Mirapex tablets 0.25 mg blister No. 30

Instructions Mirapex tablets 0.25 mg blister No. 30

Composition

active ingredient: pramipexole;

1 tablet contains 0.25 mg of pramipexole dihydrochloride monohydrate, corresponding to 0.18 mg of pramipexole;

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

Dosage form

Pills.

Main physicochemical properties:

0.25 mg tablets – white, oval, flat on both sides tablets with beveled edges and markings: P7/deep breakline/P7 on one side, Boehringer Ingelheim company logo/breakline/Boehringer Ingelheim company logo on the other side.

Pharmacotherapeutic group

Antiparkinsonian drugs. Dopamine agonists.

ATX code N04B C05.

Pharmacological properties

Pharmacodynamics

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

Pramipexole alleviates parkinsonian movement disorders by stimulating dopamine receptors in the striatum. Animal studies have shown that pramipexole inhibits the synthesis, release and turnover of dopamine.

The exact mechanism of action of MIRAPEX in the treatment of restless legs syndrome is unknown. Although the pathophysiology of restless legs syndrome is largely unknown, neuropharmacological evidence suggests involvement of the primary dopaminergic system.

Pharmacokinetics

Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability is over 90%. Peak plasma concentrations are achieved between 1 and 3 hours after administration. The rate of absorption is not reduced by concomitant food intake, but the overall extent of absorption is reduced. Pramipexole exhibits linear kinetics and, regardless of the dosage form, there is relatively little variation in plasma levels between patients. In humans, protein binding of pramipexole is very low (< 20%) and the volume of distribution is large (400 l).

Pramipexole is metabolized in humans only to a small extent.

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

Indication

Treatment of the signs and symptoms of idiopathic Parkinson's disease in adults, as monotherapy (without levodopa) or in combination with levodopa throughout the course of the disease until the late stages when the effect of levodopa decreases or becomes unstable and fluctuations in the therapeutic effect occur (the "on-off" phenomenon).

Symptomatic treatment of moderate to severe idiopathic restless legs syndrome in adults, doses not exceeding 0.75 mg.

Contraindication

Hypersensitivity to pramipexole or to any other component of the drug.

Interaction with other medicinal products and other types of interactions

Plasma protein binding

Pramipexole is very poorly bound to plasma proteins (< 20%) and has low biotransformation. Therefore, interactions with other drugs that affect plasma protein binding or elimination by biotransformation are unlikely. Since anticholinergics are eliminated primarily by hepatic metabolism, potential interactions are unlikely. Interactions with anticholinergics have not been studied. There is no pharmacokinetic interaction between selegiline and levodopa.

Inhibitors/competitors of the active renal elimination pathway

Cimetidine reduces the renal clearance of pramipexole by approximately 34%, probably by inhibiting the cationic renal tubular secretion transport system. Drugs that inhibit active renal tubular secretion or are themselves eliminated by this route, such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine and procainamide, may interact with pramipexole and lead to a decrease in pramipexole clearance. A reduction in the pramipexole dose should be considered when these drugs are co-administered with MIRAPEX.

Combination with levodopa

When increasing the dose of MIRAPEX in patients with Parkinson's disease, it is recommended to reduce the dose of levodopa, while leaving the doses of other antiparkinsonian drugs unchanged.

Due to possible additive effects, caution should be exercised if the patient is taking other sedative medicinal products in combination with pramipexole or drinking alcohol (see sections 4.4, 4.8 and 4.8).

Antipsychotic medications

The concomitant use of antipsychotic medicinal products with pramipexole should be avoided (see section 4.4) as antagonistic effects are possible.

Application features

The use of MIRAPEX in reduced doses is suggested in accordance with the section “Method of administration and dosage” for patients with Parkinson's disease with impaired renal function.

Hallucinations: Hallucinations are a known side effect of dopamine agonist and levodopa treatment. Patients should be advised that hallucinations (mostly visual) may occur.

Dyskinesia: In combination therapy with levodopa in progressive Parkinson's disease, dyskinesia may develop at the beginning of MIRAPEX titration. In such cases, the levodopa dose should be reduced.

Dystonia

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

If dystonia occurs, consideration should be given to reviewing the dopaminergic treatment regimen and adjusting the pramipexole dose.

Sudden onset of sleep and somnolence. Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. There have been uncommon reports of sudden onset of sleep onset during daily activities, in some cases without awareness or warning signs. Therefore, patients should be advised to exercise caution when driving or operating machinery during treatment with MIRAPEX. Patients experiencing somnolence and/or episodes of sudden sleep onset should refrain from driving or operating machinery. In addition, a dose reduction or reduction in the duration of treatment should be considered. Due to possible additive effects, caution should be exercised if the patient is taking other sedative medicinal products in combination with pramipexole or drinking alcohol (see sections “Interaction with other medicinal products and other types of interactions”, “Ability to influence the speed of reactions when driving vehicles or using other mechanisms” and “Adverse reactions”).

Impulse control disorders: Patients should be monitored closely for the development of impulse control disorders. Patients and caregivers should be made aware that symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating, and compulsive eating, may occur during treatment with dopamine agonists, including MIRAPEX.

If such symptoms develop, dose reduction/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 made aware that mania and delirium can occur in patients receiving pramipexole therapy. If such symptoms develop, dose reduction/discontinuation of the drug should be considered.

Severe cardiovascular disease. In case of severe cardiovascular disease, the drug should be prescribed with particular caution. Monitoring of blood pressure is recommended, especially at the beginning of treatment, taking into account the general risk of postural hypotension associated with dopaminergic therapy.

Patients with psychiatric disorders: Patients with psychiatric disorders should only be treated with dopamine agonists if the potential benefits of treatment outweigh the risks. The concomitant use of antipsychotic medicinal products with pramipexole should be avoided (see section 4.5).

Neuroleptic malignant syndrome: Symptoms resembling neuroleptic malignant syndrome have been observed after abrupt withdrawal of dopaminergic treatment (see section 4.2).

Ophthalmological examination

Regular ophthalmological examination is recommended in case of vision disorders.

Dopamine agonist withdrawal syndrome (DAWS)

Augmentation (increased symptoms). Reports indicate that treatment of restless legs syndrome with dopaminergic drugs may cause augmentation. Augmentation is manifested by an early onset of symptoms in the evening (or even during the day), an increase in symptoms and the spread of symptoms to the upper limbs. Augmentation was specifically investigated in a controlled clinical trial of 26 weeks duration. Augmentation was observed in 11.8% of patients in the pramipexole (N=152) and placebo (N=149) groups. Kaplan-Meier analysis of time to augmentation did not show any significant difference between the pramipexole and placebo groups.

Renal impairment: MIRAPEX tablets should be administered with caution to patients with renal impairment, as pramipexole is excreted via the kidneys.

Rhabdomyolysis. The only case of rhabdomyolysis was reported in a 49-year-old man with advanced Parkinson's disease treated with MIRAPEX tablets. The patient was hospitalized with an elevated creatine phosphokinase level (CKD – 10,631 IU/L). The symptoms resolved after discontinuation of treatment.

Ability to influence reaction speed when driving vehicles or other mechanisms

MIRAPEX may have a significant influence on the ability to drive and use machines. Hallucinations or drowsiness may occur.

Patients with somnolence and/or episodes of sudden onset of somnolence should refrain from driving and potentially hazardous activities where impaired alertness increases the risk of serious injury or death while taking MIRAPEX.

Use during pregnancy or breastfeeding

The effects on pregnancy and lactation have not been studied in humans. MIRAPEX should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus.

Since treatment with MIRAPEX inhibits prolactin secretion, a decrease in lactation may occur. The excretion of MIRAPEX into breast milk has not been studied in women. MIRAPEX is not recommended for use in breast-feeding women. If MIRAPEX cannot be avoided, breast-feeding should be discontinued.

No studies have been conducted on the effects on human fertility.

Method of administration and doses

All dosage information refers to pramipexole as pramipexole dihydrochloride.

Parkinson's disease.

The daily dose is administered in 3 equal doses.

Initial treatment.

As outlined below, the dose should be increased gradually, starting at 0.375 mg/day every 5 to 7 days. If patients do not experience intolerable side effects, the dose should be titrated to achieve the maximum therapeutic effect (see Table 1).

Table 1

Mirapex dose increase schedule

If further dose increases are necessary, the daily dose should be increased by 0.75 mg weekly to a maximum of 4.5 mg per day. However, it should be noted that the incidence of drowsiness increases with doses above 1.5 mg per day.

Supportive therapy

The individual dose ranges from 0.375 mg to a maximum of 4.5 mg per day. During dose escalation in the pivotal studies, the treatment effect was observed starting from a daily dose of 1.5 mg. Further dose adjustments should be made based on clinical response and the occurrence of adverse reactions. In clinical studies, approximately 5% of patients received doses below 1.5 mg. In progressive Parkinson's disease, a dose above 1.5 mg per day may be beneficial in patients for whom a reduction in the levodopa dose is planned in combination therapy with levodopa. It is recommended to reduce the levodopa dose when increasing the dose of MIRAPEX and during maintenance therapy depending on the response of each individual patient (see section "Interaction with other medicinal products and other forms of interaction").

Treatment discontinuation

Abrupt discontinuation of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome or dopamine agonist withdrawal syndrome. The dose of pramipexole should be reduced by 0.75 mg per day until a daily dose of 0.75 mg is reached. The dose should then be reduced to 0.375 mg per day (see section 4.4). Dopamine agonist withdrawal syndrome may occur during gradual dose reduction. Therefore, a temporary increase in dose may be necessary before resuming the dose reduction (see section 4.4).

Dosage for patients with renal impairment

The elimination of pramipexole depends on renal function. The following dosage regimen is suggested for initial therapy.

Patients with creatinine clearance above 50 ml/min do not require a reduction in daily dose or dosing frequency.

In patients with creatinine clearance 20-50 ml/min, the initial daily dose of MIRAPEX is administered in two divided doses, starting at 0.125 mg twice daily (0.25 mg/day). The maximum daily dose of pramipexole should not be exceeded, 2.25 mg.

In case of deterioration of renal function on the background of maintenance therapy, the daily dose of MIRAPEX is reduced by the same percentage as the creatinine clearance has decreased. For example, if creatinine clearance is reduced by 30%, the daily dose of MIRAPEX is reduced by 30%. The daily dose can be administered in two divided doses if creatinine clearance is between 20 and 50 ml/min, and in one divided dose if creatinine clearance is below 20 ml/min.

Dosage for patients with hepatic impairment

For patients with hepatic impairment, dose reduction is not considered necessary, as approximately 90% of the absorbed drug is excreted by the kidneys. The potential effect of hepatic impairment on the pharmacokinetics of MIRAPEX has not been studied.

Restless legs syndrome

The recommended starting dose of MIRAPEX is 0.125 mg once daily 2-3 hours before bedtime. For patients requiring additional symptom relief, the dose may be increased every 4-7 days to a maximum dose of 0.75 mg daily (see Table 2).

Table 2

Mirapex dose increase schedule

* If necessary

The patient's response to treatment should be assessed after 3 months and the need for continued therapy should be reconsidered. If treatment is interrupted for more than a few days, it should be restarted at the dose indicated above.

Discontinuation of treatment

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

Dosage for patients with renal impairment

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

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

Dosage for patients with hepatic impairment

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

Method of application

The 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 evidence to support 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 should not be used in children (under 18 years of age) with Tourette's syndrome due to a negative benefit/risk ratio for this condition.

Overdose

There is no clinical experience of significant overdose. Expected adverse effects related to the pharmacodynamic profile of a dopamine agonist include nausea, vomiting, hyperkinesia, hallucinations, agitation and hypotension. No antidote for dopamine agonist overdose has been established. Neuroleptics may be administered if signs of central nervous system excitation occur. Treatment of patients with overdose may require general supportive measures, including gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram monitoring.

Adverse reactions

Most adverse reactions are usually observed at the beginning of therapy, a significant part of them disappear even if therapy is continued.

Adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 - <1/10), uncommon (≥ 1/1000 - <1/100), rare (≥1/10,000 - <1/1000), rare (<1/10,000), not known (cannot be estimated from available data).

Parkinson's disease

In patients with Parkinson's disease, the most common adverse reactions (≥ 5%) when treated with pramipexole compared to placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache and fatigue. The incidence of somnolence increased with doses above 1.5 mg/day (see section 4.2). The most common adverse reaction when used in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too rapidly.

1 This adverse reaction has been observed in the post-marketing period. In 95% of cases, the frequency is not higher than uncommon, but may be lower. It is not possible to establish a precise frequency, as the adverse reaction was not observed in clinical trials among 2762 patients with Parkinson's disease treated with pramipexole.

Restless legs syndrome

In patients with restless legs syndrome treated with pramipexole, the most common adverse reactions (≥ 5%) were nausea, headache, dizziness and fatigue. Nausea and 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.

2 This adverse reaction has been observed in the post-marketing period. In 95% of cases, the frequency is not higher than uncommon, but may be lower. It is not possible to establish a precise frequency, as the adverse reaction was not observed in clinical trials among 1395 patients with restless legs syndrome treated with pramipexole.

Description of selected adverse reactions

Somnolence: Pramipexole is commonly associated with somnolence and uncommonly with excessive daytime sleepiness and episodes of sudden onset of somnolence (see section 4.4).

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

Dopamine agonist withdrawal syndrome: Non-motor adverse reactions may occur when the dose of dopamine agonists (including pramipexole) is reduced or discontinued. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain (see section 4.4).

Heart Failure: Heart failure has been observed in patients treated with pramipexole in clinical trials and post-marketing experience. In a pharmacoepidemiological study, pramipexole use was associated with an increased risk of heart failure compared with no use (hazard ratio, 1.86; 95% CI, 1.21-2.85).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product has been authorised is important. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions in accordance with applicable legislation.

Expiration date

3 years.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging

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

Vacation category

According to the recipe.

Producer

Boehringer Ingelheim Pharma GmbH & Co. KG.

Location of the manufacturer and its business address

Binger Strasse 173, 55216 Ingelheim am Rhein, Germany.