Xolepar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT XOLEPRAL (XOLEPRAL)

Composition:

Active substance: pramipexole;

One tablet contains pramipexole dihydrochloride monohydrate 0.25 mg, corresponding to pramipexole 0.175 mg, or 1 mg, corresponding to pramipexole 0.7 mg;

Excipients: b-cyclodextrin (E 459), maize starch, povidone, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

for the 0.7 mg dosage: round tablets, white to almost white, with bevelled edges, with a dividing line on both sides.

for the 0.175 mg dosage: oval tablets, white to almost white, with bevelled edges, with a dividing line on both sides.

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 subtype and has a predominant affinity for D3 receptors; it is characterized by full intrinsic activity.

Pramipexole alleviates Parkinsonian motor disturbances by stimulating striatal dopamine receptors. 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 concentrations are achieved between 1 and 3 hours. The rate of absorption is not reduced by concomitant food intake, but overall absorption is decreased. Pramipexole exhibits linear kinetics and relatively minor fluctuations in plasma levels across different patients, regardless of the pharmaceutical formulation. 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 detected 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 patients to 12 hours in elderly patients.

Clinical characteristics.

Indications.

Treatment of signs and symptoms of idiopathic Parkinson's disease in adults, as monotherapy (without levodopa) or in combination with levodopa throughout the course of the disease until late stages, when the effect of levodopa decreases or becomes unstable and fluctuations in therapeutic response occur (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 very weakly bound to plasma proteins (< 20%) in humans 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 pramipexole clearance. When co-administering these medicinal products with KSOLEPRAL, consider the possibility of reducing the pramipexole dose.

Combination with levodopa.

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

Due to the potential additive effect, caution should be exercised if the patient is using other sedative medicinal products or alcohol in combination with pramipexole (see sections "Special precautions for use", "Ability to influence reaction rate when driving or operating machinery", and "Adverse reactions").

Antipsychotic medicinal products.

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

Special precautions for use

Administration of the drug to patients with Parkinson's disease and impaired renal function in reduced doses is recommended according to the section "Dosage and administration".

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

Motor fluctuations (dyskinesia). During combination therapy with levodopa in progressive Parkinson’s disease, dyskinesia may develop during the initial titration phase of the drug. In such cases, the dose of levodopa should be reduced.

Sudden onset of sleepiness and somnolence. The use of pramipexole has been associated with somnolence and episodes of sudden onset of sleepiness, particularly in patients with Parkinson’s disease. Rare cases of sudden onset of sleepiness during daily activities have been reported, in some instances without awareness or warning signs. Therefore, patients should be advised to exercise caution when driving or operating machinery during treatment with XOLEPRA. Patients experiencing somnolence and/or episodes of sudden onset of sleepiness should refrain from driving and operating machinery. Additionally, dose reduction or discontinuation of treatment should be considered. Caution should also be exercised if patients are taking other sedative medicinal products or consuming alcohol during pramipexole therapy (see sections "Interactions with other medicinal products and other forms of interactions", "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 XOLEPRA, may be associated with 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.

Severe cardiovascular disorders. The drug should be administered with particular caution in patients with severe cardiovascular disorders. Blood pressure monitoring is recommended, especially at the beginning of treatment, due to 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 when the potential benefit outweighs the risks. Concomitant use of antipsychotic medicinal products and pramipexole should be avoided.

Neuroleptic malignant syndrome. Symptoms resembling neuroleptic malignant syndrome have been observed after abrupt withdrawal of dopaminergic therapy.

Ophthalmological examination.

Regular ophthalmological examination is recommended in case of visual disturbances.

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

Use during pregnancy or breastfeeding.

The effects on pregnancy and lactation in humans have not been studied. The drug may be used during pregnancy only if the potential 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 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.

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

Patients with somnolence and/or episodes of sudden onset of sleepiness should refrain from driving and engaging in potentially hazardous activities where decreased alertness may increase the risk of serious injury or death during treatment with the drug.

Method of administration and dosage.

All dosage information refers to pramipexole in the form of pramipexole dihydrochloride.

Parkinson's disease.

The daily dose should be divided into 3 equal doses taken throughout the day.

Initial treatment.

As shown below, the dose of the drug should be gradually increased every 5–7 days, starting at 0.375 mg per day. In patients who do not experience intolerable adverse effects, the dose should be titrated upward until the maximum therapeutic effect is achieved.

Table 1

Dose escalation schedule of the drug

Week	Dose (mg)	Total daily dose (mg)
1st	3 x 0.125	0.375
2nd	3 x 0.25	0.75
3rd	3 x 0.5	1.5

If further dose escalation is necessary, the daily dose should be increased by 0.75 mg weekly up to the maximum dose of 4.5 mg per day. However, it should be noted that 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 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 based on clinical response and the occurrence of adverse reactions. In clinical trials, approximately 5% of patients received doses below 1.5 mg. In advanced Parkinson’s disease, a dose above 1.5 mg per day may be beneficial for patients in 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 XADAGO and during maintenance therapy, depending on individual patient response (see section "Interaction with other medicinal products and other forms of interaction").

Discontinuation of treatment

Sudden withdrawal of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome. The dose of pramipexole should be tapered according to the following scheme: reduce by 0.75 mg per day down to a daily dose of 0.75 mg. After that, the dose should be further reduced to 0.375 mg per day (see section "Special precautions").

Dosing in patients with renal impairment

Excretion 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 in dosing frequency.

For patients with creatinine clearance of 20–50 mL/min, the initial daily dose should be administered in two divided doses, starting at 0.125 mg twice daily (0.25 mg/day). The maximum daily dose of pramipexole should not exceed 2.25 mg.

For patients with creatinine clearance below 20 mL/min, the daily dose should be administered as a single dose, starting at 0.125 mg/day. The maximum daily dose of pramipexole should not exceed 1.5 mg.

In case of worsening renal function during maintenance therapy, the daily dose should be reduced by the same percentage as the decline in creatinine clearance. For example, if creatinine clearance decreases by 30%, the daily dose should be reduced by 30%. The daily dose may be administered in two divided doses if creatinine clearance is between 20 and 50 mL/min, or as a single dose if creatinine clearance is below 20 mL/min.

Dosing in patients with hepatic impairment

Dose reduction is not considered necessary in patients with hepatic impairment, as nearly 90% of the absorbed drug is excreted renally. The potential impact of hepatic impairment on the pharmacokinetics of the drug 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 (as shown in Table 2 below).

Table 2

Dose escalation schedule of the medicinal product

Titration step	Single evening daily dose (mg)
1	0.125
2*	0.25
3*	0.50
4*	0.75

* If necessary

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. In clinical trials, rebound of restless legs syndrome symptoms (worsening of symptoms compared to baseline) was observed in 10% of patients after abrupt discontinuation of pramipexole. This effect was observed across all doses.

Dosing in patients with renal impairment.

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

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, since approximately 90% of the absorbed drug is excreted by the kidneys.

Route of administration.

Tablets should be taken orally with water, with or without food.

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 data on safety and efficacy.

Tourette’s syndrome. The drug should not be used in children 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 fluid administration, activated charcoal, and electrocardiographic monitoring.

Adverse Reactions

Adverse reactions are listed by system organ class and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Parkinson’s disease.

In patients with Parkinson’s disease, the most frequently reported adverse reactions (≥ 5%) during treatment with pramipexole compared to placebo were nausea, dyskinesia, arterial 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. Arterial hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too rapidly.

Infections and infestations:

Uncommon – pneumonia.

Psychiatric disorders:

Common – sleep disorders, symptoms of impulse control disorders and compulsive behaviors, confusion, hallucinations, insomnia;

Uncommon – binge eating*, pathological shopping, mania, hyperphagia*, hypersexuality, libido disorders, paranoia, pathological gambling, restlessness.

Nervous system disorders:

Very common – dizziness, dyskinesia, somnolence;

Common – headache;

Uncommon – amnesia, hyperkinesia, sudden onset of sleep, syncope.

Eye disorders:

Common – visual disturbances, including diplopia, blurred vision, and decreased visual acuity.

Cardiovascular disorders:

Common – arterial hypotension;

Uncommon – heart failure*.

Respiratory disorders:

Uncommon – dyspnea, hiccup.

Gastrointestinal disorders:

Very common – nausea;

Common – constipation, vomiting.

Skin and subcutaneous tissue disorders:

Uncommon – hypersensitivity, pruritus, rash.

General disorders:

Common – fatigue, peripheral edema.

Investigations:

Common – weight decreased, including decreased appetite;

Uncommon – weight increased.

* This adverse reaction was observed during the post-marketing period.

Restless legs syndrome.

In patients with restless legs syndrome, the most frequently reported adverse reactions (≥ 5%) during treatment with pramipexole were nausea, headache, dizziness, and fatigue. Nausea and fatigue were more frequently observed in women.

Infections and infestations:

Uncommon – pneumonia*.

Psychiatric disorders:

Common – sleep disorders, insomnia;

Uncommon – symptoms of impulse control disorders and compulsive behaviors such as binge eating, pathological shopping, hypersexuality, and pathological gambling*; confusion, mania, hallucinations, hyperphagia*, libido disorders, paranoia*, restlessness.

Nervous system disorders:

Common – dizziness, headache, somnolence;

Uncommon – amnesia*, dyskinesia, hyperkinesia*, sudden onset of sleep, syncope.

Eye disorders:

Common – visual disturbances, including diplopia, blurred vision, and decreased visual acuity.

Cardiovascular disorders:

Uncommon – heart failure*, arterial hypotension.

Respiratory disorders:

Uncommon – dyspnea, hiccup.

Gastrointestinal disorders:

Very common – nausea;

Common – constipation, vomiting.

Skin and subcutaneous tissue disorders:

Uncommon – hypersensitivity, pruritus, rash.

General disorders:

Common – fatigue;

Uncommon – peripheral edema.

Investigations:

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

* This adverse reaction was observed during the post-marketing period.

Somnolence. Treatment with pramipexole is commonly associated with somnolence and uncommonly with excessive daytime sleepiness and episodes of sudden onset of sleep (see section “Special precautions”).

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

Impulse control disorders. During treatment with dopamine agonists, including XELOPREP, symptoms of impulse control disorders may occur, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating.

Heart failure. Heart failure has been observed in patients treated with pramipexole during clinical studies and in the post-marketing period.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 25°C.

Packaging. 10 tablets in a blister. 3 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer. Alembic Pharmaceuticals Limited.

Manufacturer’s address and place of business.

Panelav, PV Tajpura, District Kheda, Panchmahal, Gujarat – 389 350, India.