Pramipexole-zn

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRAMIPEXOLE-ZN (Pramipexole-ZN)

Composition:

Active substance: pramipexole;

One tablet contains 0.25 mg or 1 mg of pramipexole dihydrochloride monohydrate, calculated as 100 % substance;

Excipients: maize starch, mannitol (E 421), celactose 80 (a mixture of monohydrate lactose and powdered cellulose (75:25)), povidone, colloidal anhydrous silicon dioxide, magnesium stearate.

Dosage form. Tablets.

Main physicochemical properties: white or almost white tablets, round cylindrical in shape, with flat surfaces, bevelled edges and a division mark on one side.

Pharmacotherapeutic group.

Antiparkinsonian 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 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 Pramipexole-ZN 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%. Maximum plasma concentrations are observed 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, regardless of the pharmaceutical formulation, relatively low interpatient 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 most important elimination pathway. 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, with renal clearance being about 400 mL/min. The elimination half-life (t½) ranges from 8 hours in younger individuals to 12 hours in elderly subjects.

Clinical characteristics.

Indications.

Treatment of signs and symptoms of idiopathic Parkinson's disease in adults either 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 (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 bound to plasma proteins to a very low extent (< 20%) and undergoes low biotransformation. Therefore, interactions with other drugs affecting plasma protein binding or elimination via biotransformation are unlikely. Since anticholinergic agents are primarily eliminated via hepatic metabolism, potential interactions are unlikely. Interaction with anticholinergic agents has not been studied. There is no pharmacokinetic interaction between 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 (e.g., cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine, procainamide) may interact with pramipexole and lead to reduced clearance of pramipexole. When co-administering these medicinal products with Pramipexole-ZN, consider the possibility of reducing the dose of pramipexole.

Combination with levodopa. During dose escalation of Pramipexole-ZN 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 a possible additive effect, caution should be exercised when patients are 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 "Undesirable effects").

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 use of Pramipexole-ZN in patients with Parkinson's disease and impaired renal function is recommended at reduced doses as specified 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 hallucinations (in most cases, visual).

Disorders of movement (Dyskinesia). During combination therapy with levodopa in progressive Parkinson’s disease, dyskinesia may develop at the beginning of titration of Pramipexole-ZN. In such cases, the dose of levodopa should be reduced.

Dystonia. Axial dystonia, including antecollis, camptocormia, and pleurothotonus (Pisa syndrome), has occasionally been observed in patients with Parkinson’s disease after initiation or gradual dose escalation of pramipexole. Although dystonia may be a symptom of Parkinson’s disease itself, 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 the pramipexole dose should be considered.

Sudden sleep onset 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 sleep during daily activities have been reported, sometimes without awareness or warning signs. Therefore, patients should be advised to exercise caution when driving or operating machinery while being treated with Pramipexole-ZN. Patients experiencing somnolence and/or episodes of sudden sleep onset should refrain from driving and operating machinery. Additionally, dose reduction or shortening of treatment duration should be considered. Caution should also be exercised if patients are taking 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", "Effect on ability to drive and use machines", and "Undesirable effects").

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-ZN, 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 informed 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-ZN should be prescribed with particular caution in patients with severe cardiovascular disorders. Monitoring of blood pressure is recommended, especially at the beginning of treatment, due to 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 case of visual disturbances.

Dopamine agonist withdrawal syndrome. Dopamine agonist withdrawal syndrome has been observed with the use of dopamine agonists, including pramipexole (see section "Undesirable effects"). To discontinue treatment, the dose of pramipexole in patients with Parkinson’s disease should be gradually reduced (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, sweating, pain, and lack of response to levodopa. Patients should be informed about possible withdrawal symptoms before dose reduction or discontinuation of pramipexole. Close monitoring is required during dose reduction and discontinuation of pramipexole. In cases of severe and/or persistent dopamine agonist withdrawal syndrome symptoms, temporary re-initiation of pramipexole at the lowest effective dose may be considered.

Augmentation 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 other limbs.

The risk of augmentation may increase with higher doses. Patients should be informed about the possibility of augmentation before starting treatment and advised to consult their physician if they experience symptoms of augmentation. If augmentation is suspected, dose adjustment to the lowest effective dose or discontinuation of pramipexole should be considered (see sections "Dosage and administration" and "Undesirable effects").

Renal impairment. Pramipexole-ZN should be used with caution in patients with renal impairment, as pramipexole is primarily excreted via the kidneys.

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

If a patient has known intolerance to certain sugars, consultation with a physician is necessary before taking this medicinal product.

Use during pregnancy or breastfeeding.

Effects on pregnancy and lactation in humans have not been studied. Pramipexole-ZN may be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

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

Effect on ability to drive and use machines.

Pramipexole-ZN may have a significant effect on the ability to drive or operate machinery. Hallucinations or somnolence may occur.

Patients experiencing somnolence and/or episodes of sudden sleep onset 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.

Dosage and Administration.

All dosage information refers to pramipexole in the form of pramipexole dihydrochloride.
Route of administration. Tablets should be taken orally with water, regardless of food intake.

Parkinson's disease. The daily dose should be divided into 3 equal doses.

Initial treatment. As shown below, the dose should be increased gradually, starting at 0.375 mg per day every 5–7 days. In cases where 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.

Maintenance therapy. Individual doses range from 0.375 mg to the 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 occurrence of adverse reactions. In clinical trials, approximately 5% of patients received doses below 1.5 mg. In advanced Parkinson's disease, doses above 1.5 mg per day may be effective in patients for whom a reduction in levodopa dose is planned in combination therapy with levodopa. It is recommended to reduce the levodopa dose when increasing the dose of Pramipexole-ZN 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. 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. After that, the dose should be reduced to 0.375 mg per day (see section "Special precautions"). Dopamine agonist withdrawal syndrome may occur during gradual dose reduction. Therefore, temporary dose escalation may be necessary before resuming dose reduction (see section "Special precautions").

Dosing in patients with renal impairment. Excretion of pramipexole depends on renal function. The dosing regimen 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-ZN should be administered in two divided doses, starting at 0.125 mg twice daily (0.25 mg per 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-ZN should be administered as a single dose, starting at 0.125 mg per day. The maximum daily dose of pramipexole should not exceed 1.5 mg.

If renal function deteriorates during maintenance therapy, the daily dose should be reduced by the same percentage as the decrease in creatinine clearance. For example, if creatinine clearance decreases by 30%, the daily dose of Pramipexole-ZN should be reduced by 30%. The daily dose may be administered in two divided doses if creatinine clearance is between 20–50 ml/min, and 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 via the kidneys. The potential impact of hepatic impairment on the pharmacokinetics of Pramipexole-ZN has not been studied.

Restless legs syndrome. The recommended initial dose of Pramipexole-ZN 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 per day (as shown in Table 2). The lowest effective dose should be used (see section "Special precautions").

Table 2

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 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, PRAMIPEXOLE-ZN can be discontinued without gradual dose reduction. In a 26-week placebo-controlled clinical study, symptom rebound of restless legs syndrome (worsening 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 across all doses.

Dosing in patients with renal impairment. Elimination of the drug depends on renal function. Patients with a creatinine clearance above 20 mL/min do not require dose reduction.

The use of PRAMIPEXOLE-ZN 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 for 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 PRAMIPEXOLE-ZN in children (under 18 years of age) have not been established. There is no justification for the use of the drug in children with Parkinson’s disease.

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

Tourette’s syndrome. The drug 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 effects 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.

Adverse Reactions

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

Adverse reactions are listed by system organ classes and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from the available data).

Parkinson’s disease. In patients with Parkinson’s disease, the most common adverse reactions (≥ 5%) observed during treatment with pramipexole compared to placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache, and fatigue. The incidence of somnolence increased 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.

1 This adverse reaction was observed in the post-marketing period. In 95 %, the frequency is no higher than uncommon, but it may be lower. Determination of the exact frequency is not possible because the adverse reaction was not observed during clinical studies in 2762 Parkinson's disease patients 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 increased fatigue. Nausea and increased fatigue occurred more frequently in women (20.8 % and 10.5 %, respectively) compared to men (6.7 % and 7.3 %, respectively) during treatment with Pramipexole-ZN.

2 This adverse reaction was observed in the post-marketing period. In 95%, the frequency is no higher than uncommon, but may be lower. Determination of the exact frequency is not possible, since the adverse reaction was not observed during clinical trials in 1395 patients with restless legs syndrome treated with pramipexole.

Description of selected adverse reactions.

Somnolence. Pramipexole use is often associated with somnolence and uncommonly with excessive daytime sleepiness and episodes of sudden sleep attacks (see section "Dosage and Administration").

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

Impulse control disorders. During treatment with dopamine agonists, including Pramipexole-ZN, symptoms of impulse control disorders may occur, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating (see section "Dosage and Administration").

Dopamine agonist withdrawal syndrome. Non-motor adverse reactions may occur when reducing the dose or discontinuing dopamine agonists (including pramipexole). Symptoms include apathy, anxiety, depression, fatigue, sweating, and pain (see section "Dosage and Administration").

Heart failure. During clinical trials and in the post-marketing period, heart failure has been observed in patients receiving pramipexole. In a pharmacoepidemiological study, 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 suspected adverse reactions. Reporting of suspected adverse reactions after medicinal product registration is important. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions in accordance with current legislation.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets per blister; 2 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovye Naroda".

Manufacturer's address and location of business activity.

41 Kulikovskaya Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.