Instructions for use Pronoran prolonged-release film-coated tablets 50 mg No. 30
Composition
active ingredient: piribedil;
1 tablet contains: 50 mg piribedil;
excipients: magnesium stearate, povidone, talc, carmellose sodium, polysorbate 80, cochineal red A (E 124), colloidal anhydrous silicon dioxide, sodium bicarbonate, sucrose, titanium dioxide (E 171), white wax.
Dosage form
Film-coated, prolonged-release tablets.
Main physicochemical properties: round, red, film-coated tablets.
Pharmacotherapeutic group
Antiparkinsonian drugs. Dopamine agonists. ATX code N04B C08.
Pharmacological properties
Pharmacodynamics.
The active substance piribedil is a dopaminergic agonist. Piribedil crosses the blood-brain barrier and binds to dopamine receptors in the brain with a strong specific affinity for dopamine receptors of the D2 and D3 subtypes.
These properties allow piribedil to be classified as a treatment for early and late-stage Parkinson's disease, acting on all major motor symptoms. In addition, unlike other dopamine agonists, piribedil also acts as an antagonist of the two main α2-adrenergic receptors of the central nervous system (α 2A and α 2C). The synergistic effect of piribedil as an antagonist of α2-adrenergic receptors and a dopamine agonist has been demonstrated in various animal models of Parkinson's disease: long-term use of piribedil caused less pronounced dyskinesia compared to levodopa with the same effectiveness in reducing the akinetic deficit of parkinsonism.
In clinical studies of the drug's pharmacodynamics in humans, it was found that the drug stimulates cortical electrogenesis of the "dopaminergic" type both during wakefulness and during sleep, and also activates various functions controlled by dopamine. This activity was confirmed using behavioral or psychometric scales.
It has also been proven that in healthy volunteers, piribedil improves attention, as well as the performance of cognitive tasks that require vigilance.
The efficacy of PRONORAN® in the treatment of Parkinson's disease as monotherapy or in combination with levodopa was studied in three double-blind randomized studies (in two studies compared to placebo and in 1 study compared to bromocriptine). A total of 1103 patients with stages I-III of Parkinson's disease on the Hehn and Yar scale participated in these studies, 543 of whom took PRONORAN®.
PRONORAN® at a dose of 150-300 mg/day has been shown to be effective in reducing all symptoms of motor dysfunction with a 30% improvement in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III total score when used for at least 7 months as monotherapy and 12 months in combination with levodopa. A similar degree of improvement in the total score was observed when assessed according to Part II of the UPDRS scale ("Activities of Daily Living").
When piribedil was used as monotherapy, a statistically significantly lower percentage of patients (16.6%) required additional levodopa treatment compared to patients receiving placebo (40.2%).
In addition, piribedil stimulates increased blood circulation in the femoral vessels (the presence of dopaminergic receptors in the femoral vessels explains the effect of piribedil on peripheral circulation).
Pharmacokinetics.
In humans, piribedil is rapidly and almost completely absorbed from the gastrointestinal tract and extensively distributed.
Peak plasma concentrations are reached 3-6 hours after administration of piribedil prolonged-release tablets. In humans, piribedil is moderately bound to plasma proteins (unbound fraction 0.2-0.3), so the risk of drug interactions due to plasma protein binding is low. Plasma elimination is biphasic, consisting of an initial phase and a second, slower phase, resulting in sustained plasma concentrations of piribedil over 24 hours when steady-state concentrations are reached. A pooled analysis of data from several studies has shown that the mean elimination half-life of piribedil administered intravenously is 12 hours, regardless of the dose administered.
Piribedil is extensively metabolized in the liver and excreted mainly in the urine: 75% of the absorbed substance is excreted by renal clearance, mainly in the form of metabolites.
Indication
Treatment of Parkinson's disease:
in monotherapy;
or in combination with levodopa, at the beginning of treatment or later.
Contraindication
Hypersensitivity to the active substance or to any of the excipients of the drug.
Cardiogenic shock.
Acute phase of myocardial infarction.
Concomitant use with neuroleptics (except clozapine) (see section "Interaction with other medicinal products and other types of interactions").
Interaction with other medicinal products and other types of interactions
Patients with extrapyramidal syndrome caused by neuroleptics should be prescribed anticholinergic drugs rather than dopaminergic antiparkinsonian drugs (dopaminergic receptors are blocked by neuroleptics).
Dopaminergic agonists may cause or exacerbate psychotic disorders (see section "Special warnings and precautions for use"). If neuroleptic therapy is necessary in patients with Parkinson's disease who are taking dopaminergic agonists, the dose of the latter should be reduced gradually until completely discontinued (abrupt withdrawal of dopaminergic agents leads to the risk of developing "neuroleptic malignant syndrome").
Neuroleptic antiemetics: Antiemetics that do not have extrapyramidal effects should be used.
Concomitant use with tetrabenazine is not recommended because there is mutual antagonism between dopaminergic antiparkinsonian drugs and tetrabenazine.
Drinking alcohol during treatment with piribedil is not recommended. Alcohol increases the sedative effect of piribedil. Reduced alertness may make driving or using other machinery dangerous.
Piribedyl should be administered with caution in combination with other sedative drugs. Such a combination increases the depression of the central nervous system. Impaired vigilance and reaction (alertness) may make driving a car or using other mechanisms dangerous.
Application features
Dyskinesia
In patients with advanced Parkinson's disease, dyskinesia may occur at the beginning of treatment with piribedil in combination with levodopa. In such cases, the dose of piribedil should be reduced.
Orthostatic hypotension
Dopamine agonists are known to affect systemic blood pressure regulation, which in turn can lead to postural orthostatic hypotension.
It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the risk of orthostatic hypotension associated with dopaminergic therapy.
Abnormal behavior
Abnormal behavior, which may manifest as confusion, agitation, and aggression, has been reported. If such symptoms occur, consideration should be given to reducing the dose or gradually discontinuing the drug.
Sleep disorders
There are reports of drowsiness and episodes of sudden sleep onset with piribedil, particularly in patients with Parkinson's disease.
Episodes of sudden daytime sleepiness, sometimes without awareness or warning symptoms, have been reported very rarely. Patients should be warned of this and advised to exercise caution when driving or operating machinery during treatment with piribedil. Patients who experience somnolence and/or sudden sleepiness should refrain from driving or operating machinery. Furthermore, a dose reduction or discontinuation of therapy may be considered.
Given the age of patients using piribedil, the risk of falls due to hypotension, sudden sleep onset, or confusion should be considered.
Disorders of habits and inclinations
Patients should be monitored regularly for the development of addiction disorders. Patients and caregivers should be informed that behavioral symptoms of addiction disorders, including pathological gambling, hypersexuality, increased libido, compulsive spending or shopping, binge eating, and compulsive eating, may occur with dopamine agonists, including PRONORAN®. If such symptoms occur, consideration should be given to reducing the dose or gradually discontinuing the drug.
Psychotic disorders
Dopaminergic agonists may cause or exacerbate psychotic disorders such as delusions, delirium and hallucinations (see section 4.5). If such symptoms occur, dose reduction or gradual discontinuation should be considered.
Peripheral edema
Peripheral edema has been observed with dopamine agonists. This should also be taken into account when prescribing piribedil.
Neuroleptic malignant syndrome
The occurrence of characteristic symptoms of neuroleptic malignant syndrome has been reported with abrupt discontinuation of dopaminergic therapy (see section 4.2).
Excipients
Due to the presence of sucrose, patients with fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase insufficiency (rare hereditary diseases) should not take this medicine.
Due to the presence of cochineal red A (E 124), there is a risk of allergic reactions (see section "Adverse reactions").
This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
Animal studies have shown that piribedil crosses the placental barrier and is distributed in fetal organs.
Due to the lack of adequate data, the use of piribedil during pregnancy and in women of reproductive age not using contraception is not recommended.
Breast-feeding
Due to the lack of relevant data, the use of this drug during breastfeeding is not recommended.
Fertility
Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/fetal development, parturition or postnatal development.
Ability to influence reaction speed when driving vehicles or other mechanisms
Patients treated with piribedil who experience somnolence and/or episodes of sudden sleep onset should be advised to refrain from driving or engaging in other activities where impaired alertness and reactions may put the patient or others at risk of serious injury or death (e.g. operating machinery) until such symptoms resolve (see section 4.4).
Method of administration and doses
Method of application
For oral use.
Take the tablets at the end of a meal - swallow without chewing, with half a glass of water.
Dosage
Treatment of Parkinson's disease:
as monotherapy: from 150 mg to 250 mg, i.e. from 3 to 5 tablets per day, which should be divided into 3 or 5 doses per day;
in combination with levodopa: from 100 mg or 150 mg, i.e. from 2 to 3 tablets per day, which should be divided into 2 or 3 doses per day.
The above doses should be reached gradually: the dose should be increased by 1 tablet at a time with an interval between dose increases that can be from three days to 2 weeks, depending on the patient's condition and tolerability of the drug. The interval between dose increases should not be less than 3 days.
Treatment discontinuation
Abrupt discontinuation of dopaminergic therapy carries a risk of neuroleptic malignant syndrome. To prevent this risk, the dose of piribedil should be reduced gradually until complete discontinuation of the drug.
Disorders of habits and inclinations
It is recommended to prescribe the minimum effective dose to prevent the risk of habituation and dependence. If symptoms of habituation and dependence occur, the dose should be reduced or the drug should be gradually discontinued (see section "Special instructions").
Patients with impaired liver or kidney function
Piribedil has not been studied in this patient group. Caution should be exercised when prescribing to patients with impaired hepatic or renal function.
Children
The use of Pronoran® in the treatment of children is not recommended, as the safety and efficacy of this drug have not been established in this group of patients. Data are not available.
Overdose
Symptoms
Given that very high doses of piribedil cause vomiting, an overdose of the drug in tablet form is unlikely.
Treatment
However, in case of accidental ingestion of a higher than therapeutic dose, the following signs and symptoms may occur:
unstable blood pressure (arterial hypertension or hypotension);
gastrointestinal symptoms (nausea, vomiting).
These symptoms disappear upon discontinuation of the drug and symptomatic treatment.
Side effects
The following adverse reactions have been observed during treatment with piribedil, and are classified by frequency as follows: 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 unknown (cannot be estimated from the available data).
Gastrointestinal tract
Common: mild gastrointestinal disorders (nausea, vomiting, flatulence), which may disappear, in particular with individual dose adjustment. The severity of symptoms can be significantly reduced by gradual dose titration (dose increase by 50 mg every 2 weeks).
From the psyche
Common: psychiatric disorders such as confusion, agitation, hallucinations (visual, auditory, mixed), which disappear upon discontinuation of treatment.
Frequency unknown: aggression, psychotic disorders (delusions, delirium).
Disorders of habits and inclinations
When using dopamine agonists, pathological gambling (gambling), hypersexuality, increased libido, compulsive spending or shopping, overeating and uncontrolled food cravings may occur (see sections “Method of administration and dosage” and “Special instructions”).
From the nervous system
Common: dizziness, which disappears when treatment is discontinued.
Frequency unknown: dyskinesia.
The use of piribedil has been associated with drowsiness and, in very rare cases, excessive daytime sleepiness and episodes of sudden sleep onset (see section 4.4).
Cardiovascular system
Uncommon: hypotension, orthostatic hypotension, which may be accompanied by fainting, malaise or unstable blood pressure.
General disorders and administration site conditions
Frequency unknown: peripheral edema.
Frequency unknown: hypersensitivity reactions (including urticaria). The product contains the dye cochineal red A (E 124), which may cause allergic reactions.
Reporting of suspected adverse reactions. Reporting of adverse reactions after registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25°C. Keep out of the reach of children.
Packaging
15 film-coated tablets in a blister pack made of aluminum foil and PVC film.
2 blisters in a cardboard packaging box.
Vacation category
According to the recipe.
Producer
Servier Industry Laboratories/Les Laboratoires Servier Іndustrie.
Location of the manufacturer and address of its place of business.
905 route de Saran, 45520 Gidy, France/905 route de Saran, 45520 Gidy, France.
Applicant
LE LABORATORY SERVIER/LES LABORATOIRES SERVIER.
Location of the applicant.
50, rue Carnot, 92284 Suresnes Cedex, France/50, rue Carnot, 92284 Suresnes Cedex, France.
If you have any questions, please call (044) 490 3441.
