Pramipex XR extended-release tablets 075 mg No. 30

Instructions for Pramipex XR extended-release tablets 075 mg No. 30

Composition

active ingredient: pramipexole;

1 extended-release tablet contains

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

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

Dosage form

Extended-release tablets.

Main physicochemical properties:

0.75 mg tablets: white or almost white cylindrical or biconvex tablets marked "052" on one side;

1.5 mg tablets: white or almost white, cylindrical or biconvex tablets marked "105" on one side.

Pharmacotherapeutic group

Dopaminergic agents. Dopamine agonists. ATX code N04B C05.

Pharmacological properties

Pharmacodynamics.

Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily of dopamine receptors; among these, it has the predominant similarity to D3 receptors, as well as full inherent activity.

Pramipexole alleviates motor dysfunction characteristic of Parkinson's disease by stimulating dopamine receptors in the striatum.

In studies conducted in healthy volunteers, a dose-dependent decrease in prolactin levels was observed.

Pharmacokinetics.

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

Taking the extended-release tablets of the drug once a day causes smaller fluctuations in the concentration of pramipexole in the blood plasma over 24 hours compared to taking pramipexole immediate-release tablets 3 times a day. Cmax in the blood plasma is reached approximately 6 hours after taking the extended-release tablets of the drug Pramipex® XR once a day. A stable effect is achieved after a maximum of 5 days of continuous use.

Co-administration with food generally does not affect the bioavailability of pramipexole. High-fat meals increased Cmax by approximately 24% after single administration and by approximately 20% after multiple administration, and delayed the time to peak plasma concentration in healthy volunteers by approximately 2 hours. Co-administration with food had no effect on the overall exposure (AUC). The increase in Cmax is not considered clinically significant.

Body weight does not affect AUC, but has been shown to affect the volume of distribution and therefore Cmax. A 30 kg increase in body weight results in a 45% increase in Cmax. However, in studies in patients with Parkinson's disease, no clinically significant effect of body weight on the therapeutic effect and tolerability of Pramipexole XR extended-release tablets was found. Pramipexole exhibits linear kinetics and little inter-patient variability in plasma levels. In humans, pramipexole is very poorly bound to plasma proteins (<20%) and has a large volume of distribution (400 L).

Pramipexole is only slightly metabolized in humans.

Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of the 14C-labeled dose is excreted renally, while less than 2% was recovered in the faeces. The total clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately 400 ml/min. The elimination half-life (t½) varies from 8 hours in young patients to 12 hours in elderly patients.

Indication

Treatment of the symptoms of idiopathic Parkinson's disease, both as monotherapy (without levodopa) and in combination with levodopa, throughout the course of the disease. Also for the treatment of late stages, when the effect of levodopa weakens or becomes unstable, and fluctuations in the therapeutic effect are observed (the phenomenon of "on-off").

Contraindication

Hypersensitivity to the components of the drug.

Interaction with other medicinal products and other types of interactions

Binding to blood plasma proteins.

The plasma protein binding of pramipexole is very low (< 20%), with little biotransformation observed in men. Therefore, interactions with other medicinal products that affect protein binding or elimination by biotransformation are unlikely. Since anticholinergics are eliminated primarily by biotransformation, the potential for interactions is limited, although interactions with anticholinergics have not been studied. There is no pharmacokinetic interaction with selegiline or levodopa.

Cimetidine reduced the renal clearance of pramipexole by approximately 34%, probably by inhibiting the cationic secretory transport system of the renal tubules. Therefore, drugs that are inhibitors of this metabolic pathway of active renal elimination or that are eliminated by this pathway, such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine and procainamide, may interact with pramipexole, resulting in a decrease in pramipexole clearance. A reduction in the pramipexole dose should be considered when these drugs are co-administered with Pramipexole XR.

Combination with levodopa.

If Pramipexole XR is taken concomitantly with levodopa, it is recommended to reduce the dose of levodopa and the dose of other drugs used in Parkinson's disease should be left unchanged when the dose of the drug is increased.

Due to possible additive effects, patients should be advised to exercise caution when taking other sedative medicines or alcohol in combination with pramipexole.

Antipsychotic medications.

Concomitant administration of antipsychotic medicinal products and pramipexole should be avoided as antagonistic effects may be expected.

Application features

When prescribing Pramipexole XR to patients with Parkinson's disease and renal insufficiency, a dose reduction is recommended (see section "Method of administration and dosage").

Hallucinations

Hallucinations are known to be a side effect of dopamine agonist and levodopa treatment. Patients should be informed that they may experience hallucinations (predominantly visual).

Dyskinesia

In advanced Parkinson's disease, dyskinesia may occur during the initial titration of Pramipexole XR in combination with levodopa therapy. In such cases, the levodopa dose should be reduced.

Dystonia

Axial dystonia including antecollis, camptocormia and pleurothotonus (Pisa syndrome) have occasionally been reported in patients with Parkinson's disease following initial or gradual dose increases of pramipexole. Although dystonia may be a symptom of Parkinson's disease, symptoms in these patients resolve after dose reduction or discontinuation of pramipexole.

If dystonia occurs, it is necessary to consider revising the treatment regimen with dopaminergic drugs and adjusting the dose of pramipexole.

Sudden onset of sleep or drowsiness

Pramipexole has been associated with somnolence and sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daytime activity, sometimes occurring without awareness or warning signs, has been reported rarely. Patients should be made aware of this. They should be advised to exercise caution when driving or operating machinery while taking Pramipexole XR. Patients who experience somnolence and/or sudden sleep onset should refrain from driving or operating machinery. In addition, a dose reduction or discontinuation of treatment should be considered. Due to possible additive effects, caution is recommended when patients take other sedative medicines or alcohol in combination with pramipexole (see sections “Interaction with other medicinal products and other types of interactions”, “Ability to influence the speed of reactions when driving vehicles or using other mechanisms” and “Adverse reactions”).

Impulse control disorders

Patients should be monitored closely for the development of impulse control disorders. Patients and caregivers should be made aware that symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating, and compulsive eating, may occur during treatment with dopamine agonists, including Pramipexole XR. If such symptoms develop, dose reduction/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 made aware that mania and delirium can occur in patients receiving pramipexole therapy. If such symptoms develop, dose reduction/discontinuation of the drug should be considered.

Patients with psychotic disorders

Patients with psychotic disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks. Concomitant use of antipsychotic medicinal products and pramipexole should be avoided.

Ophthalmological observation

Ophthalmological observation is recommended at regular intervals or when vision pathologies occur.

Dopamine agonist withdrawal syndrome has been reported with dopamine agonists, including pramipexole (see section 4.8). To discontinue treatment in patients with Parkinson's disease, the dose of pramipexole should be reduced as described in section 4.2. Limited data suggest that patients with impulse control disorders and patients 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 and pain and may be severe. Patients should be advised of these symptoms before tapering the dose of dopamine agonists and monitored regularly. In the event of severe and/or persistent withdrawal symptoms, pramipexole may be temporarily reintroduced at the lowest effective dose (see section 4.8).

Severe cardiovascular diseases

Caution should be exercised in severe cardiovascular disease. It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the general risk of orthostatic hypotension associated with dopaminergic therapy.

Neuroleptic malignant syndrome

Symptoms suggestive of neuroleptic malignant syndrome have been reported. In such cases, dopaminergic therapy was discontinued immediately.

Residues in feces

Some patients have reported the appearance of residues in the feces, which may resemble whole Pramipexole XR prolonged-release tablets. If such a report is received from a patient, the physician should review the patient's response to therapy.

Use during pregnancy or breastfeeding

Pregnancy: The effects on pregnancy or lactation have not been studied in humans. Pramipexole XR should not be used during pregnancy unless clearly necessary, i.e. when the potential benefit to the pregnant woman justifies the potential risk to the fetus.

Breastfeeding. Since treatment with pramipexole inhibits prolactin secretion in humans, inhibition of lactation is expected. The excretion of pramipexole into breast milk has not been studied. In the absence of relevant human data, Pramipexole® XR should not be used during breast-feeding. If use of this drug cannot be avoided, breast-feeding should be discontinued.

Fertility: No studies on the effects on human fertility have been conducted.

Ability to influence reaction speed when driving vehicles or other mechanisms

Pramipexole XR may significantly affect the ability to drive or use machines. Hallucinations or drowsiness may occur.

Patients treated with Pramipexole XR who experience somnolence and/or sudden sleep onset episodes during treatment should be advised to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machinery) until the recurrence and somnolence have resolved.

Method of administration and doses

Pramipexole® XR extended-release tablets are a dosage form of pramipexole intended for oral administration once daily.

Parkinson's disease

Initial therapy.

Doses should be increased gradually, starting at 0.375 mg pramipexole dihydrochloride monohydrate per day, and then increased every 5-7 days. If patients do not experience intolerable adverse reactions, then dose titration is necessary to achieve maximum therapeutic effect.

Table 1

* Tablets are used in the appropriate dosage.

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

However, it should be noted that the likelihood of drowsiness increases when taking doses of more than 1.5 mg of pramipexole dihydrochloride monohydrate per day.

Patients already taking pramipexole tablets can be switched to Pramipexole XR prolonged-release tablets. This is best done at night, while maintaining the same daily dose. After switching to Pramipexole XR prolonged-release tablets, the dose can be adjusted depending on the patient's response to treatment.

The maximum dose should be in the range of 0.375 mg to a maximum of 4.5 mg pramipexole dihydrochloride monohydrate per day. When increasing the dose in pilot studies, efficacy was observed with a daily dose of 1.5 mg pramipexole dihydrochloride monohydrate. Further dose adjustments should be made taking into account the clinical response and the 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 per day may be beneficial if levodopa dose reduction 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 the response of the individual patient.

Missed pill.

If a dose is missed, the extended-release tablet of Pramipexole® XR should be taken within 12 hours of the usual time of taking it. If more than 12 hours have passed since the missed dose, the tablet should not be taken and the next dose should be taken the next day at the usual time.

Discontinuation of treatment.

Abrupt 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 reduced gradually, in steps of 0.75 mg pramipexole dihydrochloride monohydrate per day, until the daily dose is 0.75 mg pramipexole dihydrochloride monohydrate. After that, the dose should be reduced to 0.375 mg pramipexole dihydrochloride monohydrate per day. Dopamine agonist withdrawal syndrome may occur during dose reduction, so a temporary increase in dose may be necessary (see section "Special instructions").

Kidney dysfunction.

The excretion of pramipexole depends on renal function. The following dosage regimen is suggested:

Patients with creatinine clearance above 50 ml/min do not need to reduce the daily dose or frequency of dosing;

Patients with creatinine clearance between 30 and 50 ml/min should be started on 0.375 mg pramipexole dihydrochloride monohydrate every other day. Caution should be exercised and the response and tolerability of the treatment should be carefully assessed before increasing the daily dose, which is carried out after 1 week of treatment. If necessary, the dose should be increased at weekly intervals by 0.375 mg to a maximum dose of 2.25 mg pramipexole dihydrochloride monohydrate per day;

Pramipexole XR extended-release tablets are not recommended for patients with creatinine clearance less than 30 ml/min, as there are no data available for this patient population. The use of Pramipexole XR should be considered.

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

Liver dysfunction.

In patients with hepatic impairment, dose reduction is not considered necessary, as nearly 90% of the absorbed drug is excreted by the kidneys. However, the potential effect of hepatic insufficiency on the pharmacokinetics of the drug has not been studied.

Method of application.

The tablets should be swallowed whole with water, without chewing, splitting or crushing. Food does not affect the absorption of the drug. Pramipexole® XR should be taken at approximately the same time each day.

Children.

The safety and efficacy of pramipexole in children (under 18 years of age) have not been established. There is no evidence to support the use of pramipexole in children with Parkinson's disease.

Overdose

There is no clinical experience of significant overdose. Adverse reactions expected may be those associated with the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hyperkinesia, hallucinations, anxiety and hypotension. There is no established antidote for dopamine agonist overdose. If there are signs of central nervous system stimulation, a neuroleptic may be indicated.

Treatment of overdose may require general supportive measures including gastric lavage, intravenous fluids, activated charcoal, and ECG monitoring.

Side effects

Most adverse reactions are usually observed at the beginning of therapy, a significant part of them disappear even if therapy is continued.

The most frequently reported adverse drug reactions (≥ 5%) in patients with Parkinson's disease (more frequently with pramipexole than with placebo) were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache and fatigue. The incidence of somnolence increases with doses above 1.5 mg pramipexole dihydrochloride monohydrate per day (see section 4.2). The most frequently reported adverse drug reaction with concomitant levodopa use was dyskinesia. Hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too rapidly.

1 There is evidence that this adverse reaction has been observed in the post-marketing period. With 95% confidence, the frequency category was determined as uncommon, but may be lower. It is not possible to establish a precise frequency, as the available data do not show that the adverse reaction was observed in clinical trials among 2762 patients with Parkinson's disease treated with pramipexole.

Description of selected adverse reactions:

Somnolence: Pramipexole is commonly associated with somnolence and uncommonly with excessive daytime sleepiness and sudden sleep onset episodes (see section 4.4).

Libido disorders: Pramipexole may be uncommonly associated with libido disorders (increased or decreased).

Impulse control disorders: Symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating, may occur during treatment with dopamine agonists, including pramipexole (see section 4.4).

In a retrospective cross-sectional screening and case-control study of patients with Parkinson's disease, 13.6% of all patients receiving dopaminergic or non-dopaminergic therapy had symptoms of an impulse control disorder in the previous six months. The symptoms observed included pathological gambling, compulsive shopping, binge eating, and compulsive sexual behavior (hypersexuality). Possible independent risk factors for impulse control disorders included dopaminergic therapy and higher doses of dopaminergic therapy, younger age (≤ 65 years), unmarried status, and a self-reported family history of pathological gambling.

Dopamine agonist withdrawal syndrome: Non-motor adverse reactions may occur when the dose of dopamine agonists (including pramipexole) is reduced or discontinued. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain (see section 4.4).

Heart Failure: Heart failure has been reported in patients treated with pramipexole in clinical trials and in the post-marketing setting. In a pharmacoepidemiological study, use of pramipexole was associated with an increased risk of heart failure compared with no use (hazard ratio, 1.86; 95% CI, 1.21-2.85).

Expiration date

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. 3 blisters in a cardboard pack.

Vacation category

According to the recipe.

Producer

Laboratorios Norman, S.A.

Location of the manufacturer and address of its place of business

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