Pronoran

INSTRUCTIONS for medical use of the medicinal product PRONORAN® (PRONORAN®)

Composition:

Active ingredient: piribedil;

One tablet contains: 50 mg of piribedil;

Excipients: magnesium stearate, povidone, talc, sodium carmellose, polysorbate 80, cochineal red A (E 124), colloidal anhydrous silicon dioxide, sodium bicarbonate, sucrose, titanium dioxide (E 171), white wax.

Pharmaceutical form. Prolonged-release coated tablets.

Main physicochemical properties: round-shaped, red-colored coated tablets.

Pharmacotherapeutic group. Antiparkinson agents. Dopamine agonists.
ATX code N04BC08.

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 high specific affinity for dopamine receptor subtypes D2 and D3.

These properties allow piribedil to be classified as a treatment for Parkinson's disease at both early and late stages, acting on all major motor symptoms. Furthermore, unlike other dopamine agonists, piribedil also acts as an antagonist of the two main α2-adrenergic receptors in the central nervous system (α2A and α2C). The synergistic action of piribedil as an α2-adrenergic receptor antagonist and a dopamine agonist has been demonstrated in various animal models of Parkinson's disease: prolonged administration of piribedil resulted in less pronounced dyskinesia compared to levodopa, with equivalent efficacy in reducing the akinetic deficit of parkinsonism.

In clinical studies of the drug's pharmacodynamics in humans, it was established that the drug stimulates cortical electrogenesis of the "dopaminergic" type both during wakefulness and sleep, and also activates various functions controlled by dopamine. This activity was confirmed using behavioral or psychometric scales.

It has also been demonstrated that in healthy volunteers, piribedil improves attention and performance of cognitive tasks requiring vigilance.

The efficacy of the drug PRONOORN® in the treatment of Parkinson's disease as monotherapy or in combination with levodopa was studied in three double-blind randomized trials (two trials compared with placebo and one trial compared with bromocriptine). Overall, 1103 patients with stages I–III of Parkinson's disease according to the Hoehn and Yahr scale participated in these studies, of whom 543 received PRONOORN®.

The efficacy of PRONOORN® at a dose of 150–300 mg/day was demonstrated in reducing all symptoms of motor dysfunction, with a 30% improvement in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS), part III, after at least 7 months of treatment in monotherapy and 12 months in combination with levodopa. A similar degree of improvement in the total score was observed when assessed according to UPDRS part II ("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 flow in the femoral vessels (the presence of dopaminergic receptors in the femoral vessels explains piribedil's effect on peripheral circulation).

Pharmacokinetics

In humans, piribedil is rapidly and almost completely absorbed from the gastrointestinal tract and extensively distributed.

Maximum plasma concentration is reached 3–6 hours after administration of piribedil in the form of prolonged-release tablets. In humans, plasma protein binding of piribedil is moderate (the unbound fraction is 0.2–0.3), thus the risk of drug interactions due to plasma protein binding is low. Elimination from plasma is biphasic, consisting of an initial phase and a second, slower phase, resulting in sustained plasma concentrations of piribedil over 24 hours once steady-state concentration is achieved. Combined analysis of data from several studies demonstrated that the mean elimination half-life of piribedil after intravenous administration is 12 hours, independent of the administered dose.

Piribedil is extensively metabolized in the liver and is primarily excreted in urine: 75% of the absorbed substance is eliminated via renal clearance, predominantly as metabolites.

Clinical characteristics.

Indications.

Treatment of Parkinson's disease:

• as monotherapy;
• or in combination with levodopa, at the beginning of treatment or later.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Cardiogenic shock.
• Acute phase of myocardial infarction.
• Concomitant use with neuroleptics (except clozapine) (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Concomitant use with neuroleptics (except clozapine) is contraindicated, as there is a mutual antagonism between dopaminergic anti-Parkinson medicinal products and neuroleptics (see section "Contraindications").

• Patients with extrapyramidal syndrome caused by neuroleptics should be prescribed anticholinergic agents, not dopaminergic anti-Parkinson drugs (dopaminergic receptors are blocked by neuroleptics).
• Dopaminergic agonists may induce or exacerbate psychotic disorders (see section "Special precautions for use"). If neuroleptic therapy is required in patients with Parkinson's disease who are taking dopaminergic agonists, the dose of the latter should be gradually reduced until complete discontinuation (sudden withdrawal of dopaminergic agents may lead to the risk of developing "neuroleptic malignant syndrome").
• Neuroleptic antiemetic agents: antiemetics that do not cause extrapyramidal effects should be used.

Concomitant use with tetrabenazine is not recommended, as there is a mutual antagonism between dopaminergic anti-Parkinson medicinal products and tetrabenazine.

Alcohol consumption during treatment with piribedil is not recommended. Alcohol enhances the sedative effect of piribedil. Reduced alertness may make driving or operating machinery hazardous.

Piribedil should be administered with caution in combination with other sedative medicinal products. Such combination enhances central nervous system depression. Impairment of alertness and reaction time (vigilance) may make driving or operating machinery hazardous.

Special precautions for use

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 regulation of arterial blood pressure, which may lead to postural orthostatic hypotension.

Monitoring of blood pressure is recommended, especially at the beginning of treatment, due to the risk of orthostatic hypotension associated with dopaminergic therapy.

Abnormal behavior

Cases of abnormal behavior have been reported, which may manifest as confusion, agitation, or aggression. If such symptoms occur, consideration should be given to reducing the dose or gradually discontinuing the drug.

Sleep disorders

There have been reports of somnolence and episodes of sudden sleep onset during treatment with piribedil, particularly in patients with Parkinson’s disease.

Very rare cases of sudden daytime sleep episodes, sometimes without awareness or warning signs, have been reported. Patients should be warned about this risk and advised to exercise caution while driving or operating machinery during treatment with piribedil. Patients who have experienced episodes of somnolence and/or sudden sleep onset should refrain from driving or using machinery. Furthermore, dose reduction or discontinuation of therapy may need to be considered.

Given the age of patients receiving piribedil, the risk of falls due to hypotension, sudden sleep episodes, or confusion should be taken into account.

Impulse control disorders

Patients should be regularly monitored for the development of impulse control disorders. Patients and caregivers should be informed that when using dopamine agonists, including PRONORAN®, behavioral symptoms of impulse control disorders may occur, such as pathological gambling (compulsive gambling), hypersexuality, increased libido, uncontrollable urge to spend money or shop, binge eating, and compulsive eating. If such symptoms occur, consideration should be given to reducing the dose or gradually discontinuing the medication.

Psychotic disorders

Dopaminergic agonists may cause or exacerbate psychotic disorders such as delusions, delirium, and hallucinations (see section "Interaction with other medicinal products and other forms of interaction"). If such symptoms occur, consideration should be given to reducing the dose or gradually discontinuing the medication.

Peripheral edema

Peripheral edema has been observed during treatment with dopamine agonists. This should also be considered when prescribing piribedil.

Neuroleptic malignant syndrome

Cases of symptoms characteristic of neuroleptic malignant syndrome have been reported following abrupt discontinuation of dopaminergic therapy (see section "Method of administration and dosage").

Excipients

Due to the presence of sucrose, this medicinal product is contraindicated in patients with hereditary fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency (rare inherited disorders).

Due to the presence of cochineal red A (E 124), there is a risk of allergic reactions (see section "Side effects").

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

Animal studies have demonstrated that piribedil crosses the placental barrier and distributes into fetal organs.

Due to the lack of adequate data on the use of piribedil during pregnancy, its use is not recommended in pregnant women or in women of childbearing potential who are not using contraception.

Breastfeeding

Due to the lack of adequate data, use of this medicinal product during breastfeeding is not recommended.

Fertility

Animal studies have not revealed any direct or indirect harmful effects on embryonic/fetal development, course of delivery, or postnatal development.

Ability to affect reaction speed while driving or operating machinery

Patients undergoing treatment 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 attention or reaction time could place the patient or others at risk of serious injury or death (e.g., operating machinery) until such symptoms resolve (see section "Special precautions for use").

Method of Administration and Dosage

Method of Administration

For oral use.

Take tablets at the end of a meal — swallow whole without chewing, with half a glass of water.

Dosage

Treatment of Parkinson's disease:

• as monotherapy: 150 mg to 250 mg, i.e. 3 to 5 tablets per day, divided into 3 or 5 doses;
• in combination with levodopa: 100 mg or 150 mg, i.e. 2 to 3 tablets per day, divided into 2 or 3 doses.

The above doses should be reached gradually: increase the dose by 1 tablet at a time, with intervals between dose increases ranging from 3 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.

Discontinuation of Treatment

Sudden discontinuation of dopaminergic medications may lead to the risk of developing neuroleptic malignant syndrome. To prevent this risk, the dose of piribedil should be gradually reduced until complete withdrawal of the drug.

Disorders of Habits and Impulses

It is recommended to prescribe the lowest effective dose to minimize the risk of impulse control disorders. If symptoms of impulse control disorders occur, the dose should be reduced or the drug should be gradually discontinued (see section "Special Warnings and Precautions for Use").

Patients with Hepatic or Renal Impairment

The use of piribedil has not been studied in these patient groups. Piribedil should be administered with caution in patients with hepatic or renal impairment.

Children

Pronoran® is not recommended for use in children, as the safety and efficacy of this drug have not been established in this patient population. Data are lacking.

Overdose

Symptoms

Since very high doses of piribedil induce vomiting, overdose with tablet formulation is unlikely.

Treatment

However, in case of accidental ingestion of a dose higher than the therapeutic dose, the following signs and symptoms may occur:

• unstable blood pressure (arterial hypertension or hypotension);
• gastrointestinal symptoms (nausea, vomiting).

These symptoms resolve upon discontinuation of the drug and with symptomatic treatment.

Adverse Reactions

The adverse reactions observed during treatment with piribedil are listed below, categorized 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 not known (cannot be estimated from the available data).

Gastrointestinal disorders

Common: mild gastrointestinal disturbances (nausea, vomiting, flatulence), which may resolve, particularly with individual dose adjustment. Symptoms can be significantly reduced by gradual dose titration (increasing the dose by 50 mg every 2 weeks).

Psychiatric disorders

Common: psychiatric disorders such as confusion, agitation, hallucinations (visual, auditory, mixed), which resolve upon discontinuation of treatment.

Frequency not known: aggression, psychotic disorders (delusions, delirium).

Disorders of habits and impulses

When dopamine agonists are used, pathological gambling (compulsive gambling), hypersexuality, increased libido, uncontrollable urge to spend money or shop, overeating, and uncontrolled urge to consume food may occur (see sections "Dosage and administration" and "Special precautions").

Nervous system disorders

Common: dizziness, which resolves upon discontinuation of treatment.

Frequency not known: dyskinesia.

Piribedil use has been associated with somnolence and, very rarely, excessive daytime sleepiness and episodes of sudden sleep onset (see section "Special precautions").

Cardiovascular system disorders

Uncommon: arterial hypotension, orthostatic hypotension, which may be accompanied by syncope, malaise, or unstable blood pressure.

General disorders and administration site conditions

Frequency not known: peripheral edema.

Immune system disorders

Frequency not known: hypersensitivity reactions (including urticaria). The product contains the dye Carmoisine (E 124), which may cause allergic reactions.

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25°C. Keep out of reach and sight of children.

Packaging.

15 film-coated tablets in a blister pack made of aluminum foil and PVC film.

2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Laboratoires Servier Industrie / Les Laboratoires Servier Industrie.

Manufacturer's address.

905 route de Saran, 45520 Gidy, France.

Marketing Authorization Holder.

Les Laboratoires Servier.

Address of Marketing Authorization Holder.

50, rue Carnot, 92284 Suresnes Cedex, France.

For any questions, please call (044) 490 3441.