Pramipex® xr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRAPIPEx XR (PRAMipex XR)

Composition:

Active substance: pramipexole;

Each prolonged-release tablet contains

0.75 mg of pramipexole dihydrochloride monohydrate, equivalent to 0.52 mg of pramipexole, or 1.5 mg of pramipexole dihydrochloride monohydrate, equivalent to 1.05 mg of pramipexole;

Excipients: hypromellose, calcium hydrogen phosphate, magnesium stearate, colloidal silicon dioxide.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties:

tablets 0.75 mg: white or almost white cylindrical or biconvex tablets with the imprint "052" on one side;

tablets 1.5 mg: white or almost white cylindrical or biconvex tablets with the imprint "105" on one side.

Pharmacotherapeutic group.

Antiparkinson agents. Dopaminergic agents. Dopamine agonists. ATC code N04B C05.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action

Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily of dopamine receptors; among these, it has a preferential affinity for D3 receptors, as well as full intrinsic activity at these receptors.

Pramipexole alleviates the motor impairments characteristic of Parkinson's disease by stimulating dopamine receptors in the striatum. Studies in animals have demonstrated that pramipexole inhibits the synthesis, release, and reuptake of dopamine.

Pharmacodynamic Effects

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

Pharmacokinetics.

Absorption

Pramipexole is completely absorbed after oral administration. Absolute bioavailability exceeds 90%. In a phase I study, in which pramipexole immediate-release tablets and prolonged-release tablets were evaluated under fasting conditions, the minimum and maximum plasma concentrations (Cmin, Cmax), as well as exposure (area under the concentration-time curve [AUC]) of a single daily dose of prolonged-release pramipexole tablets taken once daily, were equivalent to those of immediate-release tablets taken three times daily.

Taking prolonged-release tablets once daily results in smaller fluctuations in pramipexole plasma concentrations over 24 hours compared to taking immediate-release tablets three times daily. Cmax in plasma is reached approximately 6 hours after administration of the prolonged-release tablets of Pramipex® XR once daily. Steady-state exposure is achieved within up to 5 days of continuous use.

Concomitant intake with food generally does not affect the bioavailability of pramipexole. Consumption of a high-fat meal increased Cmax by approximately 24% after a single dose and by approximately 20% after multiple doses, and prolonged the time to reach maximum concentration by approximately 2 hours in healthy volunteers. Concomitant food intake did not affect the total exposure to the drug (AUC). The increase in Cmax is not considered clinically significant. In trials establishing the efficacy and safety of the drug, patients were informed that they could take the investigational medicinal product independently of food intake.

Body weight does not affect AUC; however, an effect of body weight on volume of distribution, and consequently on Cmax, has been observed. A decrease in patient body weight by 30 kg leads to a 45% increase in Cmax. However, in studies conducted in patients with Parkinson's disease, no clinically significant effect of body weight on the therapeutic effect and tolerability of Pramipex® XR prolonged-release tablets was observed. Pramipexole exhibits linear kinetics and low inter-patient variability in plasma drug levels.

Distribution

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

Metabolism

In humans, pramipexole is metabolized only to a negligible extent.

Elimination

Renal excretion of unchanged pramipexole is the main route of elimination. Approximately 90% of a 14C-labeled dose is excreted by the kidneys, while less than 2% was found in feces. Total clearance of pramipexole is approximately 500 mL/min, and renal clearance is approximately 400 mL/min. The elimination half-life (t½) ranges from 8 hours in younger patients to 12 hours in elderly patients.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to the active substance or to any other component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Plasma protein binding.

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

Inhibitors/competitors of the renal active excretion pathway.

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

Combination with levodopa.

When Pramipex® XR is administered concomitantly with levodopa, it is recommended to reduce the levodopa dose, while the doses of other antiparkinsonian medicinal products should remain unchanged during dose escalation of the drug.

Due to possible additive effects, patients should be advised to exercise caution when taking other sedative medicinal products or alcohol in combination with pramipexole (see sections "Special precautions for use," "Ability to influence reaction rate when driving or operating machinery," and "Adverse reactions").

Antipsychotic medicinal products.

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

Special precautions for use.

When prescribing Pramipex® XR to patients with Parkinson’s disease and renal insufficiency, dose reduction is recommended (see section "Dosage and administration").

Hallucinations

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

Disorders of impulse control

Patients should be closely monitored for the development of impulse control disorders. Patients and caregivers should be aware that symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating, may occur during treatment with dopamine agonists, including Pramipex® XR. If such symptoms develop, consideration should be given to reducing the dose or gradually discontinuing the drug.

Dyskinesia

In progressive Parkinson’s disease, dyskinesia may occur during initial titration of Pramipex® XR when used in combination with levodopa therapy. In such cases, the dose of levodopa should be reduced.

Dystonia

Axial dystonia, including antecollis, camptocormia, pleurothotonus (Pisa syndrome), has been reported occasionally in patients with Parkinson’s disease after initiation or gradual dose increase of pramipexole. Although dystonia may be a symptom of Parkinson’s disease, symptoms in these patients improved after dose reduction or discontinuation of pramipexole.

If dystonia occurs, a reassessment of the treatment regimen with dopaminergic agents and adjustment of pramipexole dosage should be considered.

Sudden sleep attacks or somnolence

Pramipexole has been associated with somnolence and sudden sleep attacks, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daytime activities, sometimes without prior warning signs or awareness, has been reported infrequently. Patients should be informed about this risk. They should be advised to exercise caution when driving or operating machinery while being treated with Pramipex® XR. Patients who experience somnolence and/or sudden sleep attacks should refrain from driving or operating machinery. Furthermore, dose reduction or discontinuation of treatment should be considered. Due to possible additive effects, caution is recommended when patients are taking other sedative medicinal products or alcohol in combination with pramipexole (see sections "Interaction with other medicinal products and other forms of interaction", "Effect on ability to drive and use machines", and "Undesirable effects").

Mania and delirium

Patients should be closely monitored for the development of mania and delirium. Patients and caregivers should be aware that mania and delirium may occur in patients receiving pramipexole therapy. If such symptoms develop, consideration should be given to reducing the dose or gradually discontinuing the drug.

Patients with psychiatric disorders

Patients with psychiatric disorders should be treated with dopamine agonists only if the potential benefit outweighs the risks. Concomitant use of antipsychotic medicinal products and pramipexole should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Ophthalmological monitoring

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

Dopamine agonist withdrawal syndrome

Dopamine agonist withdrawal syndrome has been reported with the use of dopamine agonists, including pramipexole (see section "Undesirable effects"). When discontinuing treatment in patients with Parkinson’s disease, the dose of pramipexole should be gradually reduced according to the "Dosage and administration" section. 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 dopamine agonist withdrawal syndrome. Symptoms 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 dopamine agonists, and should be monitored regularly. In cases of severe and/or persistent withdrawal symptoms, temporary re-initiation of pramipexole at the lowest effective dose may be considered (see section "Undesirable effects").

Severe cardiovascular disorders

Caution should be exercised in patients with severe cardiovascular disorders. Blood pressure should be monitored, especially at the beginning of treatment, due to the general risk of orthostatic hypotension associated with dopaminergic therapy.

Malignant neuroleptic syndrome

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

Residues in feces

Some patients have reported the presence of residues in feces resembling intact prolonged-release tablets of Pramipex® XR. In such cases, physicians should reassess the patient’s response to therapy.

Use during pregnancy or breastfeeding.

Pregnancy. The effects of pramipexole on pregnancy or lactation in humans have not been studied. Pramipexole did not show teratogenic effects in rats and rabbits, but exerted embryotoxic effects in rats at doses that were toxic to pregnant females. Pramipex® XR should not be used during pregnancy unless clearly necessary, i.e., when the potential benefit to the pregnant woman outweighs the potential risk to the fetus.

Lactation. Since pramipexole treatment suppresses prolactin secretion in humans, inhibition of lactation is expected. Passage of pramipexole into breast milk has not been studied. In rats, the concentration of radiolabeled active substance in milk was higher than in plasma. Due to the lack of adequate human data, Pramipex® XR should not be used during breastfeeding. If use of this medicinal product cannot be avoided, breastfeeding should be discontinued.

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

Effect on ability to drive and use machines.

Pramipex® XR may have a marked influence on the ability to drive or operate machinery, as hallucinations or somnolence may occur.

Patients treated with Pramipex® XR who experience somnolence and/or sudden sleep attacks should be advised to refrain from driving or engaging in activities where reduced alertness may place themselves or others at risk of serious injury, including fatal outcomes (e.g., operating machinery), until recurrent episodes and somnolence cease (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Undesirable effects").

Dosage and Administration

Prolonged-release Pramipex® XR tablets are a pharmaceutical form of pramipexole intended for oral administration once daily.

Parkinson's disease

Initial therapy.

Dosage should be gradually increased, starting at 0.375 mg pramipexole dihydrochloride monohydrate per day, with subsequent increases every 5–7 days. If patients do not experience intolerable adverse reactions, dose titration should be performed to achieve the maximum therapeutic effect.

Table 1

* Administer tablets in the appropriate dosage.

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

However, it should be noted that the likelihood of somnolence increases when doses exceeding 1.5 mg pramipexole dihydrochloride monohydrate (1.05 mg pramipexole) per day are administered (see section "Adverse Reactions").

Patients already taking pramipexole tablets may be switched to prolonged-release tablets of Pramipex® XR. This transition is best done at night, maintaining the same daily dose. After switching to prolonged-release tablets of Pramipex® XR, the dose may be adjusted according to the patient's response to treatment (see section "Adverse Reactions").

Maintenance therapy.

The individual dose of pramipexole dihydrochloride monohydrate should range from 0.375 mg (0.26 mg pramipexole) to a maximum of 4.5 mg pramipexole dihydrochloride monohydrate (3.15 mg pramipexole) per day. In clinical trials, efficacy was observed starting from a daily dose of 1.5 mg pramipexole dihydrochloride monohydrate (1.05 mg pramipexole). Further dose adjustments should be made based on clinical response and occurrence of adverse reactions. During clinical studies, approximately 5% of patients were treated with doses not exceeding 1.5 mg pramipexole dihydrochloride monohydrate. In progressive Parkinson’s disease, doses exceeding 1.5 mg pramipexole dihydrochloride monohydrate (1.05 mg pramipexole) per day may be beneficial, especially if a reduction in levodopa dosage is planned. It is recommended to reduce the levodopa dose when increasing the dose of Pramipex® XR tablets, as well as 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 tablet of Pramipex® XR should be taken within 12 hours after 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 at the usual time the following day.

Discontinuation of treatment.

Sudden discontinuation 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 0.75 mg pramipexole dihydrochloride monohydrate (0.52 mg pramipexole) per day until the daily dose reaches 0.75 mg pramipexole dihydrochloride monohydrate (0.52 mg pramipexole). After this, the dose should be further reduced to 0.375 mg pramipexole dihydrochloride monohydrate (0.26 mg pramipexole) per day (see section "Special Warnings and Precautions for Use"). Dopamine agonist withdrawal syndrome may occur during dose reduction. Therefore, temporary dose increases may be necessary before resuming dose tapering (see section "Special Warnings and Precautions for Use").

Renal impairment.

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

• Patients with creatinine clearance above 50 ml/min do not require dose adjustment or changes in dosing frequency;
• For patients with creatinine clearance between 30 and 50 ml/min, treatment should be initiated with a dose of 0.375 mg pramipexole dihydrochloride monohydrate (0.26 mg pramipexole) 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 should be increased at weekly intervals by 0.375 mg pramipexole dihydrochloride monohydrate (0.26 mg pramipexole) up to the maximum dose of 2.25 mg pramipexole dihydrochloride monohydrate (1.57 mg pramipexole) per day;
• Treatment with prolonged-release tablets of Pramipex® XR is not recommended in patients with creatinine clearance below 30 ml/min, as there are no data available for this patient group. Consideration should be given to using the medicinal products PRAmiPEX or PRAmiPEXOL ASINO tablets instead.

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

Hepatic impairment.

Dose reduction is not considered necessary in patients with hepatic impairment, as nearly 90% of the absorbed drug is excreted via the kidneys. However, the potential impact of hepatic insufficiency 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 drug administration. Pramipex® XR should be taken daily at approximately the same time.

Children.

Safety and efficacy of pramipexole in children (under 18 years of age) have not been established. There is no rationale for using pramipexole in children with Parkinson’s disease.

Overdose.

There is limited clinical experience with significant overdose. Expected adverse reactions may include those related to the pharmacodynamic profile of a dopamine agonist, such as nausea, vomiting, hyperkinesia, hallucinations, anxiety, and arterial hypotension. There is no established antidote for dopamine agonist overdose. In cases of central nervous system stimulation, administration of a neuroleptic agent may be indicated.

Management of overdose may require general supportive measures, including gastric lavage, intravenous fluid administration, activated charcoal, and ECG monitoring.

Adverse Reactions

An analysis of pooled placebo-controlled trials involving a total of 1778 Parkinson’s disease patients treated with pramipexole and 1297 patients treated with placebo showed that adverse reactions were frequently reported in both groups. At least one adverse reaction was reported in 67% of patients receiving pramipexole and in 54% of patients receiving placebo. Most adverse reactions usually occur at the beginning of therapy, and a significant proportion of them resolve even if treatment is continued.

Adverse reactions are listed below by system organ class and categorized by frequency of occurrence (number of patients in whom the reaction is expected to occur), using the following categories: 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 available data).

The most frequently reported adverse reactions (≥ 5%) in Parkinson’s disease patients treated with pramipexole (and more common 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 pramipexole dihydrochloride monohydrate per day (see section "Dosage and Administration"). Dyskinesia was the most common adverse reaction occurring during concomitant use of levodopa. Hypotension may occur at the beginning of treatment, particularly if titration of pramipexole is performed too rapidly.

1 There are data indicating that this adverse reaction was observed during the post-marketing period. With 95 % confidence, its frequency was determined as "uncommon," but it may be lower. Determining the exact frequency is not possible, since according to available data, the adverse reaction was not observed during clinical trials among 2762 patients with Parkinson's disease who were treated with pramipexole.

Description of individual adverse reactions

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

Libido disorders. Administration of pramipexole may uncommonly be associated with libido disorders (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 warnings and precautions for use").

There are data from a cross-sectional retrospective screening and a case-control study involving 3090 patients with Parkinson's disease, in which 13.6 % of all patients receiving dopaminergic or non-dopaminergic therapy had symptoms of impulse control disorders during the past six months. Observed manifestations included pathological gambling, uncontrollable urge to shop, excessive need for food, and compulsive sexual behavior (hypersexuality). Possible independent risk factors for the development of impulse control disorders included dopaminergic therapy and higher doses during dopaminergic therapy, younger age (≤ 65 years), unmarried status, and family history of pathological gambling as reported by the patient.

Dopamine agonist withdrawal syndrome. Non-motor adverse reactions may occur when the dose is reduced or treatment with dopamine agonists (including pramipexole) is discontinued. Symptoms include apathy, anxiety, depression, fatigue, sweating, and pain (see section "Special warnings and precautions for use").

Heart failure. It is known that heart failure has been observed in patients taking pramipexole during clinical trials and in the post-marketing period. In a pharmacoepidemiological 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 adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or 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.

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

Keep out of reach of children.

Packaging.

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

Prescription category. Prescription only.

Manufacturer.

Laboratorios Normon, S.A.

Manufacturer's address and location of its business operations.

Ronda de Valdecarrizo, 6, Tres Cantos, 28760 Madrid, Spain