BETAHISTINE ACCORD 8 mg Cpr Plq/30

Each tablet contains 8 mg of betahistine dihydrochloride.

Excipient: each tablet contains 50 mg of lactose monohydrate.

Betahistine is indicated for the treatment of Ménière's disease, the symptoms of which may include: vertigo, tinnitus, hearing loss and nausea.

Dosage

Adult population

The initial treatment is 8 to 16 mg three times a day orally, preferably to be taken with meals.

Maintenance doses are generally between 24 and 48 mg per day. The daily dose must not exceed 48 mg. The dosage may be adjusted to meet the particular needs of each patient. An improvement may sometimes be observed after 2 or 3 weeks of treatment.

Hepatic impairment

No specific clinical trials have been conducted in this patient group, but based on experience gained since the product was marketed, no dose adjustment appears to be necessary.

Renal impairment

No specific clinical trials have been conducted in this patient group, but based on experience gained since the product was marketed, no dose adjustment appears to be necessary.

Elderly patients

Although data from clinical studies are limited for this patient group, extensive experience gained since the medicine was marketed suggests that no dose adjustment is necessary in this patient population.

Paediatric population

BETAHISTINE ACCORD is not recommended for children and adolescents under 18 years of age. The safety and efficacy of BETAHISTINE ACCORD in children and adolescents under 18 years of age have not been established.

• Hypersensitivity to the active substance or to any of the excipients.

• Phaeochromocytoma. As betahistine is a synthetic analogue of histamine, it may induce the release of catecholamines by the tumour, resulting in severe hypertension.

Caution is recommended when treating patients who have a peptic ulcer or a history of peptic ulceration, because of the dyspepsia that may sometimes occur in patients taking betahistine.

Clinical intolerance to betahistine may occur in patients suffering from bronchial asthma. These patients should therefore be closely monitored during treatment with betahistine.

Caution is recommended in patients who have severe hypotension.

Warning regarding excipients:

This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome should not take this medicine.

No interaction studies in vivo have been performed. According to in-vitro data, no inhibition in vivo on Cytochrome P450 enzymes is expected.

Data in vitro indicate inhibition of betahistine metabolism by medicines that inhibit monoamine oxidase (MAO), including the MAO subtype B (for example, selegiline). Caution is recommended when betahistine and MAO inhibitors (including selective MAO-B) are used concomitantly.

As betahistine is an analogue of histamine, its interaction with antihistamines may theoretically affect the efficacy of either of these medicines.

Pregnancy

There are insufficient data on the use of betahistine in pregnant women. Animal studies do not indicate direct or indirect harmful effects on reproduction at clinically relevant therapeutic doses. As a precaution, it is preferable to avoid using betahistine during pregnancy.

Breast-feeding

The excretion of betahistine into breast milk is not known. Betahistine passes into milk in rats. Post-partum effects observed in animal studies were limited to very high doses. The benefit of initiating treatment in a breastfeeding woman should be weighed against the benefits of breastfeeding and the potential risks for the child.

Fertility

Animal studies have not shown an effect on fertility in rats.

The sensation of vertigo, tinnitus and hearing loss associated with Ménière's syndrome are likely to impair the ability to drive vehicles and use machines.

In clinical studies specifically designed to investigate the ability to drive and use machines, betahistine had no or negligible effects.

The following adverse effects were observed at the frequencies indicated below in patients treated with betahistine in placebo-controlled clinical studies with the following frequency: very common (≥ 1/10); common (≥ 1/100 < 1/10); uncommon (≥ 1/1 000 <1/100); rare (≥ 1/1 0000 < 1/1 000) and very rare (< 1/10 000).

Nervous system disorders:

Common: headache.

Gastrointestinal disorders:

Common: dyspepsia and nausea.

In addition to the adverse effects reported during clinical trials, the following unexpected adverse effects have been reported spontaneously in the scientific literature during post-marketing use. The available data do not allow the frequency of these side effects to be estimated, so they are classified in the 'not known' category.

Immune system disorders:

Frequency not known: hypersensitivity reactions, for example anaphylaxis.

Gastrointestinal disorders:

Frequency not known: mild gastric disorders (e.g. vomiting, gastrointestinal pain, abdominal distension and bloating) have been observed. These problems can normally be resolved by taking the dose with a meal or by reducing the dose.

Skin and subcutaneous tissue disorders

Frequency not known: cutaneous and subcutaneous hypersensitivity reactions, in particular angioneurotic oedema, urticaria, rash and pruritus.

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 reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr.

A few cases of overdose have been observed. Some patients presented with mild to moderate symptoms with doses up to 640 mg (e.g. nausea, drowsiness, abdominal pain).

More serious complications (convulsions, pulmonary or cardiac complications) have been observed in cases of intentional overdose of betahistine, particularly in combination with other overdosed medicines. Management of overdose should include standard supportive measures.

Pharmacotherapeutic class: antivertigo agents, ATC code: N07CA01.

The mechanism of action of betahistine is only partially elucidated. Several plausible hypotheses exist, supported by animal studies and human data:

• Betahistine has an effect on the histaminergic system:

Biochemical studies have shown that betahistine has weak agonist properties at H1 receptors and strong antagonist properties at H3 receptors in the central nervous system and the autonomic nervous system. The activity of H2 receptors appears negligible (for example, stimulation of gastric acid secretion).

Betahistine increases the turnover and release of histamine, most probably by blocking presynaptic H3 receptors and inducing downregulation of H3 receptors.

• Betahistine may increase blood flow to the cochlear region:

Pharmacological studies performed in animals have revealed improved blood circulation in the stria vascularis of the inner ear, probably secondary to relaxation of the precapillary sphincters of the inner ear microcirculation.

• Betahistine facilitates vestibular compensation:

In animals, betahistine accelerates vestibular recovery after unilateral neurectomy by promoting and facilitating central vestibular compensation; this effect is characterised by positive regulation of the turnover and release of histamine and is mediated by antagonism at H3 receptors. In humans, the recovery time after vestibular neurectomy was also reduced with betahistine treatment.

• Betahistine modifies neuronal activity in the vestibular nucleus:

Betahistine has also been found to exert a dose-dependent inhibitory effect on the generation of action potentials in neurons of the lateral and medial vestibular nuclei.

Ménière's syndrome is characterised by attacks of vertigo, tinnitus, headache and nausea. Over time, hearing loss may occur. Clinical studies show that betahistine can prevent attacks and reduce their severity.

Absorption

Administered orally, betahistine is readily and almost completely absorbed from all parts of the gastrointestinal tract. After absorption, the medicinal product is rapidly and almost entirely metabolised to 2-pyridylacetic acid (2-PAA). Plasma levels of betahistine are very low. Pharmacokinetic analyses are therefore based on measurements of 2-PAA levels in plasma and urine. After oral administration of betahistine, the plasma concentration of 2-PAA reaches its maximum after 1 hour.

After a meal, the observed Cmax is lower than in the fasting state. Nevertheless, the total amount of betahistine absorbed remains comparable in these two situations, which indicates that food intake only slows the absorption of betahistine.

Distribution

The percentage of betahistine bound to blood plasma proteins is less than 5%.

Metabolism

After absorption, the medicinal product is rapidly and almost entirely metabolised to 2-pyridylacetic acid. 2-PAA has a half-life of approximately 3,5 hours.

Elimination

2-PAA is readily eliminated via the urine. For doses between 8 mg and 48 mg, approximately 85% of the initial dose is found in the urine. Renal or faecal excretion of unchanged betahistine is negligible.

Linearity

Recovery rates are constant for oral doses between 8 and 48 mg, which indicates that the pharmacokinetics of betahistine are linear, and suggests that the metabolic pathway is not saturated.

Chronic toxicity

Adverse effects on the central nervous system have been observed in dogs and baboons at intravenous doses greater than or equal to 120 mg/kg.

Chronic oral toxicity studies over 18 months in rats at a dose of 500 mg/kg and over 6 months in dogs at a dose of 25 mg/kg showed that betahistine is well tolerated and without definitive toxicity

Mutagenic and carcinogenic potential

Betahistine has no mutagenic potential.

In a chronic toxicity study conducted over 18 months in rats, no carcinogenic potential of betahistine was demonstrated at doses up to 500 mg/kg

Reproductive toxicity

In reproductive toxicity studies, effects were observed only at exposures considered sufficiently greater than the maximum doses in humans, which is of little relevance in clinical use.

2 years.

To be stored at a temperature not exceeding 30°C.

To be stored in the original outer packaging, protected from moisture.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.