Oprimea

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

Composition:

Active substance: pramipexole;

1 tablet contains 0.088 mg pramipexole as 0.125 mg pramipexole dihydrochloride monohydrate, or 0.18 mg pramipexole as 0.25 mg pramipexole dihydrochloride monohydrate, or 0.35 mg pramipexole as 0.5 mg pramipexole dihydrochloride monohydrate, or 0.7 mg pramipexole as 1 mg pramipexole dihydrochloride monohydrate, or 1.1 mg pramipexole as 1.5 mg pramipexole dihydrochloride monohydrate;

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets of 0.088 mg: round white tablets with bevelled edges, marked with "R6" on one side;

tablets of 0.18 mg: oval white tablets with bevelled edges, with a line on both sides and marked with "P7" on both halves of one side of the tablet;

tablets of 0.35 mg: oval white tablets with bevelled edges, with a line on both sides and marked with "P8" on both halves of one side of the tablet;

tablets of 0.7 mg: round white tablets with bevelled edges, with a line on both sides and marked with "P9" on both halves of one side of the tablet;

tablets of 1.1 mg: round white tablets with bevelled edges, with a line on both sides.

Tablets of 0.18 mg, 0.35 mg, 0.7 mg, and 1.1 mg can be divided.

Pharmacotherapeutic group. Dopaminergic agents. Dopamine agonists. ATC code N04BC05.

Pharmacological properties.

Pharmacodynamics.

Pramipexole is a dopamine agonist that binds with high selectivity and specificity to dopamine receptors of the D2 subfamily, among which it has a predominant affinity for D3 receptors and is characterized by full intrinsic activity. Pramipexole partially alleviates Parkinsonian motor disturbances by stimulating dopamine receptors in the neostriatum (corpus striatum). Animal studies have shown that pramipexole inhibits the synthesis, release, and turnover of dopamine.

Pramipexole protects dopaminergic neurons from degeneration in response to ischemia or methamphetamine-induced neurotoxicity. The mechanism of action of pramipexole in the treatment of restless legs syndrome is unknown. Neuropharmacological data suggest the involvement of the primary dopaminergic system. Studies using positron emission tomography (PET) indicate that minor dysfunction of the striatal presynaptic dopaminergic system may influence the pathogenesis of restless legs syndrome. In vitro studies have shown that pramipexole protects neurons from the neurotoxic effects of levodopa. Dose-dependent reduction in prolactin levels has been observed.

Pharmacokinetics.

Absorption

Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability exceeds 90%, and maximum plasma concentration is reached within 1–3 hours. Concomitant administration with food does not reduce the extent of pramipexole absorption but slows the rate of absorption. Pramipexole exhibits linear kinetics and minimal fluctuation 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 of the drug in brain tissue have been observed in rats (approximately 8 times higher than in plasma).

Metabolism

Pramipexole is only minimally metabolized in the human body.

Excretion

Renal excretion of unchanged pramipexole is the main route of elimination. Approximately 90% of a radiolabeled carbon dose is excreted by the kidneys, while less than 2% is found in feces. Total clearance of pramipexole is about 500 mL/min, and renal clearance is about 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, either alone (without levodopa) or in combination with levodopa, throughout the course of the disease, up to the late stage when the effect of levodopa diminishes or becomes unstable and fluctuations in therapeutic response occur (end-of-dose fluctuations or "on-off" type fluctuations).

Symptomatic treatment in adults of moderate to severe idiopathic restless legs syndrome at doses up to 0.54 mg pramipexole (0.75 mg pramipexole dihydrochloride monohydrate) (see section "Dosage and administration").

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Plasma protein binding

Pramipexole is bound to plasma proteins to a very low extent (< 20 %) and undergoes low biotransformation. Therefore, interactions with other medicinal products affecting plasma protein binding or elimination via biotransformation are unlikely. Since anticholinergic agents are mainly eliminated via biotransformation, the potential for interaction is limited, although interaction with anticholinergic agents has not been studied. There is no pharmacokinetic interaction with selegiline and levodopa.

Inhibitors/competitors of active renal elimination pathways

Cimetidine reduces the renal clearance of pramipexole by approximately 34 %, probably by inhibiting the cationic renal tubular secretion transport system. Medicinal products that inhibit active renal tubular secretion or are themselves eliminated via this pathway, such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine, and procainamide, may interact with pramipexole and lead to reduced clearance of pramipexole. When these medicinal products are used concomitantly with pramipexole, dose reduction of pramipexole should be considered.

Combinations with levodopa

During dose escalation of pramipexole 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 possible additive effect, caution should be exercised in patients using other sedative medicinal products or consuming alcohol in combination with pramipexole (see sections "Special precautions for use", "Effects on ability to drive and use machines", and "Undesirable effects").

Antipsychotic medicinal products

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

Special precautions for use.

In patients with renal impairment, the dose of pramipexole should be reduced when used for the treatment of Parkinson's disease, according to the recommendations provided in the section "Dosage and administration".

Hallucinations

Hallucinations are a known adverse effect during treatment with dopamine agonists and levodopa. Patients should be informed about the possibility of hallucinations (mainly visual).

Dyskinesia

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

Dystonia

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

If dystonia occurs, a reassessment of the treatment regimen with dopaminergic agents should be considered, and the pramipexole dose adjusted accordingly.

Sudden onset of sleep and somnolence

Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Rare cases of sudden sleep onset during everyday activities, sometimes without awareness or warning signs, have been reported. Patients should be informed about this risk and advised to exercise caution when driving or operating machinery during pramipexole treatment. Patients who experience somnolence and/or sudden episodes of sleep should refrain from driving and operating machinery. Additionally, dose reduction or discontinuation of therapy may be considered. Due to possible additive effects, caution should be advised when using other sedative medications or alcohol in combination with pramipexole (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 pramipexole, may lead to symptoms of impulse control disorders, such as pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating.

If such symptoms develop, dose reduction or discontinuation of the drug should be considered.

Mania and delirium

Patients should be closely monitored for the development of mania and delirium. Patients and caregivers should be aware that mania and delirium may occur in patients taking pramipexole. If such symptoms occur, dose reduction or discontinuation of the drug should be considered.

Patients with psychiatric disorders

Patients with psychiatric 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 examination

Regular ophthalmological monitoring is recommended at periodic intervals or if visual disturbances occur.

Severe cardiovascular disorders

Caution should be exercised in patients with serious 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.

Neuroleptic malignant syndrome

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

Dopamine agonist withdrawal syndrome (DAWS)

DAWS has been observed with the use of dopamine agonists, including pramipexole (see section "Adverse reactions"). When discontinuing treatment in patients with Parkinson's disease, the dose of pramipexole 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 increased risk of developing DAWS. 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 withdrawal symptoms. 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

Literature reports indicate that treatment of restless legs syndrome with dopaminergic agents may lead to augmentation. Augmentation (worsening of symptoms) manifests as earlier onset of symptoms in the evening (or even during daytime), increased symptom severity, and spread to other limbs. The risk of symptom augmentation may increase with higher doses. Patients should be informed about the possibility of worsening symptoms before starting treatment and advised to consult their physician if symptoms worsen. If augmentation is suspected, dose adjustment to the lowest effective dose or discontinuation of pramipexole should be considered (see sections "Dosage and administration" and "Adverse reactions").

Use during pregnancy or breastfeeding.

Pregnancy

The effect on pregnancy and lactation in women has not been studied. Pramipexole was not teratogenic in rats and rabbits, but was embryotoxic in rats at doses that were toxic to the mother. Pramipexole should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

Lactation

Since pramipexole therapy suppresses prolactin secretion in women, a reduction in lactation is possible. Excretion of pramipexole into human breast milk has not been studied. Pramipexole is not recommended for use in breastfeeding women. If pramipexole use 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.

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

Patients experiencing somnolence and/or sudden episodes of sleep should refrain from driving and engaging in potentially hazardous activities where reduced attention could increase the risk of serious injury or death during pramipexole treatment (see sections "Interaction with other medicinal products and other forms of interaction", "Special precautions for use", and "Adverse reactions").

Dosage and Administration

The medication is taken orally with or without food. Tablets should be swallowed with water.

All dosage information refers to pramipexole as pramipexole dihydrochloride monohydrate.

Parkinson's Disease

The daily dose should be divided into 3 equal doses.

Initial Treatment

The dose should be gradually increased from an initial dose of 0.375 mg per day every 5–7 days. If the patient does not experience intolerable adverse effects, the dose should be titrated upward until the maximum therapeutic effect is achieved.

During further titration, the daily dose should be increased by 0.75 mg at weekly intervals up to the maximum dose of 4.5 mg per day. However, it should be noted that the level of somnolence increases with doses exceeding 1.5 mg per day (see section "Adverse reactions").

Maintenance therapy

Individual doses of pramipexole should range from 0.375 mg to a maximum of 4.5 mg per day. During dose escalation in pivotal studies, efficacy was observed starting at 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 treatment at doses below 1.5 mg. In progressive Parkinson's disease, pramipexole doses exceeding 1.5 mg per day may be beneficial for patients requiring a reduction in levodopa dose. Reduction of levodopa dose is recommended both during pramipexole dose escalation 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 discontinuation of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome or dopamine agonist withdrawal syndrome (DAWS). The dose of pramipexole should be reduced according to a schedule of 0.75 mg decrements down to a daily dose of 0.75 mg. Thereafter, the dose should be reduced by 0.375 mg per day (see section "Special precautions for use"). DAWS may occur during gradual dose reduction. Therefore, temporary dose increases may be necessary before resuming dose reduction (see section "Special precautions for use").

Dosing in patients with renal impairment

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 adjustment or change in dosing frequency.

Patients with creatinin clearance between 20 and 50 ml/min should start treatment at a dose of 0.25 mg per day, administered as two doses of 0.125 mg. The maximum daily dose should not exceed 2.25 mg.

Patients with creatinine clearance below 20 ml/min should receive the daily dose of pramipexole as a single dose, starting at 0.125 mg daily. The maximum daily dose should not exceed 1.5 mg.

If renal function declines during pramipexole therapy, the daily dose should be reduced proportionally to the decline in creatinine clearance; i.e., if creatinine clearance decreases by 30%, the daily dose of pramipexole should also be reduced by 30%. The daily dose should be administered in two divided doses if creatinine clearance is between 20 and 50 ml/min, and as a single dose if creatinine clearance is below 20 ml/min.

Dosing in patients with hepatic impairment

Dose adjustment in patients with hepatic impairment is probably not necessary, since 90% of the drug is eliminated via the kidneys. The potential impact of impaired liver function on the pharmacokinetics of Oprimaea has not been studied.

Restless legs syndrome

The recommended starting dose of the medicinal product 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 a maximum of 0.75 mg per day (as shown in the table below). The lowest effective dose should be used (see section "Special precautions for use", subsection "Augmentation of restless legs syndrome").

The patient's response to treatment should be evaluated after 3 months of therapy. The need for continuing treatment should be reassessed. If treatment is interrupted for more than a few days, it 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, Opremia can be discontinued without tapering the dose. In a 26-week placebo-controlled clinical trial, relapse of restless legs syndrome symptoms (worsening of symptom severity compared to baseline) was observed in 10% of patients (14 out of 135 patients) after abrupt discontinuation of pramipexole. This effect was observed across all doses.

Dosing in patients with renal impairment

Elimination of pramipexole depends on renal function and is closely related to creatinine clearance. Dose adjustment is not required in patients with creatinine clearance above 20 mL/min.

The use of pramipexole in patients undergoing hemodialysis and in patients with severe renal impairment has not been studied.

Dosing in patients with hepatic impairment

Dose adjustment in patients with hepatic impairment is not required, as approximately 90% of the drug is excreted by the kidneys.

Children.

Parkinson's disease. The 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 safety and efficacy data.

Tourette's syndrome. Pramipexole should not be used in children (under 18 years of age) with Tourette's syndrome due to an unfavorable benefit-risk ratio for this condition.

Overdose.

Symptoms

Experience with significant overdose is limited. Expected adverse events are those related to the pharmacodynamic profile of dopamine agonists, including nausea, vomiting, hyperkinesia, hallucinations, agitation, and arterial hypotension.

Treatment

There is no established antidote for dopamine agonist overdose. In case of signs of central nervous system agitation, neuroleptics may be administered. Management of overdose may require general supportive measures, including gastric lavage, intravenous fluids, activated charcoal, and electrocardiogram monitoring.

Adverse reactions

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

Adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Parkinson’s disease

In patients with Parkinson’s disease treated with pramipexole, the most common adverse reactions (≥ 5%) compared to placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache, and fatigue. The incidence of somnolence increased when doses higher than 1.5 mg per day were administered (see section "Dosage and administration"). The most common adverse reaction when administered in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too rapidly.

1 This adverse reaction was observed during the post-marketing period. In 95 %, the frequency is not higher than uncommon, but may be lower. Determination of the exact frequency is not possible, since the adverse reaction was not observed during clinical trials involving 2762 Parkinson's disease patients treated with pramipexole.

Restless legs syndrome.

In patients with restless legs syndrome treated with pramipexole, the most common adverse reactions (≥ 5 %) were nausea, headache, dizziness, and increased fatigue. Nausea and increased fatigue were observed more frequently in women (20.8 % and 10.5 %, respectively) compared to men (6.7 % and 7.3 %, respectively).

2 This adverse reaction was observed during the post-marketing period. In 95%, the frequency is not higher than uncommon, but may be lower. Determination of the exact frequency is not possible, since the adverse reaction was not observed during clinical trials in 1395 patients with restless legs syndrome treated with pramipexole.

Description of selected adverse reactions

Somnolence. The use of pramipexole is often associated with somnolence and uncommonly with excessive daytime sleepiness and episodes of sudden sleep attacks (see section "Special precautions").

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

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

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

Heart failure. Heart failure has been observed in patients treated with pramipexole during clinical trials and the post-marketing period. In a pharmacoe pidemiological study, the use of pramipexole 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, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Keep in the original packaging to protect from light.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister; 2, 3, 6, 9 or 10 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of its operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.