Pramipexole ic

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRA MIP EXOL IS

Composition:

Active substance: pramipexole;

1 tablet contains pramipexole dihydrochloride monohydrate 0.25 mg (equivalent to 0.18 mg of pramipexole) or pramipexole dihydrochloride monohydrate 1 mg (equivalent to 0.7 mg of pramipexole);

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white, flat cylindrical tablets with beveled edges and a score line; the company trademark is imprinted on one side of the tablet, and a dividing line is on the other side.

Pharmacotherapeutic group.

Dopaminergic agents. Dopamine agonists. Pramipexole. 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 a preferential affinity for D3 receptors; it exhibits full intrinsic activity.

Pramipexole alleviates Parkinsonian motor deficits 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 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.

Absorption

Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability exceeds 90%. Maximum plasma concentration is reached within 1–3 hours after dosing. Concomitant administration with food does not reduce the extent of pramipexole absorption but decreases the rate of absorption. Pramipexole exhibits linear kinetics and relatively low interpatient variability in plasma levels.

Distribution

In humans, the plasma protein binding of pramipexole is very low (< 20%), and the volume of distribution is large (400 L).

Metabolism

In humans, pramipexole is metabolized to only a negligible extent.

Elimination

Renal excretion of unchanged pramipexole is the main route of drug elimination. Approximately 90% of a radiolabeled 14C dose is excreted by the kidneys, while less than 2% is recovered in feces.

Total clearance of pramipexole is approximately 500 ml/min, and renal clearance is about 400 ml/min. Elimination half-life ranges from 8 hours in young individuals to 12 hours in elderly subjects.

Clinical characteristics.

Indications.

Treatment of symptoms of idiopathic Parkinson's disease in adults, either as monotherapy (without levodopa) or in combination with levodopa, throughout the course of the disease up to the advanced stages when the effect of levodopa diminishes or becomes unstable and fluctuations in therapeutic response occur (the "on-off" phenomenon).

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

Contraindications.

Hypersensitivity to pramipexole or to any other component of the medicinal product.

Interaction with other medicinal products and other forms of interactions.

Plasma protein binding

Pramipexole is only minimally bound to plasma proteins (< 20%) and undergoes negligible biotransformation. Therefore, interactions with other medicinal products affecting plasma protein binding or elimination via biotransformation are unlikely. Since anticholinergic agents are primarily eliminated via biotransformation, the potential for interaction is limited, although interactions with anticholinergic agents have not been studied. There is no pharmacokinetic interaction with selegiline or levodopa.

Inhibitors/competitors of active renal elimination pathways

Cimetidine reduces the renal clearance of pramipexole by approximately 34%, likely by inhibiting the tubular cationic secretory transport system in the kidneys. Therefore, medicinal products that inhibit active renal elimination 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 co-administering these medicinal products with pramipexole, dose reduction of pramipexole should be considered.

Combination with levodopa

When increasing the dose of pramipexole in patients with Parkinson's disease, a reduction in the dose of levodopa is recommended, while doses of other antiparkinsonian agents should remain unchanged.

Due to the potential for 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", "Effect on ability to drive and use machines", and "Adverse reactions").

Antipsychotic medicinal products

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

Special precautions for use.

Patients with Parkinson's disease who have renal impairment should be prescribed reduced doses of Pramipexole IS according to the section "Dosage and administration".

Hallucinations

Hallucinations are known adverse reactions associated with dopamine agonists and levodopa therapy. Patients should be informed that hallucinations may occur (in most cases visual).

Dyskinesia

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

Dystonia

Axial dystonia, including antecollis, camptocormia, and pleurothotonus ("Pisa syndrome"), has been reported occasionally in patients with Parkinson's disease after initiation or dose escalation of pramipexole. Although dystonia may be a symptom of Parkinson's disease, the severity of dystonia symptoms in these patients decreased after dose reduction or discontinuation of pramipexole. If dystonia occurs, the treatment regimen with dopaminergic drugs should be reassessed and the pramipexole dose adjusted.

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 cases of sudden sleep onset 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 who experience somnolence and/or sudden sleep episodes should refrain from driving or operating machinery. Additionally, dose reduction or discontinuation of treatment should be considered. Due to possible additive effects, caution should be exercised if patients are taking other sedative medicinal products or consuming alcohol during pramipexole therapy (see sections "Interaction with other medicinal products and other forms of interaction", "Ability to influence reaction speed when driving or operating machinery", and "Adverse reactions").

Impulse control disorders

Patients should be closely monitored for the development of impulse control disorders. Patients and caregivers should be aware that behavioral symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating, may occur during dopamine agonist therapy, including pramipexole. If such symptoms develop, dose reduction or gradual 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 gradual discontinuation of the medicinal product should be considered.

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").

Ophthalmological examination

Ophthalmological examination is recommended at regular intervals or in case of visual disturbances.

Neuroleptic malignant syndrome

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

Dopamine agonist withdrawal syndrome

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 gradually reduced according to the recommendations provided in the section "Dosage and administration". Limited data suggest that patients with impulse control disorders and those receiving high daily or high cumulative doses of dopamine agonists may be at increased risk of developing dopamine agonist withdrawal syndrome. Symptoms of withdrawal syndrome may include apathy, anxiety, depression, increased 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. Patients should be closely monitored during dose reduction and discontinuation of pramipexole. In cases of severe 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)

Treatment of restless legs syndrome with pramipexole may lead to augmentation. Augmentation is characterized by earlier onset of symptoms in the evening (or even during daytime), increased intensity of symptoms, and spread of symptoms to the upper limbs.

The risk of augmentation increases with higher doses. Before initiating treatment, patients should be informed about the possibility of augmentation and advised to consult their physician if symptoms of augmentation occur. If augmentation is suspected, consideration should be given to reducing the dose to the minimum effective dose or discontinuing pramipexole (see sections "Dosage and administration" and "Adverse reactions").

Severe cardiovascular disorders

Pramipexole 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.

Renal impairment

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

Rhabdomyolysis

A single case of rhabdomyolysis has been reported in a 49-year-old man with progressive Parkinson's disease treated with pramipexole. The patient was hospitalized with elevated creatine phosphokinase levels (CPK – 10,631 IU/L). Symptoms resolved after discontinuation of treatment.

Use during pregnancy or breastfeeding.

Pregnancy

The effects of pramipexole on pregnancy and lactation in humans have not been studied. Pramipexole should not be used during pregnancy except when clearly necessary, i.e., when the potential benefit to the woman outweighs the potential risk to the fetus.

Period of breastfeeding

Since pramipexole treatment suppresses prolactin secretion, a reduction in lactation is possible. Excretion of pramipexole into human breast milk has not been studied. Due to the lack of data, pramipexole should not be administered to breastfeeding women. If pramipexole use cannot be avoided, breastfeeding should be discontinued.

Fertility

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

Ability to influence 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 who develop somnolence and/or sudden sleep attacks while taking pramipexole should be advised to refrain from driving or engaging in activities where reduced alertness may expose themselves or others to risk of serious injury or death (e.g., operating machinery) until recurrent episodes and somnolence have resolved (see sections "Interaction with other medicinal products and other forms of interaction", "Special precautions for use", "Adverse reactions").

Dosage and method of administration.

All dosage information refers to pramipexole as pramipexole dihydrochloride monohydrate.

Parkinson's disease

The daily dose should be taken in three divided doses of equal parts.

Initial treatment

The dose of the medicinal product should be gradually increased as shown below, starting with 0.375 mg per day, increasing every 5–7 days. If patients do not experience intolerable adverse effects, the dose should be titrated upward until the maximum therapeutic effect is achieved (see Table 1).

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 per day. However, it should be noted that the incidence of somnolence increases with doses above 1.5 mg per day (see section "Side Effects").

Maintenance therapy

The individual dose ranges from 0.375 mg to a maximum of 4.5 mg per day. During dose escalation in the main studies, therapeutic 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 trials, approximately 5% of patients received doses below 1.5 mg. In progressive Parkinson's disease, a dose higher than 1.5 mg per day may be beneficial for patients in whom reduction of levodopa dose is planned during combination therapy with levodopa. Reduction of levodopa dose is recommended when increasing the dose of pramipexole and during maintenance therapy, depending on the response of each individual patient (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 gradually reduced by 0.75 mg per day until reaching a daily dose of 0.75 mg. After that, the dose should be reduced to 0.375 mg per day (see section "Special precautions for use"). Dopamine agonist withdrawal syndrome may occur during gradual dose reduction. Therefore, temporary dose increase may be necessary before resuming dose reduction (see section "Special precautions for use").

Dosing in patients with renal impairment

Elimination of pramipexole from the body depends on renal function. The dosing regimen described below is recommended for initial therapy.

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

For patients with creatinine clearance of 20–50 ml/min, initiate pramipexole at a daily dose of 0.25 mg divided into two doses (0.125 mg twice daily). The maximum daily dose of pramipexole should not exceed 2.25 mg.

For patients with creatinine clearance below 20 ml/min, initiate pramipexole at a daily dose of 0.125 mg given as a single dose. The maximum daily dose of pramipexole should not exceed 1.5 mg.

If renal function deteriorates during maintenance therapy, the daily dose of pramipexole should be reduced proportionally to the decline in creatinine clearance. For example, if creatinine clearance decreases by 30%, the daily dose of pramipexole 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, since approximately 90% of absorbed pramipexole 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 pramipexole is 0.125 mg once daily, taken 2–3 hours before bedtime. For patients who require additional symptom relief, the dose may be increased every 4–7 days up to the maximum dose of 0.75 mg per day (see Table 2). The lowest effective dose of pramipexole should be used (see section "Special precautions for use").

Table 2

Therapeutic response should be evaluated after 3 months of treatment, and the necessity of continuing therapy should be reviewed. If treatment is interrupted for more than a few days, reinitiation of the medicinal product should be performed by gradually increasing the dose according to the scheme outlined above.

Discontinuation of treatment

Since the daily dose for the treatment of restless legs syndrome does not exceed 0.75 mg, treatment with Pramipexole IS can be discontinued without gradual dose reduction. In a 26-week placebo-controlled clinical study, recurrence of restless legs syndrome symptoms (worsening of symptom severity compared to baseline) was observed in 10% of patients after abrupt discontinuation of pramipexole. This effect was observed across all doses.

Dosing in patients with renal impairment

Elimination of pramipexole from the body depends on renal function. Patients with creatinine clearance above 20 mL/min do not require reduction of the daily dose.

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

Dosing in patients with hepatic impairment

Dose reduction is not considered necessary in patients with hepatic impairment, as approximately 90% of absorbed pramipexole is excreted by 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 in children (under 18 years of age) have not been established. There is no justification for the use of pramipexole in children with Parkinson's disease.

Restless legs syndrome

The use of pramipexole is not recommended in children (under 18 years of age) due to insufficient safety and efficacy data.

Tourette syndrome

Pramipexole should not be used in children (under 18 years of age) with Tourette 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 case of signs 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.

Side effects

Most side effects usually occur at the beginning of therapy, and a significant proportion of them disappear even if treatment continues.

Side effects are classified by system organ classes and frequency of occurrence. Frequency is defined as follows: 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 treated with pramipexole compared to placebo, the most common side effects (≥ 5%) were nausea, dyskinesia, arterial hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache, and increased fatigue. The incidence of somnolence increased with doses exceeding 1.5 mg per day (see section "Dosage and administration"). The most common side effect when administered in combination with levodopa was dyskinesia. Arterial 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*.

Psychiatric disorders: common – insomnia, hallucinations, abnormal dreams, confusion, symptoms of impulse control disorder and compulsive behavior; uncommon – pathological gambling, pathological shopping, anxiety, hypersexuality, delusions, libido disorders, paranoia, delirium, overeating*, hyperphagia*; rare – mania.

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

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

Cardiac disorders: common – arterial hypotension; uncommon – heart failure*.

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.

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

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

* This adverse reaction was reported during post-marketing surveillance. With 95% confidence, the frequency category does not exceed "uncommon", but may be lower. An exact frequency category cannot be determined, as the adverse reaction was not observed in clinical trials involving 2,762 Parkinson's disease patients treated with pramipexole.

Restless legs syndrome

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) than in men (6.7% and 7.3%, respectively) during pramipexole treatment.

Infections and infestations: uncommon – pneumonia**.

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

Psychiatric disorders: common – insomnia, abnormal dreams; uncommon – anxiety, confusion, hallucinations, libido disorders, delusions**, hyperphagia**, paranoia**, mania**, delirium**, symptoms of impulse control disorder and compulsive behavior** (such as pathological gambling, pathological shopping, hypersexuality, overeating).

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

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

Cardiac disorders: uncommon – heart failure**, arterial 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.

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

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

** This adverse reaction was reported during post-marketing surveillance. With 95% confidence, the frequency category does not exceed "uncommon", but may be lower. An exact frequency category cannot be determined, as the adverse reaction was not observed in clinical trials involving 1,395 patients with restless legs syndrome treated with pramipexole.

Description of selected adverse reactions

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

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

Impulse control disorders. Symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, overeating, and compulsive eating, may occur during treatment with dopamine agonists, including pramipexole (see section "Special precautions").

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, increased fatigue, increased sweating, and pain (see section "Special precautions").

Heart failure. Heart failure has been observed in patients treated with pramipexole during clinical trials and in the post-marketing period. In a pharmacoe pidemiological study, pramipexole use was associated with an increased risk of heart failure compared to non-use of the medicinal product.

Reporting of suspected adverse reactions

Healthcare professionals are requested to report any suspected adverse reactions according to the national reporting system in order to maintain monitoring of the benefit-risk balance of the medicinal product.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer.

Limited liability company "INTERSHEM".

Manufacturer's location and address of business activity.

40-A, 21st km, Starokyivska Road, Odesa, Ukraine, 65025.