Pyritan: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PIRITAN (PIRITAN®)

Composition:

Active substance: pramipexole dihydrochloride monohydrate;

1 tablet contains pramipexole dihydrochloride monohydrate 0.25 mg, corresponding to 0.18 mg of pramipexole, or pramipexole dihydrochloride monohydrate 1.0 mg, corresponding to 0.7 mg of pramipexole;

Excipients: mannitol (E 421), maize starch, povidone (PVPK30), povidone K90 (PVPK90), magnesium stearate, colloidal silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablelets 0.25 mg: oval, biconvex tablets, white to almost white, with bevelled edges, with a deep score line on one side and a regular score line on the other side;

tablets 1.0 mg: round, biconvex tablets, white to almost white, with bevelled edges, with a deep score line on one side and smooth on the other side.

Pharmacotherapeutic group. Antiparkinson drugs. Dopaminergic agents. Dopamine agonists.

ATC code N04BC05

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Pramipexole is a dopamine agonist with high selectivity and specificity for dopamine receptors of the D2 subtype, with preferential affinity for D3 receptors, as well as full intrinsic activity at these receptors.

Pramipexole alleviates Parkinsonian motor disturbances by stimulating striatal dopamine receptors. Animal studies have demonstrated that pramipexole inhibits dopamine synthesis, release, and reuptake.

The precise mechanism of action of pramipexole in the treatment of restless legs syndrome is unknown. Neuropharmacological data suggest involvement of the primary dopaminergic system.

Pharmacodynamic effects

In volunteers, a dose-dependent decrease in prolactin levels was observed. In a clinical study involving healthy volunteers, rapid dose titration of pramipexole (every 3 days) up to 4.5 mg as the salt (3.15 mg pramipexole) per day resulted in increased blood pressure and heart rate. This effect was not observed in studies conducted in patients.

Pharmacokinetics

Absorption

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 low inter-patient variability in plasma levels.

Distribution

In humans, protein binding of pramipexole is very low (< 20%), and the volume of distribution is large (400 L). High concentrations were observed in rat brain tissue (approximately 8 times higher than in plasma).

Biotransformation

Pramipexole is only minimally metabolized in humans.

Elimination

Renal excretion of unchanged pramipexole is the main route of elimination. Approximately 90% of a radiolabeled 14C dose is excreted via 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. The elimination half-life (t½) ranges from 8 hours in younger individuals to 12 hours in elderly individuals.

Clinical characteristics

Indications

Pramipexole is indicated in adults for the treatment of signs and symptoms of idiopathic Parkinson's disease, 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 (dose wearing-off or "on-off" fluctuations).

Pramipexole is indicated in adults for symptomatic treatment of moderate to severe idiopathic restless legs syndrome at doses not exceeding 0.75 mg pramipexole dihydrochloride monohydrate (0.54 mg pramipexole) (see section "Dosage and administration").

Contraindications
Hypersensitivity to the active substance or to any of the other components 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 negligible extent (< 20%). Minimal biotransformation is observed in males. Therefore, interactions with other medicinal products affecting protein binding or elimination via biotransformation are unlikely. Since anticholinergic agents are primarily eliminated via biotransformation, potential interaction is unlikely, although interactions with anticholinergic agents have not been studied. There is no pharmacokinetic interaction between selegiline and levodopa.

Inhibitors/competitors of active renal excretion pathways

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

Combination with levodopa

When increasing the dose of pramipexole in combination with levodopa, it is recommended to reduce the dose of levodopa, while the doses of other anti-Parkinson medicinal products should remain unchanged.

Due to possible additive effects, patients should be advised to exercise caution when taking other sedative medicinal products or alcohol in combination with pramipexole (see sections "Special precautions for use", "Effects 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"), for example, when antagonistic effects may be expected.

Special precautions for use

Renal impairment

When prescribing pramipexole to patients with Parkinson's disease and impaired renal function, dosage reduction is recommended as described in the section "Posology and method of administration".

Hallucinations

Hallucinations are known to occur as a side effect of treatment with dopamine agonists and levodopa. Patients should be informed that hallucinations (mainly visual) may occur.

Dyskinesia

During combination therapy with levodopa in progressive Parkinson's disease, dyskinesia may develop during initial titration of pramipexole. If this occurs, the dose of levodopa should be reduced.

Dystonia

Axial dystonia, including antecollis, camptocormia, and pleurothotonus (Pisa syndrome), has been occasionally observed in patients with Parkinson's disease after initiation or dose escalation of pramipexole. Although dystonia may be a symptom of Parkinson's disease, symptoms of dystonia in patients with Parkinson's disease improve after dose reduction or discontinuation of pramipexole.

If dystonia occurs, the treatment regimen with dopaminergic medicinal products should be reviewed and the dose of pramipexole adjusted.

Sudden sleep attacks and somnolence

Use of pramipexole has been associated with somnolence and sudden sleep attacks, particularly in patients with Parkinson's disease. Sudden sleep attacks during daytime activities, sometimes without awareness or warning signs, have been reported infrequently. Patients should be informed about this risk. They should be advised to exercise caution when driving or operating machinery during treatment with pramipexole. Patients who experience somnolence and/or sudden sleep attacks should refrain from driving or operating machinery. In addition, dose reduction or discontinuation of treatment should be considered. Due to possible additive effects, caution is recommended if patients are taking other sedative medicinal products in combination with pramipexole or consuming alcohol (see sections "Interaction with other medicinal products and other forms of interaction", "Ability to affect reaction speed when driving or operating machinery", 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 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, particularly pramipexole.

If such symptoms develop, consideration should be given to reducing the dose or gradually discontinuing the medication.

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, consideration should be given to reducing the dose or gradually discontinuing the medication.

Patients with psychotic disorders

Patients with psychotic disorders should only be treated with dopamine agonists 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 monitoring

Regular ophthalmological monitoring at consistent intervals or in case of visual disturbances is recommended.

Severe cardiovascular disease

Caution should be exercised in patients with severe cardiovascular disease. Blood pressure monitoring is recommended, especially at the beginning of treatment, due to the general risk of postural hypotension associated with dopaminergic therapy.

Malignant neuroleptic syndrome

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

Dopamine agonist withdrawal syndrome

Cases of dopamine agonist withdrawal syndrome have been reported after discontinuation of dopamine agonist therapy, including pramipexole (see section "Undesirable effects"). To discontinue pramipexole treatment in patients with Parkinson's disease, the dose should be gradually reduced (see section "Posology and method of administration"). According to some data, patients with impulse control disorders and those receiving high daily 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. Before reducing the dose or discontinuing pramipexole, patients should be informed about the possible symptoms of withdrawal syndrome. Patients should be closely monitored 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

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 the day), worsening of symptoms, and spread of symptoms to other limbs.

The risk of augmentation may increase with higher doses. Before initiating treatment, patients should be informed about the risk of augmentation and advised to consult their physician if symptoms of augmentation occur. If augmentation is suspected, consideration should be given to adjusting the dose to the lowest effective dose or discontinuing pramipexole (see sections "Posology and method of administration" and "Undesirable effects").

Use during pregnancy or breastfeeding

Pregnancy

The effects of pramipexole on pregnancy and lactation in humans have not been studied. Pramipexole showed no teratogenic effects in studies in rats and rabbits, but demonstrated embryotoxic effects in rats at doses that were toxic to pregnant females. Pramipexole should not be used during pregnancy except in cases of absolute necessity when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

Since pramipexole treatment suppresses prolactin secretion in humans, inhibition of lactation is expected. Excretion of pramipexole into human breast milk has not been studied. In rats, concentrations of radiolabeled active substance in breast milk were higher than in plasma. Due to the lack of adequate human data, pramipexole is not recommended during breastfeeding. If use cannot be avoided, breastfeeding should be discontinued.

Fertility

Studies on the effect of pramipexole on human fertility have not been conducted. In animal studies, pramipexole affected the oestrous cycle and reduced fertility in females, which was expected for a dopamine agonist. However, these studies did not reveal direct or indirect harmful effects on male fertility.

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 who experience somnolence and/or sudden sleep attacks during treatment with pramipexole should be advised to refrain from driving or engaging in any other activity where reduced alertness may place themselves or others at risk of serious injury or fatal outcome (e.g., operating machinery) until sudden sleep attacks and somnolence have resolved (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Undesirable effects").

Dosage and Administration

Parkinson's disease

The daily dose should be divided into 3 equal doses.

Initial treatment

The dose of pramipexole should be increased gradually: start with a dose of 0.375 mg pramipexole dihydrochloride monohydrate (0.264 mg pramipexole) per day, then increase every 5–7 days. If patients do not experience intolerable adverse reactions, the dose should be titrated until the maximum therapeutic effect is achieved (see Table 1).

Table 1

Dosage escalation scheme for pramipexole
Week	Pramipexole dose (mg)	Total daily dose of pramipexole (mg)	Pramipexole dihydrochloride monohydrate dose (mg)	Total daily dose of pramipexole dihydrochloride monohydrate (mg)
1st	3 × 0.088	0.264	3 × 0.125	0.375
2nd	3 × 0.18	0.54	3 × 0.25	0.75
3rd	3 × 0.35	1.1	3 × 0.5	1.50

If further dose escalation is necessary, the daily dose should be increased by 0.75 mg of pramipexole dihydrochloride monohydrate (0.54 mg pramipexole) weekly up to the maximum dose of 4.5 mg pramipexole dihydrochloride monohydrate (3.3 mg pramipexole) per day. However, it should be noted that the incidence of somnolence increases when doses above 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole) per day are used (see section "Adverse Reactions").

Maintenance therapy

The individual dose ranges from 0.375 mg pramipexole dihydrochloride monohydrate (0.264 mg pramipexole) to the maximum of 4.5 mg pramipexole dihydrochloride monohydrate (3.3 mg pramipexole) per day. During dose escalation in clinical trials, treatment efficacy was observed starting at a daily dose of 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole). Further dose adjustments should be made according to the clinical response and the occurrence of adverse reactions. In clinical trials, approximately 5% of patients were treated with doses lower than 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole). For patients with progressive Parkinson's disease, doses exceeding 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole) per day may be beneficial, especially if levodopa dose reduction is planned. It is recommended to reduce the levodopa dose during pramipexole dose escalation and also during maintenance therapy with this medicinal product, depending on the individual patient's response (see section "Interaction with other medicinal products and other forms of interaction").

Discontinuation of treatment

Sudden discontinuation of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome or dopamine agonist withdrawal syndrome. The pramipexole dose should be gradually reduced by 0.75 mg pramipexole dihydrochloride monohydrate (0.54 mg pramipexole) per day until the daily dose is reduced to 0.75 mg pramipexole dihydrochloride monohydrate (0.54 mg pramipexole). After this, the dose should be reduced by 0.375 mg pramipexole dihydrochloride monohydrate (0.264 mg pramipexole) per day (see section "Special precautions"). Dopamine agonist withdrawal syndrome may occur during gradual dose reduction. Therefore, temporary dose increases may be necessary before resuming dose reduction (see section "Special precautions").

Dosage in patients with renal impairment

Elimination of pramipexole depends on renal function. The following dosage regimen is recommended for initial therapy:

Patients with creatinine clearance above 50 mL/min do not require dose adjustment or changes in dosing frequency.
Patients with creatinine clearance of 20–50 mL/min should start initial daily dose in two divided doses, beginning with 0.125 mg pramipexole dihydrochloride monohydrate (0.088 mg pramipexole) twice daily (0.25 mg/day pramipexole dihydrochloride monohydrate / 0.176 mg pramipexole / day). The maximum daily dose should not exceed 2.25 mg pramipexole dihydrochloride monohydrate (1.57 mg pramipexole).
Patients with creatinine clearance below 20 mL/min should receive the daily dose as a single dose, starting with 0.125 mg/day pramipexole dihydrochloride monohydrate (0.088 mg pramipexole / day). The maximum daily dose should not exceed 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole).
In case of worsening renal function during maintenance therapy, the daily pramipexole dose should be reduced by the same percentage as the reduction in creatinine clearance. For example, if creatinine clearance decreases by 30%, the daily pramipexole dose 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.

Dosage in patients with hepatic impairment

Dose adjustment is probably not necessary in patients with hepatic impairment, since approximately 90% of the absorbed active substance is excreted via the kidneys. However, 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 pramipexole dihydrochloride monohydrate (0.088 mg pramipexole) 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 pramipexole dihydrochloride monohydrate (0.54 mg pramipexole) per day (see Table 2). The lowest effective dose should be used (see section "Special precautions", subsection "Augmentation of restless legs syndrome").

Table 2

Dosage escalation scheme for pramipexole
Titration stage	Evening daily dose of pramipexole (mg)	Evening daily dose of pramipexole dihydrochloride monohydrate (mg)
1	0.088	0.125
2*	0.18	0.25
3*	0.35	0.50
4*	0.54	0.75

* 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 with dose titration as described above.

Discontinuation of treatment

Since the daily dose for the treatment of restless legs syndrome does not exceed 0.75 mg pramipexole dihydrochloride monohydrate (0.54 mg pramipexole), pramipexole may be discontinued without tapering the dose. In a 26-week placebo-controlled clinical trial, 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 similar across all doses.

Dosing in patients with renal impairment

Elimination of pramipexole 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, since nearly 90% of the absorbed active substance is excreted by the kidneys.

Method of administration

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

Children

Parkinson's disease

Safety and efficacy of pramipexole in children (under 18 years of age) have not been established. There is no rationale 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 data on safety and efficacy.

Tourette syndrome

Pramipexole should not be used in children (under 18 years of age) with Tourette syndrome due to insufficient data on safety and efficacy and due to an unfavorable benefit-risk ratio for this indication.

Overdose

There is no clinical experience of significant overdose. Adverse reactions related to the pharmacodynamic profile of a dopamine agonist are expected, including nausea, vomiting, hyperkinesia, hallucinations, anxiety, and arterial hypotension.

There is no established antidote for dopamine agonist overdose. In cases of central nervous system stimulation, administration of a neuroleptic agent may be indicated. Management of overdose may require general supportive measures, including gastric lavage, intravenous fluid administration, activated charcoal, and electrocardiogram monitoring.

Adverse Reactions

An analysis of combined placebo-controlled trials involving a total of 1,923 patients receiving pramipexole and 1,354 patients receiving placebo showed that adverse reactions occurred frequently in both groups. At least one adverse reaction was reported in 63% of patients treated with pramipexole and in 52% of patients treated with placebo.

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

Adverse reactions are listed by organ systems, with frequencies 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), and frequency not known (cannot be estimated based on available data).

Parkinson’s Disease

Adverse reactions most frequently reported (≥5%) in patients with Parkinson’s disease (more common with pramipexole than with placebo) include: nausea, dyskinesia, arterial hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache, and fatigue. The incidence of somnolence increases with doses exceeding 1.5 mg pramipexole dihydrochloride monohydrate per day (see section "Dosage and Administration"). Dyskinesia was the most commonly reported adverse reaction when pramipexole was used in combination with levodopa. Arterial hypotension may occur at the beginning of treatment, especially if pramipexole titration is too rapid.

Infections and infestations

Uncommon: pneumonia.

Endocrine system disorders

Uncommon: disorders of antidiuretic hormone secretion¹.

Psychiatric disorders

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

Uncommon: pathological gambling, compulsive 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

Uncommon: heart failure¹.

Vascular disorders

Common: arterial hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea, hiccup.

Gastrointestinal disorders

Very common: nausea.

Common: constipation, vomiting.

Skin and subcutaneous tissue disorders

Uncommon: hypersensitivity, pruritus, rash.

Reproductive system and breast disorders

Rare: spontaneous penile erection.

General disorders and administration site conditions

Common: fatigue, peripheral edema.

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

Investigations

Common: weight decreased, including decreased appetite.

Uncommon: weight increased.

¹ This adverse reaction was observed during the post-marketing period. With 95% confidence, the frequency category was defined as uncommon, but it may be lower. The exact frequency cannot be established, as this adverse reaction was not observed during 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 commonly reported adverse reactions (≥5%) were nausea, headache, dizziness, and fatigue. Nausea and fatigue occurred more frequently in women (20.8% and 10.5%, respectively) than in men (6.7% and 7.3%, respectively) during pramipexole treatment.

Infections and infestations

Uncommon: pneumonia¹.

Endocrine system disorders

Uncommon: disorders of antidiuretic hormone secretion¹.

Psychiatric disorders

Common: insomnia, sleep disorders.

Uncommon: anxiety, confusion, hallucinations, libido disorders, delusions¹, hyperphagia¹, paranoia¹, mania¹, delirium¹, symptoms of impulse control disorders and compulsive behaviors¹ (such as pathological gambling, compulsive shopping, hypersexuality, binge eating).

Nervous system disorders

Very common: augmentation of restless legs syndrome.

Common: headache, dizziness, somnolence.

Uncommon: sudden sleep attacks, syncope, dyskinesia, amnesia¹, hyperkinesia¹.

Eye disorders

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

Cardiac disorders

Uncommon: heart failure¹.

Vascular disorders

Uncommon: arterial hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea, hiccup.

Gastrointestinal disorders

Very common: nausea.

Common: constipation, vomiting.

Skin and subcutaneous tissue disorders

Uncommon: hypersensitivity, pruritus, rash.

Reproductive system and breast disorders

Rare: spontaneous penile erection.

General disorders

Common: fatigue.

Uncommon: peripheral edema.

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

Investigations

Uncommon: weight decreased, including decreased appetite; weight increased.

¹ This adverse reaction was observed during the post-marketing period. With 95% confidence, the frequency category was defined as uncommon, but it may be lower. The exact frequency cannot be established, as this adverse reaction was not observed during clinical trials involving 1,395 restless legs syndrome patients treated with pramipexole.

Description of selected adverse reactions

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

Libido disorders. Pramipexole use 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 and case-control study involving 3,090 Parkinson’s disease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic therapy experienced symptoms of impulse control disorders during the previous six months. Observed manifestations included pathological gambling, compulsive shopping, excessive eating, and compulsive sexual behavior (hypersexuality). Potential independent risk factors for impulse control disorders include dopaminergic therapy and higher doses of dopaminergic treatment, younger age (≤65 years), unmarried status, and a family history of pathological gambling as reported by the patient.

Dopamine agonist withdrawal syndrome. Non-motor adverse reactions may occur upon dose reduction or discontinuation of dopamine agonists (including pramipexole). Symptoms include apathy, anxiety, depression, fatigue, sweating, and pain (see section "Special precautions").

Heart failure. Heart failure has been observed in patients treated with pramipexole during clinical trials and the post-marketing period. 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 [confidence interval]: 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 via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

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 per blister, 3 or 6 blisters per cardboard box.

Prescription status.

Prescription-only.

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's address and place of business.

54 Davydovskoho Hryhoriia St., Sumy, Sumy Oblast, 40020, Ukraine.

INSTRUCTION

for medical use of the medicinal product

PIRITAN

(PIRITAN®)

Composition:

Active substance: pramipexole dihydrochloride monohydrate;

1 tablet contains pramipexole dihydrochloride monohydrate 0.25 mg, equivalent to 0.18 mg pramipexole, or pramipexole dihydrochloride monohydrate 1.0 mg, equivalent to 0.7 mg pramipexole;

Excipients: mannitol (E 421), maize starch, povidone (PVPK30), povidone K90 (PVPK90), magnesium stearate, colloidal silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablelets 0.25 mg: oval, biconvex tablets, white to almost white, with bevelled edges, with a deep break line on one side and a plain break line on the other side;

tablets 1.0 mg: round, biconvex tablets, white to almost white, with bevelled edges, with a deep break line on one side and smooth surface on the other side.

Pharmacotherapeutic group. Antiparkinson agents. Dopaminergic agents. Dopamine agonists.

ATC code N04BC05

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Pramipexole is a dopamine agonist with high selectivity and specificity for dopamine receptors of the D2 subfamily, with preferential affinity for D3 receptors, and has full intrinsic activity at these receptors.

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

The exact mechanism of action of pramipexole in the treatment of restless legs syndrome is unknown. Neuropharmacological data suggest involvement of the primary dopaminergic system.

Pharmacodynamic Effects

In volunteers, dose-dependent reduction in prolactin levels was observed. In a clinical study involving healthy volunteers, rapid dose titration of pramipexole (every 3 days) to 4.5 mg as the salt (3.15 mg pramipexole) per day, faster than recommended, resulted in increased blood pressure and heart rate. This effect was not observed in studies conducted in patients.

Pharmacokinetics

Absorption

Distribution

In humans, pramipexole protein binding is very low (< 20%), and the volume of distribution is large (400 L). High concentrations were observed in rat brain tissue (approximately 8 times higher than in plasma).

Biotransformation

Pramipexole is only minimally metabolized in humans.

Elimination

Renal excretion of unchanged drug is the main route of pramipexole 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 approximately 400 ml/min. The elimination half-life (t½) ranges from 8 hours in young individuals to 12 hours in elderly individuals.

Clinical characteristics

Indications

Pramipexole is indicated in adults for the treatment of signs and symptoms of idiopathic Parkinson's disease as monotherapy (without levodopa) or in combination with levodopa, throughout the disease course up to the advanced stages when the effect of levodopa diminishes or becomes unstable and fluctuations in therapeutic response occur (wearing-off or on-off fluctuations).

Contraindications
Hypersensitivity to the active substance or to any of the other components 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 minimal biotransformation is observed in men. Therefore, interactions with other medicinal products affecting protein binding or elimination via biotransformation are unlikely. Since anticholinergic agents are primarily eliminated via biotransformation, potential interaction is unlikely, although interaction with anticholinergic agents has not been studied. There is no pharmacokinetic interaction between selegiline and levodopa.

Inhibitors/competitors of active renal excretion pathways

Cimetidine reduced the renal clearance of pramipexole by approximately 34%, likely by inhibiting the cationic secretory transport system of the renal tubules. Therefore, medicinal products that are inhibitors of this active renal excretion pathway or are themselves eliminated via this pathway—such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine, and procainamide—may interact with pramipexole, resulting in reduced pramipexole clearance. When co-administering these medicinal products with pramipexole, consideration should be given to reducing the dose of pramipexole.

Combination with levodopa

When increasing the dose of pramipexole in combination with levodopa, it is recommended to reduce the dose of levodopa, while the doses of other antiparkinsonian medicinal products should remain unchanged.

Antipsychotic medicinal products

Concomitant use of antipsychotic medicinal products with pramipexole should be avoided (see section "Special precautions for use"), for example, when antagonistic effects may be expected.

Special precautions for use

Renal function impairment

When prescribing pramipexole to patients with Parkinson's disease and impaired renal function, dose reduction is recommended as described in the section "Dosage and administration".

Hallucinations

Hallucinations are known as an adverse effect of treatment with dopamine agonists and levodopa. Patients should be informed that hallucinations (mainly visual) may occur.

Dyskinesia

During combination therapy with levodopa in progressive Parkinson's disease, dyskinesia may develop during initial titration of pramipexole. If this occurs, the levodopa dose 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 increase of pramipexole. Although dystonia may be a symptom of Parkinson's disease, symptoms of dystonia in these patients improve after dose reduction or discontinuation of pramipexole.

If dystonia occurs, the treatment regimen with dopaminergic agents should be reviewed and the pramipexole dose adjusted accordingly.

Sudden sleep attacks and somnolence

The use of pramipexole has been associated with somnolence and sudden sleep attacks, particularly in patients with Parkinson's disease. Sudden sleep attacks during daytime activities, sometimes occurring without awareness or warning signs, have been reported infrequently. Patients should be informed about this risk. They should be advised to exercise caution when driving or operating machinery during treatment with pramipexole. Patients who experience somnolence and/or sudden sleep attacks should refrain from driving or operating machinery. Furthermore, dose reduction or discontinuation of treatment should be considered. Due to possible additive effects, caution is recommended if patients are taking other sedative medicinal products in combination with pramipexole or consuming alcohol (see sections "Interaction with other medicinal products and other forms of interaction", "Ability to affect reaction speed when driving or operating machinery", and "Adverse reactions").

Impulse control disorders

If such symptoms develop, consideration should be given to reducing the dose or gradually discontinuing the medication.

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 develop, consideration should be given to reducing the dose or gradually discontinuing the medication.

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").

Ophthalmological monitoring

Regular ophthalmological monitoring at equal intervals or whenever visual disturbances occur is recommended.

Severe cardiovascular disease

Malignant neuroleptic syndrome

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

Dopamine agonist withdrawal syndrome

Cases of dopamine agonist withdrawal syndrome have been reported following discontinuation of dopamine agonist therapy, including pramipexole (see section "Adverse reactions"). To discontinue pramipexole treatment in patients with Parkinson's disease, the dose should be gradually reduced (see section "Dosage and administration"). According to some data, patients with impulse control disorders and those receiving high daily 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. Before reducing the dose or discontinuing pramipexole, patients should be informed about possible symptoms of withdrawal syndrome. Patients should be closely monitored 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

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

Use during pregnancy or breastfeeding

Pregnancy

The effects of pramipexole on pregnancy and lactation in humans have not been studied. Pramipexole showed no teratogenic effects in rats and rabbits, but exerted embryotoxic effects in rats at doses causing toxic effects in pregnant females. Pramipexole should not be used during pregnancy except when absolutely necessary and when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

Since pramipexole treatment suppresses prolactin secretion in humans, inhibition of lactation is expected. Passage of pramipexole into human breast milk has not been studied. In rats, concentrations of radiolabeled active substance in breast milk were higher than in plasma. Due to the lack of adequate human data, pramipexole is not recommended during breastfeeding. If use cannot be avoided, breastfeeding should be discontinued.

Fertility

Studies on the effect of pramipexole on human fertility have not been conducted. Animal studies showed that pramipexole affected the oestrous cycle and reduced fertility in females, which is expected for a dopamine agonist. However, these studies did not reveal direct or indirect harmful effects on male fertility.

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 who experience somnolence and/or sudden sleep attacks during pramipexole treatment should be advised to refrain from driving or engaging in any other activity where reduced alertness may put themselves or others at risk of serious injury or fatal outcome (e.g., operating machinery) until sudden sleep attacks and somnolence no longer occur (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Adverse reactions").

Dosage and Administration

Parkinson's disease

The daily dose should be divided into 3 equal doses.

Initial treatment

The pramipexole dose should be increased gradually: start with a dose of 0.375 mg pramipexole dihydrochloride monohydrate (0.264 mg pramipexole) per day, then increase 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

Dosage escalation schedule for pramipexole
Week	Pramipexole dose (mg)	Total daily dose of pramipexole (mg)	Pramipexole dihydrochloride monohydrate dose (mg)	Total daily dose of pramipexole dihydrochloride monohydrate (mg)
1st	3 × 0.088	0.264	3 × 0.125	0.375
2nd	3 × 0.18	0.54	3 × 0.25	0.75
3rd	3 × 0.35	1.1	3 × 0.5	1.50

If further dose escalation is necessary, the daily dose should be increased by 0.75 mg pramipexole dihydrochloride monohydrate (0.54 mg pramipexole) weekly up to the maximum dose of 4.5 mg pramipexole dihydrochloride monohydrate (3.3 mg pramipexole) per day. However, it should be noted that the incidence of somnolence increases with doses above 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole) per day (see section "Adverse Reactions").

Maintenance Therapy

The individual dose ranges from 0.375 mg pramipexole dihydrochloride monohydrate (0.264 mg pramipexole) to the maximum of 4.5 mg pramipexole dihydrochloride monohydrate (3.3 mg pramipexole) per day. During dose escalation in clinical trials, therapeutic efficacy was observed starting at a daily dose of 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole). Further dose adjustments should be made according to the clinical response and taking into account the occurrence of adverse reactions. In clinical trials, approximately 5% of patients were treated with doses lower than 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole). For patients with progressive Parkinson's disease, doses of pramipexole exceeding 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole) per day may be beneficial, especially if levodopa dose reduction is planned. It is recommended to reduce the dose of levodopa during dose escalation of pramipexole and also during maintenance therapy with this medicinal product, depending on the individual patient's response (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Discontinuation of Treatment

Sudden discontinuation of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome or dopamine agonist withdrawal syndrome. The dose of pramipexole should be gradually reduced by 0.75 mg pramipexole dihydrochloride monohydrate (0.54 mg pramipexole) per day until the daily dose is reduced to 0.75 mg pramipexole dihydrochloride monohydrate (0.54 mg pramipexole). After that, the dose should be reduced by 0.375 mg pramipexole dihydrochloride monohydrate (0.264 mg pramipexole) per day (see section "Special Warnings and Precautions for Use"). Dopamine agonist withdrawal syndrome may occur during gradual dose reduction. Therefore, temporary dose increases may be necessary before resuming dose reduction (see section "Special Warnings and Precautions for Use").

Dosing in Patients with Renal Impairment

The elimination of pramipexole depends on renal function. The following dosing regimen is recommended for initial therapy:

Patients with creatinine clearance above 50 mL/min do not require dose reduction or adjustment of dosing frequency;
Patients with creatinine clearance of 20–50 mL/min should start initial daily therapy in two divided doses, beginning with 0.125 mg pramipexole dihydrochloride monohydrate (0.088 mg pramipexole) twice daily (0.25 mg/day pramipexole dihydrochloride monohydrate / 0.176 mg pramipexole/day). The maximum daily dose should not exceed 2.25 mg pramipexole dihydrochloride monohydrate (1.57 mg pramipexole);
Patients with creatinine clearance below 20 mL/min should take the daily dose as a single dose, starting with 0.125 mg/day pramipexole dihydrochloride monohydrate (0.088 mg pramipexole/day). The maximum daily dose of pramipexole should not exceed 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole);
In case of worsening renal function during maintenance therapy, the daily dose of pramipexole 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 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 adjustment is probably not required in patients with hepatic impairment, since approximately 90% of the absorbed active substance is excreted by the kidneys. However, 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 pramipexole dihydrochloride monohydrate (0.088 mg pramipexole) 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 pramipexole dihydrochloride monohydrate (0.54 mg pramipexole) per day (see Table 2). The lowest effective dose should be used (see section "Special Warnings and Precautions for Use", subsection "Augmentation of Restless Legs Syndrome").

Table 2

Titration schedule for increasing pramipexole dose
Titration stage	Evening daily dose of pramipexole (mg)	Evening daily dose of pramipexole dihydrochloride monohydrate (mg)
1	0.088	0.125
2*	0.18	0.25
3*	0.35	0.50
4*	0.54	0.75

* 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, dose titration should be restarted as described above.

Discontinuation of treatment

Since the daily dose for the treatment of restless legs syndrome does not exceed 0.75 mg of pramipexole dihydrochloride monohydrate (0.54 mg of pramipexole), pramipexole can be discontinued without tapering the dose. In a 26-week placebo-controlled clinical trial, recurrence of restless legs syndrome symptoms (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 similar across all doses.

Dosing in patients with renal impairment

Elimination of pramipexole from the body depends on renal function. Dose reduction 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 active substance 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 prescribing pramipexole to 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 insufficient safety and efficacy data and an unfavorable benefit-risk ratio for this indication.

Overdose

There is no clinical experience with significant overdose. Reactions related to the pharmacodynamic profile of a dopamine agonist are expected, including nausea, vomiting, hyperkinesia, hallucinations, anxiety, and arterial hypotension.

There is no established antidote for dopamine agonist overdose. In the presence of signs of central nervous system stimulation, administration of a neuroleptic agent may be indicated. Management of overdose may require general supportive measures, including gastric lavage, intravenous fluid administration, activated charcoal, and electrocardiogram monitoring.

Side effects

An analysis of pooled placebo-controlled trials involving a total of 1,923 patients treated with pramipexole and 1,354 patients treated with placebo showed that adverse reactions occurred frequently in both groups. At least one adverse reaction was reported in 63% of patients receiving pramipexole and in 52% of patients receiving placebo.

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

Adverse reactions are listed by system organ class and frequency of occurrence (number of patients expected to experience the reaction), categorized 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), and frequency not known (cannot be estimated from available data).

Parkinson’s disease

Adverse reactions most commonly reported (≥ 5%) in patients with Parkinson’s disease (more frequently with pramipexole than with placebo) were: nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache, and fatigue. The incidence of somnolence increases with doses exceeding 1.5 mg of pramipexole dihydrochloride monohydrate per day (see section "Dosage and administration"). The most common adverse reaction when used in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of treatment, especially if pramipexole titration is too rapid.

Infections and infestations

Uncommon: pneumonia.

Endocrine system disorders

Uncommon: disturbance of antidiuretic hormone secretion^1.

Psychiatric disorders

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

Uncommon: pathological gambling, pathological shopping behavior, anxiety, hypersexuality, delusions, libido disorders, paranoia, delirium, binge eating^1, hyperphagia^1.

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

Uncommon: heart failure^1.

Vascular disorders

Common: hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea, hiccup.

Gastrointestinal disorders

Very common: nausea.

Common: constipation, vomiting.

Skin and subcutaneous tissue disorders

Uncommon: hypersensitivity, pruritus, rash.

Reproductive system and breast disorders

Rare: spontaneous penile erection.

General disorders and administration site conditions

Common: fatigue, peripheral edema.

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

Investigations

Common: weight loss, including decreased appetite.

Uncommon: weight gain.

^1 This adverse reaction was observed during the post-marketing period. With 95% confidence, the frequency category was determined as uncommon, but may be lower. The exact frequency cannot be established, as the adverse reaction was not observed during 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 commonly reported adverse reactions (≥ 5%) were nausea, headache, dizziness, and fatigue. Nausea and fatigue occurred more frequently in women (20.8% and 10.5%, respectively) than in men (6.7% and 7.3%, respectively).

Infections and infestations

Uncommon: pneumonia^1.

Endocrine system disorders

Uncommon: disturbance of antidiuretic hormone secretion^1.

Psychiatric disorders

Common: insomnia, sleep disorders.

Uncommon: anxiety, confusion, hallucinations, libido disorders, delusions^1, hyperphagia^1, paranoia^1, mania^1, delirium^1, symptoms of impulse control disorders and compulsive behavior^1 (such as pathological gambling, pathological shopping, hypersexuality, binge eating).

Nervous system disorders

Very common: augmentation of restless legs syndrome.

Common: headache, dizziness, somnolence.

Uncommon: sudden sleep attacks, syncope, dyskinesia, amnesia^1, hyperkinesia^1.

Eye disorders

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

Cardiac disorders

Uncommon: heart failure^1.

Vascular disorders

Uncommon: hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea, hiccup.

Gastrointestinal disorders

Very common: nausea.

Common: constipation, vomiting.

Skin and subcutaneous tissue disorders

Uncommon: hypersensitivity, pruritus, rash.

Reproductive system and breast disorders

Rare: spontaneous penile erection.

General disorders

Common: fatigue.

Uncommon: peripheral edema.

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

Investigations

Uncommon: weight loss, including decreased appetite, weight gain.

^1 This adverse reaction was observed during the post-marketing period. With 95% confidence, the frequency category was determined as uncommon, but may be lower. The exact frequency cannot be established, as the adverse reaction was not observed during clinical trials involving 1,395 restless legs syndrome patients treated with pramipexole.

Description of selected adverse reactions

Somnolence. Pramipexole is frequently associated with somnolence and occasionally with excessive daytime sleepiness and sudden sleep attacks (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 lead to 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 and case-control study involving 3,090 Parkinson’s disease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic therapy exhibited symptoms of impulse control disorders over the previous six months. Manifestations included pathological gambling, compulsive shopping, binge eating, and compulsive sexual behavior (hypersexuality). Potential independent risk factors for impulse control disorders included dopaminergic therapy and higher doses of dopaminergic therapy, younger age (≤ 65 years), unmarried status, and a family history of pathological gambling as reported by the patient.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

10 tablets per blister, 3 or 6 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Kusum Healthcare Pvt Ltd /
Kusum Healthcare Pvt Ltd.

Manufacturer’s address and location of operations.

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India /
Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.