Pramipex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRAMIPLEX (PRAMIPLEX)

Composition:

Active substance: pramipexole;

1 tablet contains pramipexole dihydrochloride monohydrate 0.25 mg or 1.0 mg;

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

Pharmaceutical form. Tablets.

Main physico-chemical properties:

tablets of 0.25 mg – white or almost white, flat-surfaced, round-shaped tablets with beveled edges, with a cross on one side;

tablets of 1.0 mg – white or almost white, flat-surfaced, round-shaped tablets with beveled edges, with a line on one side and marking "1" on the other.

Pharmacotherapeutic group. Dopaminergic agents. Dopamine agonists.

ATC code N04BC05.

Pharmacological properties.

Pharmacodynamics.

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

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

The exact mechanism of action of pramipexole in the treatment of restless legs syndrome is unknown. Although the pathophysiology of restless legs syndrome is generally not well understood, neuropharmacological data suggest involvement of the central dopaminergic system.

Pharmacokinetics.

Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability exceeds 90%. Peak plasma concentrations are reached between 1 and 3 hours after administration. Food does not reduce the rate of absorption, but decreases the overall extent of absorption.

Pramipexole exhibits linear kinetics and, regardless of the pharmaceutical formulation, shows relatively low inter-patient variability in plasma levels.

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 negligible extent.

Renal excretion of unchanged pramipexole is the major elimination pathway. Approximately 90% of a radiolabeled (14C) dose is excreted via the kidneys, while less than 2% is recovered in feces. Total clearance of pramipexole is approximately 500 mL/min, with renal clearance of about 400 mL/min. Elimination half-life (t½) ranges from 8 hours in younger patients to 12 hours in elderly individuals.

Clinical characteristics.

Indications.

Treatment of 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 late stages, when the effect of levodopa diminishes or becomes unstable and fluctuations in therapeutic response occur (on-off phenomenon).

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

Contraindications.

Hypersensitivity to pramipexole or to any other component 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 undergoes low biotransformation. Therefore, interaction with another drug affecting plasma protein binding or elimination via biotransformation is unlikely. Since anticholinergic agents are primarily eliminated via hepatic metabolism, interaction is unlikely. Interaction with anticholinergic agents has not been studied. There is no pharmacokinetic interaction with selegiline and levodopa.

Inhibitors/competitors of active renal elimination pathways.

Cimetidine reduces the renal clearance of pramipexole by approximately 34%, likely by inhibiting the cationic renal tubular secretion transport system. Medicinal products that inhibit active renal tubular secretion or are themselves eliminated via this pathway—such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine, and procainamide—may interact with pramipexole and lead to reduced clearance of pramipexole. When these medicinal products are used concomitantly with pramipexole, dose reduction of pramipexole should be considered.

Combination with levodopa.

During dose escalation of pramipexole in patients with Parkinson's disease, reduction of the levodopa dose is recommended, while doses of other antiparkinsonian medicinal products should remain unchanged.

Due to possible additive effects, caution should be exercised if the patient is using other sedative medicinal products in combination with pramipexole or consuming alcohol (see sections "Special precautions for use", "Ability to affect reaction speed when driving or operating machinery", and "Adverse reactions").

Antipsychotic medicinal products.

Concomitant use of antipsychotic medicinal products with pramipexole should be avoided (see section "Special precautions for use") due to possible antagonistic effects.

Special precautions for use.

Prescribing pramipexole to patients with Parkinson's disease and impaired renal function is recommended at reduced doses as described in the section "Dosage and administration".

Hallucinations

Hallucinations are known adverse reactions associated with dopamine agonists and levodopa therapy. Patients should be informed about the possibility of developing hallucinations (mostly visual) during treatment with the medicinal product.

Disorders of dyskinesia

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

Dystonia

Axial dystonia, including antecollis, camptocormia, and pleurothotonus (Pisa syndrome), has occasionally occurred in patients with Parkinson's disease after initiation or dose escalation 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, reassessment of the treatment regimen with dopaminergic medicinal products and adjustment of pramipexole dosage should be considered.

Sudden onset of sleep and somnolence

The use of pramipexole has been associated with somnolence and episodes of sudden sleep attacks, particularly in patients with Parkinson's disease. Rare cases of sudden onset of sleepiness during daytime activities have been reported, sometimes without awareness or warning signs. Therefore, patients should be advised to exercise caution when driving or operating machinery during treatment with pramipexole. Patients experiencing somnolence and/or sudden sleep episodes should refrain from driving and operating machinery. Additionally, dose reduction or shortening of treatment duration should be considered. Due to the potential additive effect, caution should be exercised if patients are taking other sedative medicinal products in combination with pramipexole or consuming alcohol (see sections "Interaction with other medicinal products and other forms of interactions", "Ability to affect reaction rate 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 pramipexole, may lead to symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating.

If such symptoms develop, dose reduction or discontinuation of the medicinal product 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 medicinal product should be considered.

Severe cardiovascular disorders

The medicinal product should be prescribed with particular caution in patients with severe cardiovascular disorders. Blood pressure monitoring is recommended, especially at the beginning of treatment, considering the general risk of postural hypotension associated with dopaminergic therapy.

Patients with psychiatric disorders

The medicinal product should be used in patients with psychiatric disorders only when 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 interactions").

Neuroleptic malignant syndrome

Symptoms resembling neuroleptic malignant syndrome have been observed following abrupt withdrawal of dopaminergic therapy (see section "Dosage and administration").

Ophthalmological examination

Regular ophthalmological examination is recommended in cases of visual disturbances.

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 dose of pramipexole in patients with Parkinson's disease should be reduced according to the section "Dosage and administration". Limited data suggest that patients with impulse control disorders and patients receiving high daily doses and/or high cumulative doses of dopamine agonists may be at higher risk of developing dopamine agonist withdrawal syndrome. Symptoms include apathy, anxiety, depression, fatigue, sweating, and pain, and may be severe. 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 pronounced and/or persistent dopamine agonist withdrawal syndrome symptoms, temporary re-initiation of pramipexole at the lowest effective dose may be considered.

Augmentation (worsening of symptoms) in restless legs syndrome

Reports indicate that treatment of restless legs syndrome with dopaminergic agents 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 the upper limbs.

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

Renal impairment

Pramipexole should be administered with caution in patients with renal impairment, as pramipexole is excreted via the kidneys.

Rhabdomyolysis

A case of rhabdomyolysis has been reported in a patient with progressive Parkinson's disease treated with pramipexole. The patient presented with elevated creatine phosphokinase levels (CK – 10,631 IU/l). Symptoms resolved after discontinuation of treatment.

Use during pregnancy or breastfeeding.

Pregnancy

The effect on human pregnancy has not been studied. Pramipexole may be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus.

Breastfeeding

Since pramipexole treatment suppresses prolactin secretion, a decrease in lactation is possible. Excretion of pramipexole into human breast milk has not been studied; therefore, the medicinal product is not recommended during breastfeeding. If use of pramipexole cannot be avoided, breastfeeding should be discontinued.

Fertility

Studies on the effect on human fertility have not been conducted.

Ability to affect reaction rate when driving or operating machinery.

Pramipexole may have a significant effect on the ability to drive or operate machinery. Hallucinations or somnolence may occur. Patients experiencing somnolence and/or sudden sleep episodes should refrain from driving and from engaging in potentially hazardous activities where reduced attention could increase the risk of serious injury or death during treatment with pramipexole.

Method of administration and dosage.

All dosage information refers to pramipexole as pramipexole dihydrochloride.

Tablets are taken orally, regardless of food intake, with water.

Parkinson's disease.

The daily dose should be divided into 3 equal doses.

Initial treatment.

As shown below, the dose should be gradually increased from an initial 0.375 mg per day every 5–7 days. In cases where patients do not experience intolerable adverse reactions, the dose should be titrated upward until the maximum therapeutic effect is achieved.

Table 1

If further dose escalation is necessary, the daily dose should be increased by 0.75 mg weekly up to the maximum dose of 4.5 mg/day. However, it should be noted that the incidence of somnolence increases with doses above 1.5 mg/day.

Maintenance therapy.

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

Discontinuation of treatment.

Sudden discontinuation of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome or dopamine agonist withdrawal syndrome. The dose of pramipexole should be tapered according to the following scheme: mg/day down to a daily dose of 0.75 mg/day. After that, the dose should be reduced to 0.375 mg/day (see section "Special precautions for use"). Dopamine agonist withdrawal syndrome may occur during dose reduction; therefore, temporary dose increase may be necessary until dose reduction can be resumed (see section "Special precautions for use").

Dosing in patients with renal impairment.

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

Patients with creatinine clearance above 50 mL/min do not require dose reduction or adjustment in dosing frequency.

For patients with creatinine clearance of 20–50 mL/min, the initial daily dose of Pramipex should be administered in two divided doses, starting at 0.125 mg twice daily (0.25 mg/day). The maximum daily dose of pramipexole should not exceed 2.25 mg.

For patients with creatinine clearance below 20 mL/min, the daily dose of Pramipex should be administered as a single dose, starting at 0.125 mg/day. The maximum daily dose of pramipexole should not exceed 1.5 mg.

In case of worsening renal function during maintenance therapy, the daily dose of Pramipex should be reduced proportionally to the decline in creatinine clearance. For example, if creatinine clearance decreases by 30%, the daily dose of Pramipex should be reduced by 30%. The daily dose may be administered in two divided doses if creatinine clearance is between 20–50 mL/min, or as a single dose if creatinine clearance is below 20 mL/min.

Dosing in patients with hepatic impairment.

Dose reduction is not considered necessary for patients with hepatic impairment, as nearly 90% of the absorbed drug is excreted by the kidneys. The potential impact of hepatic impairment on the pharmacokinetics of pramipexole has not been studied.

Restless legs syndrome.

The recommended initial dose of Pramipex is 0.125 mg 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/day (as shown in Table 2 below). The lowest effective dose should be used (see section "Special precautions for use").

Table 2

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

Discontinuation of treatment.

Since the daily dose for the treatment of restless legs syndrome does not exceed 0.75 mg, PRAMIPEX can be discontinued without tapering the dose. However, recurrence of restless legs syndrome symptoms (worsening of symptom severity compared to baseline) may occur in 10% of patients following abrupt discontinuation of pramipexole. This effect is possible with all doses.

Renal impairment.

Elimination of PRAMIPEX depends on renal function. Dose adjustment is not required in patients with creatinine clearance above 20 mL/min.

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

Hepatic impairment.

Dose reduction is not considered necessary in patients with hepatic impairment, as nearly 90% of the absorbed drug is excreted via the kidneys.

Children.

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

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

Tourette’s syndrome. PRAMIPEX should not be used in children (under 18 years of age) with Tourette’s syndrome due to an unfavorable benefit-risk ratio for this condition.

Overdose.

Clinical experience with significant overdose is limited. Expected adverse effects related to the pharmacodynamic profile of a dopamine agonist include nausea, vomiting, hyperkinesia, hallucinations, CNS excitation, and arterial hypotension. There is no established antidote for dopamine agonist overdose. In case of signs of central nervous system excitation, neuroleptics may be administered. Management of patients with overdose may require general supportive measures, including gastric lavage, intravenous fluid administration, activated charcoal, and ECG monitoring.

Adverse reactions.

Based on the analysis of combined placebo-controlled studies involving a total of 1,923 patients treated with pramipexole and 1,354 patients treated with placebo, adverse reactions were commonly reported in both groups. Adverse drug reactions were reported in 63% of patients receiving pramipexole and in 52% of patients receiving placebo.

Most adverse drug reactions usually occur early in treatment and tend to resolve even with continued therapy.

Adverse reactions are listed by system organ class and frequency of occurrence: 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), frequency not known (cannot be estimated from available data).

Parkinson’s disease.

In patients with Parkinson’s disease, the most common adverse reactions (≥5%) associated with pramipexole treatment compared to placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache, and fatigue. The incidence of somnolence increases with doses exceeding 1.5 mg 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, especially if pramipexole is titrated too rapidly.

Infections and infestations: uncommon – pneumonia.

Endocrine system disorders: uncommon – disturbance of antidiuretic hormone secretion^1.

Psychiatric disorders: common – sleep disorders, symptoms of impulse control disorders and compulsive behaviour, confusion, hallucinations, insomnia; uncommon – binge eating^1, pathological gambling, hyperphagia^1, hypersexuality, libido disorders, paranoia, pathological shopping, anxiety, delusions, delirium; rare – mania.

Nervous system disorders: very common – dizziness, dyskinesia, somnolence; common – headache; uncommon – amnesia, hyperkinesia, sudden onset of sleep, syncope.

Eye disorders: common – visual disturbances, including diplopia, blurred vision, and decreased visual acuity.

Cardiac disorders: uncommon – heart failure^1.

Vascular disorders: common – hypotension.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnea, hiccups.

Gastrointestinal disorders: very common – nausea; common – constipation, vomiting.

Skin and subcutaneous tissue disorders: uncommon – hypersensitivity, pruritus, rash.

Reproductive system and breast disorders: rare – spontaneous erection.

General disorders: common – asthenia, peripheral edema; frequency not known – dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, sweating, and pain).

Investigations: common – weight decreased, including decreased appetite; uncommon – weight increased.

^1 This adverse reaction has been reported in the post-marketing period. In 95% of patients, the frequency was no more than uncommon, but may be lower. The exact frequency cannot be determined, as these adverse reactions were not observed during clinical trials among 2,762 Parkinson’s disease patients treated with pramipexole.

Restless legs syndrome.

In patients with restless legs syndrome, the most common adverse reactions (≥5%) associated with pramipexole treatment 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) during pramipexole treatment.

Infections and infestations: uncommon – pneumonia^2.

Endocrine system disorders: uncommon – disturbance of antidiuretic hormone secretion^2.

Psychiatric disorders: common – sleep disorders, insomnia; uncommon – symptoms of impulse control disorders and compulsive behaviour^2, such as binge eating, pathological shopping, hypersexuality, and pathological gambling; confusion, mania^2, hallucinations, hyperphagia^2, libido disorders, paranoia^2, anxiety, delusions^2, delirium^2.

Nervous system disorders: very common – augmentation of restless legs syndrome; common – dizziness, headache, somnolence; uncommon – amnesia^2, dyskinesia, hyperkinesia^2, sudden onset of sleep, syncope.

Eye disorders: common – visual disturbances, including diplopia, blurred vision, and decreased visual acuity.

Cardiac disorders: uncommon – heart failure^2.

Vascular disorders: uncommon – hypotension.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnea, hiccups.

Gastrointestinal disorders: very common – nausea; common – constipation, vomiting.

Skin and subcutaneous tissue disorders: uncommon – hypersensitivity, pruritus, rash.

Reproductive system and breast disorders: rare – spontaneous erection.

General disorders: common – asthenia; uncommon – peripheral edema; frequency not known – dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, sweating, and pain).

Investigations: uncommon – weight decreased, including decreased appetite, weight increased.

^2 This adverse reaction has been reported in the post-marketing period. In 95% of patients, the frequency was no more than uncommon, but may be lower. The exact frequency cannot be determined, as this adverse reaction was not observed during clinical trials among 1,395 restless legs syndrome patients treated with pramipexole.

Description of selected adverse reactions

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

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

Impulse control disorders. During treatment with dopamine agonists, including pramipexole, 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").

In a cross-sectional retrospective screening study involving 3,090 Parkinson’s disease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment experienced symptoms of impulse control disorders during the previous six months. Observed manifestations included pathological gambling, compulsive shopping, binge eating, and compulsive sexual behavior (hypersexuality). Potential independent risk factors for impulse control disorders include dopaminergic treatment, higher doses of dopaminergic agents, younger age (≤65 years), being unmarried, and a family history of gambling, as self-reported by patients.

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 clinical studies and in the post-marketing period in patients treated with pramipexole. Pharmacoe pidemiological data indicate that pramipexole use is associated with an increased risk of heart failure compared to non-use (risk ratio 1.86; 95% CI, 1.21–2.85).

Reporting of suspected adverse reactions

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

Shelf life.

3 years.

Storage conditions.

Keep out of reach of children. Store in the original packaging at a temperature not exceeding 25 °C.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

LLC "Pharma Start".

Manufacturer’s address and place of business.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

Marketing authorization holder.

LLC "ASINO UKRAINE".

Address of the marketing authorization holder.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

In case of adverse effects or questions regarding the safety of the medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, tel/fax: +38 044 281 2333.