Treatment of Parkinson's disease:
either as single-agent therapy (treatment of essential forms with tremor), or in combination with levo-dopa, from the outset or secondarily, in particular in forms with tremor.

Posology
Treatment of Parkinson’s disease:
• as monotherapy: 150 mg to 250 mg, i.e. 3 to 5 tablets daily, to be divided into 3 to 5administrations per day.
• as a supplement to dopatherapy: 80 to 140 mg (approximately 20 mg of piribedil per 100 mgof L. Dopa), the 20 mg piribedil tablet is more suitable due to division of the doses.
These doses must be attained gradually: increase by one tablet every three days.
Discontinuation of treatment
Sudden discontinuation of dopamine agents may result in neuroleptic malignant syndrome. To avoid this risk the dose of piribedil must be reduced gradually until complete discontinuation of treatment.
Impulse control disorders
To avoid the risk of impulse control disorders, prescription of the minimum effective dose is recommended. Dose reduction or gradual discontinuation of treatment should be considered if such symptoms occur (see section 4.4).
Kidney or liver failure
Piribedil has not been studied in these groups of patients. It is recommended to treat these patients with caution.

Paediatric population
The safety and efficacy of piribedil in children under the age of 18 years have not been established. There is no available data. There is no justified use of piribedil in the paediatric population for this indication.
Method of administration
Oral route.
The tablets should be swallowed, without chewing, with half a glass of water at the end of the meal.

This medicine is contraindicated in the following situations: • hypersensitivity to piribedil or to any of the excipients listed in section 6.1, • cardiovascular shock, • acute phase of myocardial infarction, • in association with anti-emetic neuroleptics (see section 4.5).

Dyskinesia:
In advanced stage Parkinson’s disease, in conjunction with levodopa, dyskinesia may occur at the start of treatment with piribedil. In this case, the dose of piribedil should be reduced.
Orthostatic hypotension:
Dopamine agonists are known to alter systemic blood pressure regulation resulting in postural orthostatic hypotension.
Monitoring of blood pressure is recommended, particularly at the start of treatment, given the risk of orthostatic hypotension associated with dopamine treatment.
Abnormal behaviour:
Abnormal behaviour has been reported and may be associated with manifestations of confusion, agitation, aggression. Dose reduction or gradual discontinuation of treatment should be considered if such symptoms occur.
Sleep disorders:
Piribedil has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease.
Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with piribedil. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dosage or termination of therapy may be considered.
Given the age of the population treated, the risk of falls, whether related to hypotension, sudden sleep onset or delirium, must be taken into account.

Impulse control disorders
The onset of impulse control disorders must be regularly monitored in these patients. The patients and those close to them must be informed of the behavioural symptoms of impulse control disorders such as: pathological gambling (compulsive gambling), hypersexuality, increased libido, compulsive spending or shopping, excessive consumption of food and compulsive food disorders, which may appear in patients treated with dopaminergic agonists including TRIVASTAL. A decrease of the doses or progressive discontinuation of the treatment must be envisaged if such symptoms appear.
Psychotic disorders
Dopamine agonists may cause or worsen psychotic disorders such as delusion, delirium, hallucinations (see section 4.5). Dose reduction or gradual discontinuation of treatment should be considered if such symptoms occur.
Peripheral oedema
Peripheral oedema has been observed during the use of dopamine agonists. This should be taken into account when prescribing piribedil.
Neuroleptic malignant syndrome
Characteristic symptoms of neuroleptic malignant syndrome have been reported following sudden discontinuation of dopamine treatment (see section 4.2).
Due to the presence of sucrose, this medicine is contra-indicated in case of fructose intolerance, glucose and galactose malabsorption syndrome or sucrase-isomaltase deficiency.

Contraindicated combinations
+ Antiemetic neuroleptics
Reciprocal antagonism between the dopaminergic agent and the neuroleptic. Use an anti-emetic without extrapyramidal effects.
Inadvisable combinations
+ Antipsychotic neuroleptics (except clozapine)
Reciprocal antagonism between the dopaminergic agent and the neuroleptics.
The dopaminergic agent can provoke or aggravate psychotic disorders. If a neuroleptic treatment is required in parkinsonian patients treated with dopaminergic agents, the latter must be gradually reduced until withdrawal (the sudden withdrawal of dopaminergic agents can expose to a “neuroleptic malignant syndrome” risk).
+ Tetrabenazine
Reciprocal antagonism between the dopaminergic agent and tetrabenazine.

+ Alcohol consumption
Alcohol increases the sedative effect of piribedil.
Impaired vigilance may make driving vehicles and the use of machinery dangerous.
Combination to be taken into account:
+ Other sedatives
Increase in central depression.
The impairment of alertness could make driving and using machines dangerous.

Pregnancy
The available data in mice show piribedil passes through the placental barrier, and is distributed in foetal organs.
In the absence of relevant data, the use of this drug during pregnancy and in women of childbearing age not using contraception is not recommended.
Lactation
In the absence of relevant data, the use of this drug during breastfeeding is not recommended.
Fertility
Studies conducted in animals have not shown any direct or indirect harmful effects on embryonic/foetal
development, parturition or post-natal development.

Patients being treated with piribedil and presenting with somnolence and/or sudden sleep episodes must be informed 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 machines) until such recurrent episodes and somnolence have resolved (see section 4.4).

The following undesirable effects have been observed during treatment with piribedil and ranked under the following frequency:
Very common (≥1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100);
rare (≥ 1/10000, < 1/1000); very rare (< 1/10000), not known (cannot be estimated from the available data).
The following signs may appear:
Gastrointestinal disorders
• Common: minor gastrointestinal disorders (nausea, vomiting, flatulence) which may disappear, particularly if the individual dose is adjusted (gastro-intestinal symptoms can be greatly reduced by stepwise uptitration: 50 mg increase every 2 weeks).
Psychiatric disorders
• Common: psychic disorders such as confusion, hallucinations (visual, auditory, mixed) or agitation have been observed, which disappear when treatment is stopped.
• Unknown frequency: aggression, psychotic disorders (delusion, delirium).

• Impulse control disorders
Symptoms such as: pathological gambling (compulsive gambling), hypersexuality, increased libido, compulsive spending or shopping, excessive consumption of food and compulsive food disorders may appear in patients treated with dopaminergic agonists including TRIVASTAL (see sections 4.2 and 4.4).
Nervous system disorders
• Common: dizziness has been observed which disappears when treatment is stopped.
• Unknown frequency: dyskinesia
• Piribedil is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.
Cardiovascular disorders
• Uncommon: hypotension, orthostatic hypotension, unstable blood pressure causing syncope or malaise.
General disorders and anomalies at the administration site
• Unknown frequency: peripheral oedema
• Risk of allergic reactions due to the presence of Cochineal red A (E124).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system of SFDA–

• Saudi Arabia:

-  National Pharmacovigilance Center (NPC) - Fax: +966-11-205-7662 - SFDA call Center 19999 -  Toll free phone: 8002490000 -  E-mail:  npc.drug@sfda.gov.sa -  Website:  www.sfda.gov.sa/npc

 

• Other GCC states:

- Please contact the relevant competent authority.

 

Given the emetic effect of piribedil at very high doses, overdosage is unlikely with the tablet form.
The signs of overdose are:
• blood pressure instability (arterial hypertension or hypotension),
• digestive symptoms (nausea, vomiting).
These symptoms disappear on discontinuation of administration and with symptomatic treatment.

Pharmacotherapeutic group: DOPAMINERGIC AGONISTS, ATC Code: N04BC08
Mechanism of action:
Piribedil: dopaminergic agonist (stimulates dopamine receptors and the cerebral dopaminergic pathways). In humans, the mechanism of action is demonstrated by the clinical pharmacology studies:
• stimulation of “dopaminergic” type cortical electrogenesis both while awake
and during sleep,
• clinical activity on the different functions controlled by dopamine, with this activity being demonstrated via the use of behavioural or psychometric scales.
In addition, piribedil results in an increase in femoral blood flow (the existence of dopaminergic receptors in the femoral vascular bed explains the action of piribedil on peripheral circulation).

Absorption
Piribedil is absorbed rapidly.
Distribution
The maximum concentration is reached one hour after oral administration of piribedil. Plasma elimination is biphasic and is composed of a first phase characterised by a half-life of 1.7 hours and a second, slower phase characterised by a half-life of 6.9 hours.
Biotransformation
Metabolism of piribedil is intense, with two main metabolites (a hydroxylated derivative and a dihydroxylated derivative).
Elimination
Piribedil is excreted essentially in the urine: 68% of the piribedil absorbed is excreted by the renal route in the form of metabolites and 25% is excreted in bile.
Pharmacokinetic/pharmacodynamic correlations
The prolonged-release tablet containing 50 mg of piribedil allows in vivo gradual absorption and release of the active ingredient.
The kinetic studies conducted in humans show extension of the therapeutic coverage which exceeds
24 hours.
Urinary excretion is approximately 50% at the 24th hour and is total at the 48th hour.

Subchronic or chronic administration of piribedil has been well-tolerated in animals. No teratogenic potential has been demonstrated for piribedil in animals. In vitro and in vivo tests have shown no genotoxic potential. No carcinogenicity studies have been conducted.

Povidone, magnesium stearate, talc, sodium hydrogen carbonate, carmellose sodium, white beeswax, titanium dioxide (E171), cochineal red A aluminium lake (E124), polysorbate 80, sucrose, anhydrous colloidal silica.

Not applicable.

3 years.

Do not store above 25°C.

10, 20, 30, 40, 50, 60 or 100 tablets in blisters (PVC/Aluminium).
Not all pack sizes may be marketed.

No special requirements.