Pramipexole asino

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRA MIPEXOLE ACINO (Pramipexole Acino)

Composition:

Active substance: pramipexole;

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

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

Pharmaceutical form. Tablets.

Main physicochemical characteristics:

tablets 0.25 mg – white or almost white, flat surface, round-shaped with bevelled edge, with a cross on one side;

tablets 1.0 mg – white or almost white, flat surface, round-shaped with bevelled edge, with a line on one side and the marking "1" on the other side.

Pharmacotherapeutic group. Dopaminergic agents. Dopamine agonists.

ATC code N04B C05.

Pharmacological properties.

Pharmacodynamics.

Pramipexole is a dopamine agonist with high selectivity and specificity for dopamine receptors of the D2 subfamily 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 the synthesis, release, and turnover of dopamine.

The exact mechanism of action of the drug 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 dopaminergic system.

Pharmacokinetics.

Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability exceeds 90%. Maximum plasma concentration is reached between 1 and 3 hours after administration. The rate of absorption is not reduced when taken with food, but overall absorption is decreased. Pramipexole exhibits linear kinetics and relatively minor plasma concentration fluctuations across different patients, regardless of the pharmaceutical form. 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 most important elimination pathway. Approximately 90% of a radiolabeled 14C dose is excreted renally, while less than 2% is found in feces. Total clearance of pramipexole is approximately 500 ml/min, and renal clearance is approximately 400 ml/min. Elimination half-life (t½) ranges from 8 hours in young individuals to 12 hours in elderly subjects.

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 decreases 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 medicinal product affecting plasma protein binding or elimination via biotransformation is unlikely. Since anticholinergic agents are primarily eliminated by 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 pramipexole clearance. 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, it is recommended to reduce the dose of levodopa, while doses of other antiparkinsonian agents should remain unchanged.

Due to a possible additive effect, 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 influence reaction rate 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.

The administration of pramipexole to patients with Parkinson's disease and impaired renal function in reduced doses is recommended according to 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 this medicinal product.

Disorders of movement (dyskinesia). Dyskinesia may develop at the beginning of pramipexole titration when used in combination with levodopa 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 gradual dose increase of pramipexole. Although dystonia may be a symptom of Parkinson's disease, symptoms of dystonia in these patients improved after dose reduction or discontinuation of pramipexole.

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

Sudden sleep attacks and somnolence. The use of pramipexole is associated with somnolence and episodes of sudden sleep attacks, particularly in patients with Parkinson's disease. Rare reports of sudden onset of somnolence during daily activities have been reported, in some cases 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 attacks should refrain from driving and operating machinery. Additionally, dose reduction or shortening of treatment duration should be considered. Caution is required when patients are using other sedative medicinal products in combination with pramipexole or consuming alcohol, due to possible additive effects (see sections "Interaction with other medicinal products and other forms of interaction", "Ability to affect reaction speed when driving or operating machinery", and "Adverse reactions").

Impulse control disorders. Patients should be closely monitored for the development of impulse control disorders. Patients and caregivers should be aware that treatment with dopamine agonists, including pramipexole, 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 develop, dose reduction or discontinuation of the drug should be considered.

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

Severe cardiovascular disorders. Pramipexole should be administered 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. Dopamine agonists should be used in patients with psychiatric disorders 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").

Neuroleptic malignant syndrome. Symptoms resembling neuroleptic malignant syndrome have been observed after 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 dopamine agonists, including pramipexole (see section "Adverse reactions"). To discontinue treatment, the dose of pramipexole should be gradually reduced in patients with Parkinson's disease (see section "Dosage and administration"). Limited data suggest that patients with impulse control disorders and those receiving high daily doses and/or high cumulative doses of dopamine agonists may be at higher risk of developing dopamine agonist withdrawal syndrome. Withdrawal syndrome may include apathy, anxiety, depression, fatigue, increased sweating, pain, and lack of response to levodopa. Before reducing the dose or discontinuing pramipexole, patients should be informed about possible withdrawal symptoms. Close monitoring is required during dose reduction and discontinuation of pramipexole. In cases of pronounced and/or persistent symptoms of dopamine agonist withdrawal syndrome, 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. Augmentation was specifically evaluated in a controlled clinical trial over 26 weeks. Augmentation was observed in 11.8% of patients in both the pramipexole group (N = 152) and the placebo group (N = 149). Kaplan-Meier analysis of time to augmentation showed no significant difference between the pramipexole and placebo groups.

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 symptoms of augmentation occur. 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 primarily 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 had elevated creatine phosphokinase levels (CPK – 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 to the mother outweighs the potential risk to the fetus.

Breastfeeding period

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

Fertility

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

Ability to affect reaction speed 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 attacks should refrain from driving and engaging in potentially hazardous activities where reduced attention could increase the risk of serious injury or fatal outcomes during treatment with pramipexole.

Method of administration and dosage.

All dosage information refers to pramipexole as pramipexole dihydrochloride.

Parkinson's disease

The daily dose should be divided into 3 equal doses.

Initial treatment

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

Table 1

Dosage escalation scheme for Pramipexole Asino
Week	Dose (mg)	Total daily dose (mg)
1st	3 x 0.125	0.375
2nd	3 x 0.25	0.75
3rd	3 x 0.5	1.5

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 titration, 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 advanced 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 dose is recommended when increasing the dose of Pramipexole Asino and during maintenance therapy, depending on the patient's response (see section "Interaction with other medicinal products and other forms of interactions").

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: reduce by _ 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"). Dopamine agonist withdrawal syndrome may occur during dose reduction; therefore, temporary dose increase may be necessary until the dose reduction is resumed (see section "Special precautions").

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 Pramipexole Asino 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 Pramipexole Asino 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 patients with renal impairment receiving maintenance therapy, the daily dose of Pramipexole Asino 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 Pramipexole Asino 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 renally. The potential impact of hepatic impairment on the pharmacokinetics of pramipexole has not been studied.

Restless legs syndrome

The recommended initial dose of Pramipexole Asino 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").

Table 2

Dosage escalation schedule for Pramipexole Asino
Titration step	Single evening daily dose (mg)
1	0.125
2*	0.25
3*	0.50
4*	0.75
*If needed.

The patient's response to treatment should be assessed 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 specified above.

Discontinuation of treatment

Since the daily dose for the treatment of restless legs syndrome does not exceed 0.75 mg, treatment with Pramipexole Asino can be discontinued without gradual dose reduction. 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 at all doses.

Dosing in patients with renal impairment

Elimination of Pramipexole Asino from the body 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.

Dosing in patients with 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.

Method of administration

Tablets should be taken orally with water, independent of food intake.

Children.

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

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

Tourette’s syndrome. Pramipexole Asino 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 lacking. Expected adverse reactions related to the pharmacodynamic profile of a dopamine agonist include nausea, vomiting, hyperkinesia, hallucinations, agitation, and arterial hypotension. There is no established antidote for dopamine agonist overdose. In cases of central nervous system agitation, neuroleptics may be administered. Management of patients with overdose may require general supportive measures, including gastric lavage, intravenous fluid administration, activated charcoal, and electrocardiogram monitoring.

Adverse Reactions

Based on analysis of pooled placebo-controlled studies involving a total of 1,923 patients receiving pramipexole and 1,354 patients receiving placebo, adverse reactions were commonly reported in both groups. 63% of patients receiving pramipexole and 52% of patients receiving placebo reported at least one adverse drug reaction.

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 commonly reported adverse reactions (≥5%) during treatment with pramipexole compared to placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache, and fatigue. The incidence of somnolence increases with doses higher than 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 behavior, confusion, hallucinations, sleep disorders; uncommon – binge eating^1, pathological shopping behavior, hyperphagia^1, hypersexuality, libido disorders, paranoia, pathological gambling, 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 – increased fatigue, peripheral edema; frequency not known – dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, increased 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 established, as these adverse reactions were not observed during clinical trials in 2,762 Parkinson’s disease patients treated with pramipexole.

Restless Legs Syndrome

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

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 behavior^2, such as binge eating, pathological shopping behavior, hypersexuality, and pathological gambling; confusion, mania^2, hallucinations, hyperphagia^2, libido disorders, paranoia^2, anxiety, delusions^2, delirium^2.

Nervous system disorders: very common – worsening 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 – increased fatigue; uncommon – peripheral edema; frequency not known – dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, increased 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 established, as this adverse reaction was not observed during clinical trials in 1,395 patients with restless legs syndrome treated with pramipexole.

Description of Selected Adverse Reactions

Somnolence. Pramipexole is frequently associated with somnolence and occasionally with excessive daytime sleepiness and episodes of sudden onset of sleep (see section "Special Precautions").

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

Impulse control disorders. Treatment with dopamine agonists, including pramipexole, 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 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 past 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 therapy, higher doses of dopaminergic agents, younger age (≤65 years), unmarried status, and 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, increased sweating, and pain (see section "Special Precautions").

Heart failure

Heart failure has been reported in clinical studies and in the post-marketing period in patients receiving pramipexole. Data from a pharmacoepidemiological study indicate that pramipexole use was 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 authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in a place inaccessible to children, in the original packaging, at a temperature not exceeding 25 °C.

Packaging. 10 tablets per blister; 3 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer. LLC "Pharma Start".

Manufacturer’s address and location of business activity.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

Marketing Authorization Holder.

LLC "ASINO UKRAINE".

Address of Marketing Authorization Holder.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

In case of adverse reactions or questions regarding the safety and efficacy 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.