Medopeksol

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

Composition:

Active substance: pramipexole;

1 tablet contains pramipexole dihydrochloride monohydrate 0.125 mg, equivalent to pramipexole 0.088 mg; or pramipexole dihydrochloride monohydrate 0.25 mg, equivalent to pramipexole 0.18 mg; or pramipexole dihydrochloride monohydrate 1 mg, equivalent to pramipexole 0.7 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

0.088 mg tablets: white, round, flat tablets with a diameter of approximately 6.5 mm;

0.18 mg tablets: white, oblong, biconvex tablets with notches on both sides. Size approximately 8 x 4 mm;

0.7 mg tablets: white, round, flat tablets with a score line on one side. Diameter approximately 9 mm.

Pharmacotherapeutic group. Antiparkinson drugs. Dopamine agonists.

ATC code N04B C05.

Pharmacological properties.

Pharmacodynamics.

Pramipexole is a dopamine agonist with high selectivity and specificity for dopamine receptors of the D2 subfamily and has a preferential affinity for D3 receptors; it is characterized by full intrinsic activity.

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

The exact mechanism of action of pramipexole in the treatment of restless legs syndrome is unknown. Although the pathophysiology of restless legs syndrome is generally not well understood, neuropharmacological data suggest involvement of the central dopaminergic system.

Pharmacokinetics.

Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability exceeds 90%. Maximum plasma concentration is reached between 1 and 3 hours. The rate of absorption is not reduced by concomitant food intake, although overall absorption is not decreased. Pramipexole exhibits linear kinetics and, regardless of the pharmaceutical form, relatively minor fluctuations in plasma levels among different patients.

In humans, protein binding of pramipexole is very low (<20%), and the volume of distribution is high (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 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: 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 (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 interactions.

Plasma protein binding

Pramipexole is bound to plasma proteins to a negligible extent (<20%) and undergoes low biotransformation. Therefore, interactions with other drugs affecting plasma protein binding or elimination via biotransformation are unlikely. Since anticholinergic agents are primarily eliminated via hepatic metabolism, 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 renal clearance of pramipexole by approximately 34%, likely by inhibiting the cationic tubular secretion transport system in the kidneys. Medicinal products that inhibit active renal tubular secretion or are themselves eliminated via this pathway—such as cimetidine, amantadine, mexiletine, zidovudin, cisplatin, quinine, and procainamide—may interact with pramipexole and lead to reduced pramipexole clearance. When these medicinal products are used concomitantly with Medopexol, dose reduction of the latter should be considered.

Combination with levodopa

During dose escalation of Medopexol in patients with Parkinson’s disease, it is recommended to reduce the dose of levodopa, while doses of other antiparkinsonian agents should remain unchanged.

Due to the potential additive effects, caution should be exercised when patients are using other sedative medicinal products or consuming 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.

Medopeksole is recommended to be administered in reduced doses to patients with Parkinson's disease and impaired renal function, as specified in the section "Dosage and administration".

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

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

Dystonia. Axial dystonia, including antecollis, camptocormia, and pleurothotonus (Pisa syndrome), has occasionally occurred in patients with Parkinson's disease after initial dosing or gradual dose escalation of pramipexole. Although dystonia can be a symptom of Parkinson's disease, symptoms of dystonia 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 adjustment of pramipexole dosage should be made.

Sudden sleep attacks and somnolence. The use of pramipexole is associated with somnolence and episodes of sudden onset of sleep, particularly in patients with Parkinson's disease. Rare cases of sudden sleep episodes 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 Medopeksole. Patients experiencing somnolence and/or sudden sleep episodes should refrain from driving and operating machinery. Additionally, consideration should be given to reducing the dose or shortening the duration of treatment. Caution should also be exercised if patients are taking other sedative medications or consuming alcohol in combination with pramipexole 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. Patients should be closely monitored for the development of impulse control disorders. Patients and caregivers should be aware that treatment with dopamine agonists, including Medopeksole, may lead to symptoms of impulse control disorders such as pathological gambling, increased libido, hypersexuality, compulsive spending, binge eating, and compulsive eating.

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

Severe cardiovascular disorders. The drug should be prescribed 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 with pramipexole should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Dopamine agonist withdrawal syndrome. Dopamine agonist withdrawal syndrome has been observed with the use of dopamine agonists, including pramipexole (see section "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. Withdrawal 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 case of pronounced and/or persistent symptoms of dopamine agonist withdrawal syndrome, 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 manifests as 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 dose escalation. Before initiating treatment, patients should be informed about the possibility of augmentation and advised to consult a physician if they experience symptoms of augmentation. If augmentation is suspected, consideration should be given to adjusting the dose to the lowest effective dose or discontinuing pramipexole (see sections "Dosage and administration" and "Adverse reactions").

Renal impairment. The drug should be administered 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. Medopeksole may be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

No studies on the effect on human fertility have been conducted.

Ability to influence reaction speed when driving or operating machinery.

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

Patients experiencing somnolence and/or sudden sleep episodes while taking Medopeksole should refrain from driving and from engaging in potentially dangerous activities where decreased alertness could increase the risk of serious injury or fatal outcomes.

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 taken in 3 divided doses of equal amounts.

Initial treatment

The dose should be increased gradually, starting from 0.375 mg daily, every 5–7 days as shown below. If patients do not experience intolerable adverse effects, the dose should be titrated upward until the maximum therapeutic effect is achieved.

If further dose escalation is necessary, the daily dose should be increased by 0.75 mg per week up to the maximum dose of 4.5 mg per day. However, it should be noted that the frequency of somnolence increases with doses above 1.5 mg per day.

Maintenance therapy

The individual dose ranges from 0.375 mg to a maximum of 4.5 mg per day. Therapeutic effect has been observed starting from a daily dose of 1.5 mg during dose escalation. Further dose adjustments should be made according to clinical response and adverse reactions. In progressive Parkinson's disease, doses above 1.5 mg per day may be appropriate for patients in whom a reduction of levodopa dose is planned during combination therapy with levodopa. It is recommended to reduce the dose of levodopa when increasing the dose of Medopexol and during maintenance therapy, depending on the patient's response (see section "Interaction with other medicinal products and other forms of interaction").

Discontinuation of treatment

Sudden interruption of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome. The dose of pramipexole should be reduced 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 "Dosage recommendations"). Dopamine agonist withdrawal syndrome may occur during gradual dose reduction; therefore, temporary dose escalation may be necessary before resuming dose reduction (see section "Special precautions").

Dosing in patients with renal impairment

Excretion of pramipexole depends on renal function. The 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.

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

If renal function deteriorates during maintenance therapy, the daily dose of Medopexol should be reduced by the same percentage as the decrease in creatinine clearance. For example, if creatinine clearance decreases by 30%, the daily dose of Medopexol should be reduced by 30%. The daily dose may be administered in two divided doses if creatinine clearance is between 20–50 ml/min, or as a single dose if creatinine clearance is below 20 ml/min.

Dosing in patients with hepatic impairment

Dose reduction is not considered necessary for patients with hepatic impairment, 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 of Medopexol 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 the table below). The lowest effective dose should be used (see section "Special precautions". Augmentation of restless legs syndrome).

The patient's response to treatment should be evaluated after 3 months, and the necessity of continuing therapy should be reviewed. If treatment is interrupted for more than a few days, therapy should be restarted at the dose specified above.

Discontinuation of treatment

Since the daily dose for the treatment of restless legs syndrome does not exceed 0.75 mg, Medopexol may be discontinued without tapering the dose. In a 26-week placebo-controlled clinical trial, symptom rebound of restless legs syndrome (worsening of symptom severity compared to baseline) was observed in 10% of patients (14 out of 135 patients) following abrupt discontinuation of pramipexole. This effect was observed across all doses.

Dosing in patients with renal impairment

Elimination of Medopexol 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 approximately 90% of the absorbed drug is excreted by the kidneys.

Method of administration

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

Children

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

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

Tourette syndrome. Medopexol should not be used in children or adolescents with Tourette syndrome due to an unfavorable benefit-risk ratio of such treatment.

Overdose

Clinical experience with significant overdose is lacking. Expected adverse effects related to the pharmacodynamic profile of a dopamine agonist include nausea, vomiting, hyperkinesia, hallucinations, agitation, and arterial hypotension. There is no established antidote for dopamine agonist overdose. In cases of central nervous system agitation, neuroleptics may be administered. Management of patients in overdose may require general supportive measures, including gastric lavage, intravenous fluid administration, activated charcoal, and cardiac monitoring via electrocardiography.

Adverse Reactions

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

The frequency of adverse reactions is classified as follows: very common (≥1/10);
common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <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, the adverse reactions (≥5%) were nausea, dyskinesia, arterial hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache, and fatigue. The incidence of somnolence increases when doses above 1.5 mg per day are used (see section "Dosage and Administration"). The most common adverse reaction when administered in combination with levodopa is dyskinesia. Arterial hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too rapidly.

Infections and infestations: uncommon – pneumonia.

Endocrine system disorders: uncommon – disturbance of antidiuretic hormone secretion¹.

Psychiatric disorders: common – sleep disorders, symptoms of impulse control disorder and compulsive behavior, confusion, hallucinations, insomnia; uncommon – binge eating¹, pathological shopping, delusions, hyperphagia¹, hypersexuality, libido disorders, paranoia, pathological gambling, anxiety, delirium; rare – mania.

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.

Cardiac disorders: common – arterial 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 – hypersensitivity, pruritus, rash.

Reproductive system and breast disorders: rare – spontaneous erection.

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

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

¹ This adverse reaction was observed in the post-marketing period. In 95%, the frequency is no more than uncommon, but may be lower. The exact frequency cannot be determined, 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 increased 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 – sleep disorders, insomnia; uncommon – symptoms of impulse control disorder and compulsive behavior (binge eating, pathological shopping, hypersexuality, and pathological gambling); confusion, mania², hallucinations, hyperphagia², libido disorders, delusions², paranoia², anxiety, delirium².

Nervous system disorders: very common – augmentation of restless legs syndrome; common – dizziness, headache, somnolence; uncommon – amnesia², dyskinesia, hyperkinesia², sudden onset of sleep, syncope.

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

Cardiovascular disorders: uncommon – heart failure², 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 erection.

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

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

² This adverse reaction was observed in the post-marketing period. In 95%, the frequency is no more than uncommon, but may be lower. The exact frequency cannot be determined, 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 frequently associated with somnolence, sometimes with excessive daytime sleepiness and episodes of sudden sleep attacks (see section "Special Warnings and Precautions for Use").

Libido disorders. Pramipexole use may uncommonly cause libido disorders (increased or decreased).

Impulse control disorders. During treatment with dopamine agonists, including Medopexol, symptoms of impulse control disorders may occur, including pathological gambling, increased libido, hypersexuality, compulsive spending, binge eating, and compulsive eating (see section "Special Warnings and Precautions for Use").

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, excessive sweating, and pain (see section "Special Warnings and Precautions for Use").

Heart failure. Heart failure has been observed in patients taking pramipexole. 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).

Reporting of 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 any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging in a place inaccessible to children.

Packaging. 10 tablets per blister. 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Specifar SA/Specifar SA.

Manufacturer’s address. 1, 28 Octovriou str., Agia Varvara, 12351, Greece.

Marketing authorization holder. Medochemie LTD.

Address of marketing authorization holder. 1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus.