.

Overdose.

There is no clinical experience of significant overdose. The expected side effects may be reactions 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 case of signs of central nervous system stimulation, the use of a neuroleptic agent may be indicated. Treatment of overdose may require general supportive measures, along with gastric lavage, intravenous fluids, and monitoring of the electrocardiogram.

Side effects.

Analysis of combined placebo-controlled trials, in which a total of 1,923 patients who received pramipexole and 1,354 patients who received placebo participated, showed that side effects were frequently reported in both groups. In 63% of patients who received pramipexole and 52% of patients who received placebo, at least one side effect was reported.

Most side effects are usually observed at the beginning of therapy, and a significant portion of them disappears even if therapy continues.

Side effects are presented by classes of systems and organs 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 - <1/10), uncommon (≥ 1/1000 - <1/100), rare (≥ 1/10000 - <1/1000), very rare (<1/10000), unknown (cannot be established based on available data).

Parkinson's disease.

Side effects of the drug in patients with Parkinson's disease, which were most frequently reported (≥ 5%) (more frequently with pramipexole treatment than with placebo), were nausea, dyskinesia, arterial hypotension, dizziness, sleepiness, insomnia, constipation, hallucinations, headache, and fatigue. The frequency of sleepiness increases when taking doses higher than 1.5 mg of pramipexole dihydrochloride monohydrate (1.1 mg of pramipexole) per day (see "Method of administration and doses"). The most common side effect when used in combination with levodopa was dyskinesia. Arterial hypotension may occur at the beginning of treatment, especially if titration of pramipexole is carried out too quickly.

1 This side effect was observed in the post-marketing period. With 95% confidence, the frequency category was determined as uncommon, but may be lower. Establishing the exact frequency is impossible, as the side effect was not observed during clinical trials in 2,762 patients with Parkinson's disease treated with pramipexole.

Restless legs syndrome, most common side effects

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

1 This side effect was observed in the post-marketing period. With 95% confidence, the frequency category was determined as uncommon, but may be lower. Establishing the exact frequency is impossible, as the side effect was not observed during clinical trials in 1,395 patients with restless legs syndrome treated with pramipexole.

Description of individual side effects

Sleepiness. The use of pramipexole is often associated with sleepiness and rarely with excessive daytime sleepiness and sudden onset of sleep.

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

Impulse control disorders. Treatment with dopamine agonists, including MIRAPEX, may be associated with symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating (see "Special instructions").

In a cross-sectional retrospective screening and case-control study involving 3,090 patients with Parkinson's disease, 13.6% of all patients who received dopaminergic or non-dopaminergic therapy had symptoms of impulse control disorders during the last six months. The observed manifestations included pathological gambling, compulsive buying, eating, and hypersexuality. Possible independent risk factors for the development of impulse control disorders included dopaminergic therapy and higher doses during dopaminergic therapy, younger age (≤ 65 years), unmarried status, and a family history of pathological gambling.

Dopamine agonist withdrawal syndrome. In case of dose reduction or discontinuation of dopamine agonists (including pramipexole), non-motor side effects may occur. Symptoms include apathy, anxiety, depression, fatigue, sweating, and pain (see "Special instructions").

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

Reporting of suspected side effects

Reporting of side effects after registration of a medicinal product is important. It allows for the monitoring of the benefit/risk ratio of the medicinal product. Healthcare professionals, as well as patients or their representatives, should report all suspected side effects and lack of efficacy of the medicinal product through the automated information system for pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25°C.

Store in a place inaccessible to children.

Packaging.

10 tablets in a blister pack; 3 blister packs in a carton box.

Release category.

By prescription only.

Manufacturer.

Boehringer Ingelheim Pharma GmbH & Co. KG.

Manufacturer's location and address.

Binger Strasse 173, 55216 Ingelheim am Rhein, Germany.