Oprimea

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

Composition:

Active substance: pramipexole;

One prolonged-release tablet contains 0.26 mg pramipexole as 0.375 mg pramipexole dihydrochloride monohydrate, or 0.52 mg pramipexole as 0.75 mg pramipexole dihydrochloride monohydrate, or 1.05 mg pramipexole as 1.5 mg pramipexole dihydrochloride monohydrate, or 1.57 mg pramipexole as 2.25 mg pramipexole dihydrochloride monohydrate, or 2.1 mg pramipexole as 3 mg pramipexole dihydrochloride monohydrate, or 2.62 mg pramipexole as 3.75 mg pramipexole dihydrochloride monohydrate, or 3.15 mg pramipexole as 4.5 mg pramipexole dihydrochloride monohydrate;

Excipients: hypromellose, type 2208; maize starch; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Prolonged-release tablets.

Main physico-chemical properties:

tablets of 0.26 mg: white or almost white, possibly with specks, round, slightly biconvex, with bevelled edges and engraved "P1" on one side;

tablets of 0.52 mg: white or almost white, possibly with specks, round, slightly biconvex, with bevelled edges and engraved "P2" on one side;

tablets of 1.05 mg: white or almost white, possibly with specks, round, slightly biconvex, with bevelled edges and engraved "P3" on one side;

tablets of 1.57 mg: white or almost white, possibly with specks, round, slightly biconvex, with bevelled edges and engraved "P12" on one side;

tablets of 2.1 mg: white or almost white, possibly with specks, round, slightly biconvex, with bevelled edges and engraved "P4" on one side;

tablets of 2.62 mg: white or almost white, possibly with specks, round, slightly biconvex, with bevelled edges and engraved "P13" on one side and "262" on the other;

tablets of 3.15 mg: white or almost white, possibly with specks, round, slightly biconvex, with bevelled edges and engraved "P5" on one side and "315" on the other.

Pharmacotherapeutic group. Anti-parkinson drugs. Dopaminergic agents. Dopamine agonists. ATC code N04BC05.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Pramipexole is a dopamine agonist that binds with high selectivity and specificity to dopamine receptors of the D2 subfamily, among which it has a preferential 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.

Children.

The European Medicines Agency (EMEA) has waived the obligation to submit the results of studies involving pediatric patients with Parkinson's disease who were treated with pramipexole.

Pharmacokinetics.

Absorption.

Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability exceeds 90%.

In Phase I studies, when pramipexole was administered fasting, minimum and maximum plasma concentrations (Cmin, Cmax) and exposure (AUC) were equivalent for once-daily extended-release tablets and the same dose of immediate-release tablets administered three times daily.

Administration of pramipexole as extended-release tablets results in less frequent fluctuations in plasma concentration over 24 hours compared to administration of immediate-release tablets three times daily.

Maximum plasma concentration was observed approximately 6 hours after administration of once-daily pramipexole extended-release tablets. A steady-state level is achieved no earlier than day 5 of continuous treatment.

Concomitant food intake generally does not affect pramipexole bioavailability. Consumption of a high-fat meal increases peak concentration (Cmax) by approximately 24% after a single dose and by approximately 20% after multiple dosing, and delays time to maximum concentration by approximately 2 hours in healthy volunteers. Total exposure (AUC) is unaffected by concomitant food intake. The increase in Cmax is not considered clinically significant. In Phase III safety and efficacy studies of pramipexole extended-release tablets, patients took the investigational product regardless of meals.

While body weight does not affect AUC, it has been found to influence volume of distribution and, consequently, peak concentration Cmax. A reduction in body weight by 30 kg leads to a 45% increase in Cmax. However, in Phase III studies, the effect of body weight on the therapeutic effect and tolerability of pramipexole extended-release tablets was not considered clinically significant.

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 in brain tissue were observed in rats (approximately 8 times higher than in plasma).

Metabolism.

Pramipexole is metabolized only to a negligible extent in humans.

Excretion.

Renal excretion of unchanged pramipexole is the main elimination pathway. Approximately 90% of a radiolabeled carbon 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. Elimination half-life (T½) ranges from 8 hours in younger patients to 12 hours in elderly patients.

Clinical characteristics.

Indications.

Treatment of symptoms of idiopathic Parkinson's disease in adults as monotherapy (without levodopa) or in combination with levodopa, i.e., throughout the disease course up to the late 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 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 negligible 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

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, zidovudin, cisplatin, quinine, and procainamide, may interact with pramipexole and lead to reduced pramipexole clearance. When these medicinal products are used concomitantly with pramipexole, dose reduction of pramipexole should be considered.

Combinations with levodopa

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

Due to a possible additive effect, caution should be exercised in patients taking other sedative medicinal products or consuming alcohol during pramipexole therapy (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"), for example, when antagonistic effects may be expected.

Special precautions for use.

When prescribing pramipexole for the treatment of Parkinson’s disease to patients with renal impairment, the dose should be reduced 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 developing hallucinations (mainly visual).

Dyskinesia.

During the terminal stage of Parkinson’s disease, dyskinesia may occur when pramipexole is combined with levodopa, particularly at the beginning of dose titration. In such cases, the dose of pramipexole should be reduced.

Dystonia.

Axial dystonia, including antecollis, camptocormia, and pleurothotonus (Pisa syndrome), has been reported occasionally in patients with Parkinson’s disease following initiation or gradual dose increase 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, reassessment of the treatment regimen with dopaminergic agents and adjustment of pramipexole dosage should be considered.

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 daily 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 treatment with Opremea®. Patients experiencing somnolence and/or episodes of sudden sleep onset should refrain from driving and operating machinery. Additionally, dose reduction or discontinuation of therapy should be considered. Due to possible additive effects, caution should be exercised when concomitantly using other sedative medications or alcohol with Opremea® (see sections "Interaction with other medicinal products and other forms of interaction", "Effect on ability to drive and use machines", and "Adverse reactions").

Impulse control disorders.

Patients should be closely monitored for the development of impulse control disorders. Patients and caregivers should be informed that treatment with dopamine agonists, including Opremea®, 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 receiving pramipexole therapy. If such symptoms occur, dose reduction or discontinuation of the drug should be considered.

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 medications and pramipexole should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Ophthalmological examination.

Regular ophthalmological monitoring is recommended, or whenever visual abnormalities occur.

Severe cardiovascular diseases.

Caution should be exercised in patients with serious 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.

Neuroleptic malignant syndrome.

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

Dopamine agonist withdrawal syndrome (DAWS).

DAWS has been observed with 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 and/or high cumulative doses of dopamine agonists may be at higher risk of developing DAWS. Withdrawal syndrome may include apathy, anxiety, depression, fatigue, sweating, pain, and lack of response to levodopa. Patients should be informed about possible withdrawal symptoms before dose reduction or discontinuation of pramipexole. Close monitoring is required during dose reduction and discontinuation of pramipexole. In cases of severe and/or persistent dopamine agonist withdrawal syndrome symptoms, temporary reinitiation of pramipexole at the lowest effective dose may be considered.

Residues in feces.

Some patients have reported the presence of residues in feces resembling intact prolonged-release tablets of Opremea®. If such a report is received from a patient, the physician should reassess the patient’s response to therapy.

Use during pregnancy or breastfeeding.

Pregnancy

The effects of pramipexole on pregnancy and lactation in women have not been studied. Pramipexole was not teratogenic in animals but was embryotoxic at doses toxic to adult animals. Pramipexole should be used during pregnancy only if the potential 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. Due to the lack of adequate human data, Opremea® should not be used during breastfeeding. If use of this medicinal product 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 fertility in females, as expected for dopamine agonists. However, these studies did not indicate a direct or indirect harmful effect on male fertility.

Effect on ability to drive and use machines.

Opremea® may substantially affect the ability to drive a car and operate machinery. Hallucinations or somnolence may occur.

Patients taking Opremea® who experience episodes of somnolence and/or sudden sleep onset should be advised to refrain from driving and participating in activities where reduced alertness may pose a risk of serious injury or death to themselves or others until such adverse reactions are resolved (see sections "Interaction with other medicinal products and other forms of interaction", "Special precautions for use", and "Adverse reactions").

Dosage and Administration.

Oprimea®, prolonged-release tablets, is a pharmaceutical form of pramipexole intended for oral administration once daily.

Initial Therapy.

Doses should be gradually increased, starting at 0.26 mg (0.375 mg as the salt) per day, followed by increments every 5–7 days. If patients do not experience intolerable adverse reactions, dose titration should be performed to achieve the maximum therapeutic effect.

Dose escalation schedule for OpriMEA® prolonged-release tablets
Week	Daily dose (mg)	Daily dose (mg, as salt)
1	0.26	0.375
2	0.52	0.75
3	1.05	1.5

If necessary, the daily dose should be increased by 0.52 mg (0.75 mg as the salt) at weekly intervals up to a maximum dose of 3.15 mg pramipexole (4.5 mg as the salt) per day.

It should be noted that the likelihood of somnolence increases with doses exceeding 1.05 mg pramipexole (1.5 mg as the salt) per day (see section "Adverse Reactions"). Patients already taking Opremea® tablets may be switched to prolonged-release Opremea® tablets. This switch is best done at night, maintaining the same daily dose. After switching to prolonged-release Opremea®, the dose may be adjusted according to the patient's response to treatment (see subsection "Pharmacodynamics").

Maintenance treatment.

The individual dose of pramipexole should range from 0.26 mg (0.375 mg as the salt) to a maximum of 3.15 mg pramipexole (4.5 mg as the salt) per day. In clinical trials, efficacy was observed starting from a daily dose of 1.05 mg (1.5 mg as the salt) pramipexole. Further dose adjustments should be made based on clinical response and adverse reactions. During clinical trials, approximately 5% of patients received doses not exceeding 1.05 mg (1.5 mg as the salt) pramipexole. In progressive Parkinson's disease, doses exceeding 1.05 mg (1.5 mg as the salt) per day may be effective, particularly when planning therapy aimed at reducing the dose of levodopa. It is recommended to reduce the dose of levodopa during dose escalation of Opremea® and also during maintenance therapy with this drug, depending on individual patient responses (see section "Interaction with other medicinal products and other forms of interaction").

Missed dose.

If a dose is missed, the prolonged-release Opremea® tablet should be taken within 12 hours of the usual dosing time. If more than 12 hours have passed since the missed dose, the tablet should not be taken; instead, the next dose should be taken the following day at the usual time.

Discontinuation of treatment.

Sudden withdrawal of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome or dopamine agonist withdrawal syndrome. Therefore, the dose of pramipexole should be gradually reduced by 0.52 mg pramipexole (0.75 mg as the salt) per day until the daily dose reaches 0.52 mg pramipexole (0.75 mg as the salt). After that, the dose should be further reduced to 0.26 mg (0.375 mg as the salt) per day (see section "Special 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 precautions for use").

Dosing in patients with renal impairment.

Elimination of pramipexole depends on renal function. The following dosing regimen is recommended:

• Patients with creatinine clearance above 50 ml/min do not require dose reduction or adjustment of dosing frequency;
• Patients with creatinine clearance between 30 and 50 ml/min should start treatment with a dose of 0.26 mg (0.375 mg as the salt) every other day. Caution should be exercised before increasing the daily dose after one week of treatment, and a careful assessment of treatment response and tolerability should be performed. If necessary, the dose may be increased at weekly intervals by 0.26 mg (0.375 mg as the salt) up to a maximum dose of 1.57 mg (2.25 mg as the salt) per day;
• The use of prolonged-release Opremea® tablets is not recommended in patients with creatinine clearance below 30 ml/min due to lack of data in this patient population. Consideration should be given to using Opremea® tablets.

If renal function deteriorates during maintenance therapy, the above recommendations should be followed.

Dosing in patients with hepatic impairment.

Dose adjustment is likely not necessary in patients with hepatic impairment, as approximately 90% of the absorbed active substance is excreted by the kidneys. However, the potential impact of hepatic impairment on the pharmacokinetics of the drug has not been studied.

Method of administration.

Tablets should be swallowed whole with water, without chewing, dividing, or crushing. Food intake does not affect administration of the drug. Prolonged-release Opremea® tablets should be taken every day at approximately the same time.

Children.

The safety and efficacy of pramipexole in children (under 18 years of age) have not been established; therefore, the drug should not be used in this patient population.

Overdose.

Symptoms

Experience with significant overdose is limited. Expected adverse effects 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 overdose with a dopamine agonist. 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 fluid administration, activated charcoal, and electrocardiogram monitoring.

Adverse Reactions

Most adverse reactions to the medicinal product were mild to moderate in severity, usually began early in the course of therapy, and tended to resolve even with continued treatment.

Adverse reactions are listed below by system organ class, with frequencies categorized according to the following classification: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); and not known (cannot be estimated from the available data).

The most frequently reported adverse reactions in patients with Parkinson’s disease (≥ 5%), occurring more often 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"). Dyskinesia was the most commonly occurring adverse reaction when pramipexole was administered concomitantly with levodopa. Hypotension may occur at the beginning of treatment, particularly if titration of pramipexole is conducted too rapidly.

System organ class/frequency	Adverse reactions
Infections and infestations
Uncommon	Pneumonia
Endocrine system disorders
Uncommon	Disorders of antidiuretic hormone secretion1
Psychiatric disorders
Common	Abnormal dreams, behavioural symptoms of impulse control disorder and compulsion, confusion, hallucinations, insomnia
Uncommon	Overeating1, uncontrollable urge to shop, delirium, hyperphagia1, hypersexuality, libido disorders, paranoia, gambling disorder, 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 disturbance, including diplopia, blurred vision and decreased visual acuity
Cardiac disorders
Common	Arterial hypotension
Uncommon	Heart failure1
Respiratory system disorders
Uncommon	Dyspnoea, hiccup
Gastrointestinal disorders
Very common	Nausea
Common	Constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon	Hypersensitivity, pruritus, rash
Reproductive system disorders
Rare	Spontaneous erection
General disorders
Common	Malaise, peripheral oedema
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 in the post-marketing period. In 95%, the frequency is not higher than "uncommon". Determination of the exact frequency is not possible, since the adverse reaction was not observed during clinical trials involving 2762 patients with Parkinson’s disease treated with pramipexole.

Somnolence.

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

Libido disorders.

Administration of pramipexole may uncommonly be associated with disorders of libido (increased or decreased).

Impulse control disorders.

When treating 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 for use").

A study was conducted involving patients with Parkinson’s disease, in which 13.6% of all patients receiving dopaminergic or non-dopaminergic therapy experienced symptoms of impulse control disorders during the past 6 months. Observed manifestations included pathological gambling, irresistible urge to shop, excessive appetite, and compulsive sexual behavior (hypersexuality). Possible independent risk factors for developing impulse control disorders included dopaminergic therapy and higher doses of dopaminergic therapy, younger age (≤ 65 years), unmarried status, and family history of pathological gambling as reported by the patient.

Dopamine agonist withdrawal syndrome.

Reduction in dose or discontinuation of dopamine agonists (including pramipexole) may result in non-motor adverse reactions. Symptoms include apathy, anxiety, depression, fatigue, sweating, and pain (see section "Special precautions for use").

Heart failure.

Heart failure has been observed in patients treated with pramipexole during clinical trials and the post-marketing period. In a pharmacoe pidemiological study, 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 of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of this medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report any 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.

No special temperature storage conditions are required for this medicinal product.

Store in the original packaging to protect from moisture.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 3 or 9 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

TAD Pharma GmbH.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

Heinz-Lohmann-Strasse 5, 27472 Cuxhaven, Germany.