Parkizol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PAKIZOL (PARKIZOL)

Composition:

Active substance: pramipexole dihydrochloride monohydrate;

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

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets of 0.25 mg: oval, flat tablets ranging from white to almost white, beveled edge, smooth on one side and marked with a line on the other;

tablets of 1 mg: round, flat tablets ranging from white to almost white, beveled edge, smooth on one side and marked with a line 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 subfamily, showing preferential affinity for D3 receptors, and 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 central dopaminergic system.

Pharmacokinetics.

Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability exceeds 90%. Maximum plasma concentration is observed between 1 and 3 hours after administration. The rate of absorption is not reduced by concomitant food intake, but overall absorption is decreased. Pramipexole exhibits linear kinetics and, regardless of the pharmaceutical formulation, relatively low plasma level fluctuations among different patients. In humans, protein binding of pramipexole is very low (< 20%), and the volume of distribution is large (400 L).

Pramipexole is metabolized in humans only to a negligible extent.

Renal excretion of unchanged pramipexole is the major elimination pathway. Approximately 90% of a radiolabeled dose (14C) is excreted by the kidneys, 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 younger patients to 12 hours in elderly individuals.

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 (the "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, interactions with other drugs affecting plasma protein binding or elimination via biotransformation are unlikely. Since anticholinergic agents are primarily eliminated via hepatic metabolism, potential interaction is 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—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, consideration should be given to reducing the dose of pramipexole.

Combination with levodopa

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

Due to the potential for additive effects, caution should be exercised if 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 "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.

In patients with Parkinson's disease who have renal impairment, the drug should be administered in reduced doses according to the section "Dosage and administration".

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

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

Dystonia.

Axial dystonia, including antecollis, camptocormia, and pleurosthotonos (Pisa syndrome), has sometimes occurred in patients with Parkinson's disease after initial dosing or gradual dose escalation of pramipexole. Although dystonia may be a symptom of Parkinson's disease, dystonic symptoms in these patients improved after dose reduction or discontinuation of pramipexole.

If dystonia occurs, a reassessment of the treatment regimen with dopaminergic agents should be considered, and the dose of pramipexole should be 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 onset of sleepiness 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 during treatment with this drug. 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 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", "Ability to influence reaction speed when driving or operating machinery", and "Adverse reactions").

Impulse control disorders and compulsive behavior. Patients should be closely monitored for the development of impulse control disorders. Patients and caregivers should be aware that symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating, may occur during treatment with dopamine agonists, including pramipexole. 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 taking pramipexole. If such symptoms develop, dose reduction or discontinuation of the drug should be considered.

Severe cardiovascular disorders. The drug should be prescribed with particular caution in patients with severe cardiovascular disorders. Monitoring of blood pressure is recommended, especially at the beginning of treatment, considering the general risk of postural hypotension associated with dopaminergic therapy.

Patients with psychiatric disorders. Patients with psychiatric disorders should be treated with dopamine agonists 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 "Interaction with other medicinal products and other forms of interaction").

Ophthalmological examination. Regular ophthalmological examination is recommended in case of visual disturbances.

Dopamine agonist withdrawal syndrome (DAWS).

Dopamine agonist withdrawal syndrome has been observed during treatment with 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 (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. The 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 severe 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. 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 possibility of augmentation and advised to consult their physician if they experience worsening of 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").

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 time-to-augmentation analysis showed no significant difference between the pramipexole and placebo groups.

Renal impairment. Parkizol tablets should be used with caution in patients with renal impairment, as pramipexole is primarily excreted by the kidneys.

Rhabdomyolysis. A single case of rhabdomyolysis was 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.

Effects on pregnancy and lactation in humans have not been studied. The drug may be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus.

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

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

Ability to influence reaction speed when driving or operating machinery.

The drug may have a significant effect on the ability to drive and operate machinery. Hallucinations or somnolence may occur.

Patients experiencing somnolence and/or sudden sleep attacks while taking the drug should refrain from driving and from engaging in potentially dangerous activities where impaired attention could increase the risk of serious injury or death.

Dosage and Administration

All dosage information refers to pramipexole as pramipexole dihydrochloride.

Parkinson's Disease

The daily dose should be administered in three divided doses of equal amounts.

Initial Treatment

The dose of the medicinal product should be gradually increased as shown below, starting at 0.375 mg per day, increasing every 5–7 days. If patients do not experience intolerable adverse reactions, 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. The incidence of somnolence increases with doses above 1.5 mg per day.

Maintenance therapy

The individual dose ranges from 0.375 mg to the maximum dose of 4.5 mg per day. During dose escalation in the main studies, a therapeutic effect was observed starting from a daily dose of 1.5 mg. Further dose adjustments should be made based on clinical response and taking into account the 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 beneficial for patients for whom a reduction in levodopa dose is planned during combination therapy with levodopa. It is recommended to reduce the levodopa dose when increasing the dose of the medicinal product 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 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 increase may be necessary before resuming dose reduction (see section "Special precautions").

Dosing in patients with renal impairment

Elimination 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 of dosing frequency.

For patients with creatinine clearance of 20–50 ml/min, the initial daily dose of Parkizol should be administered in two doses, starting with 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 should be administered as a single dose, starting with 0.125 mg per day. The maximum daily dose of pramipexole should not exceed 1.5 mg.

In patients with renal impairment during maintenance therapy, the daily dose should be reduced by the same percentage by which creatinine clearance has decreased. For example, if creatinine clearance decreases by 30%, the daily dose should be reduced by 30%. The daily dose can 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 has not been studied.

Restless legs syndrome

The recommended initial dose 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 (see Table 2). The lowest effective dose should be used (see section "Special precautions" – Augmentation in restless legs syndrome).

Table 2

* If necessary.

The patient's response to treatment should be evaluated after 3 months, and the need for continuing therapy should be reviewed. If treatment is interrupted for more than a few days, therapy should be restarted by re-titrating the dose as indicated above.

Discontinuation of treatment

Since the daily dose for the treatment of restless legs syndrome does not exceed 0.75 mg, the drug may be discontinued without tapering the dose. During a 26-week placebo-controlled clinical study, symptom rebound of restless legs syndrome (worsening of symptoms compared to baseline levels) 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. Dose reduction is not required in patients with creatinine clearance above 20 mL/min.

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

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

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 limited. Expected adverse effects related to the pharmacodynamic profile of a dopamine agonist include nausea, vomiting, hyperkinesia, hallucinations, agitation, and arterial hypotension. An antidote for dopamine agonist overdose has not been established. 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 fluids, activated charcoal, and electrocardiogram monitoring.

Adverse Reactions

Most adverse reactions usually occur at the beginning of therapy, and a significant proportion of them resolve even if the treatment continues.

Adverse reactions are listed by system organ classes 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 treated with pramipexole compared to placebo, the most common adverse reactions (≥ 5%) 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.

Infections and infestations

Uncommon: pneumonia.

Endocrine system disorders

Uncommon: disturbance of antidiuretic hormone secretion¹.

Psychiatric disorders

Common: insomnia, hallucinations, sleep disorders, confusion, symptoms of impulse control disorders and compulsive behavior.

Uncommon: pathological gambling, pathological shopping, anxiety, hypersexuality, delusions, libido disorders, paranoia, delirium, binge eating¹, hyperphagia¹.

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: hypotension.

Uncommon: heart failure¹.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea, hiccup.

Gastrointestinal disorders

Very common: nausea.

Common: constipation, vomiting.

Skin and subcutaneous tissue disorders

Uncommon: increased sensitivity, pruritus, rash.

General disorders

Common: fatigue, peripheral edema.

Frequency not known: dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, increased sweating, and pain).

Investigations

Common: weight decrease, including decreased appetite.

Uncommon: weight increase.

¹ This adverse reaction was observed during the post-marketing period. In 95% of cases, the frequency is no higher than "uncommon," but may be lower. The exact frequency cannot be established, as this adverse reaction was not observed during clinical trials in 2,762 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 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: pneumonia².

Endocrine system disorders

Uncommon: disturbance of antidiuretic hormone secretion².

Psychiatric disorders

Common: insomnia, sleep disorders.

Uncommon: anxiety, confusion, hallucinations, libido disorders, delusions², hyperphagia², paranoia², mania², delirium², symptoms of impulse control disorders and compulsive behavior² (pathological shopping, pathological gambling, hypersexuality, binge eating).

Nervous system disorders

Very common: augmentation of restless legs syndrome.

Common: headache, dizziness, somnolence.

Uncommon: sudden sleep attacks, syncope, dyskinesia, amnesia², hyperkinesia².

Eye disorders

Uncommon: visual disturbances, including decreased visual acuity, diplopia, and blurred vision.

Cardiac disorders

Uncommon: heart failure², hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea, hiccup.

Gastrointestinal disorders

Very common: nausea.

Common: constipation, vomiting.

Skin and subcutaneous tissue disorders

Uncommon: increased sensitivity, pruritus, rash.

General disorders

Common: fatigue.

Uncommon: peripheral edema.

Frequency not known: dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, increased sweating, and pain).

Investigations

Uncommon: weight decrease, including decreased appetite; weight increase.

² This adverse reaction was observed during the post-marketing period. In 95% of cases, the frequency is no higher 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 restless legs syndrome patients treated with pramipexole.

Description of selected adverse reactions

Somnolence. Pramipexole use is often associated with somnolence and less frequently with excessive daytime sleepiness and episodes of sudden sleep attacks (see section "Special Warnings and Precautions for Use").

Libido disorders. Pramipexole use 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 Warnings and Precautions for Use").

Dopamine agonist withdrawal syndrome. When reducing the dose or discontinuing dopamine agonists (including pramipexole), non-motor adverse reactions may occur. Symptoms include apathy, anxiety, depression, fatigue, increased sweating, and pain (see section "Special Warnings and Precautions for Use").

Heart failure. Heart failure has been observed in patients treated with pramipexole during clinical trials and the post-marketing period. In a pharmacoe pidemiological 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).

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister, 3 blisters per cardboard pack.

Prescription category. Prescription only.

Manufacturer.

San Pharmaceuticals Industries Ltd.

Manufacturer's address and place of business.

Survey No. 214, Plot No. 20, Gavt. Ind. Area, Phase II, Piparia, Silvassa – 396230, U.T. Dadra and Nagar Haveli, India.