Betagis

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Betagis (Betagis)

Composition:

Active substance: betahistine dihydrochloride;

1 tablet contains 16 mg of betahistine dihydrochloride;

Excipients: microcrystalline cellulose; mannitol (E 421); citric acid monohydrate; colloidal anhydrous silicon dioxide; potato starch; talc.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets, round-shaped, biconvex surface, with a score line on one side.

Pharmacotherapeutic group. Agents for the treatment of vestibular disorders.

ATC code N07CA01.

Pharmacological Properties.

Pharmacodynamics.

The mechanism of action of betahistine has been only partially elucidated. Several plausible hypotheses have been confirmed by data from studies conducted in animals and humans.

Effect of betahistine on the histaminergic system.

It has been established that betahistine exhibits partial agonist activity at H₁ receptors and antagonist activity at H₃ histamine receptors in nervous tissue, with negligible activity at H₂ histamine receptors. Betahistine increases histamine turnover and release by blocking presynaptic H₃ receptors and inducing down-regulation of these H₃ receptors.

Betahistine may increase blood flow in the cochlear region as well as in the entire brain.

Pharmacological studies in animals have demonstrated improved circulation in the vessels of the stria vascularis of the inner ear, possibly due to relaxation of precapillary sphincters in the microcirculatory system of the inner ear. Betahistine has also been shown to increase cerebral blood flow in humans.

Betahistine promotes vestibular compensation.

Betahistine accelerates the recovery of vestibular function after unilateral neurectomy in animals by stimulating and facilitating the process of central vestibular compensation. This effect is characterized by enhanced regulation of histamine turnover and release and is mediated via H₃ receptor antagonism. In humans, treatment with betahistine also reduced the time required for vestibular function recovery after neurectomy.

Betahistine alters neuronal activity in the vestibular nuclei.

It has also been demonstrated that betahistine exerts a dose-dependent inhibitory effect on the generation of action potentials in neurons of the lateral and medial vestibular nuclei.

The pharmacodynamic properties of betahistine, as demonstrated in animals, may provide a positive therapeutic effect of the drug on the vestibular system.

The efficacy of betahistine has been demonstrated in clinical studies in patients with vestibular vertigo and Ménière’s disease: severity and frequency of vertigo attacks were reduced.

Pharmacokinetics.

Absorption. After oral administration, betahistine is rapidly and almost completely absorbed throughout the gastrointestinal tract. Following absorption, betahistine is rapidly and almost entirely metabolized to the metabolite 2-pyridylacetic acid. Plasma concentrations of unchanged betahistine are very low; therefore, all pharmacokinetic analyses are performed by measuring the plasma and urinary concentrations of the metabolite 2-pyridylacetic acid.

When administered with food, the maximum concentration (C_max) of the drug is lower than when administered fasting. However, the total extent of betahistine absorption is identical in both cases, indicating that food intake only delays the absorption process.

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

Biotransformation. After absorption, betahistine is rapidly and almost completely metabolized to 2-pyridylacetic acid (which has no pharmacological activity).

After oral administration of betahistine, the maximum plasma concentration (and urinary concentration) of 2-pyridylacetic acid is reached within 1 hour and declines with a half-life of approximately 3.5 hours.

Elimination. 2-Pyridylacetic acid is rapidly excreted in urine. After administration of betahistine in doses of 8–48 mg, approximately 85% of the initial dose is recovered in urine. Renal or fecal excretion of unchanged betahistine is negligible.

Linearity. The elimination rate remains constant following oral doses of 8–48 mg, indicating linear pharmacokinetics of betahistine and suggesting that the metabolic pathway involved is not saturable.

Clinical characteristics.

Indications.

Meniere's disease and Meniere's syndrome, characterized by three main symptoms:

• vertigo, sometimes accompanied by nausea and vomiting;
• hearing loss (deafness);
• tinnitus.

Symptomatic treatment of vestibular vertigo of various origins.

Contraindications.

Hypersensitivity to betahistine or to any of the excipients of the medicinal product.

Pheochromocytoma.

Interaction with other medicinal products and other forms of interaction.

In vivo studies aimed at investigating the interaction of betahistine with other medicinal products have not been conducted. In vitro data allow predicting the absence of inhibition of cytochrome P450 enzyme activity in vivo.

In vitro data indicate that the metabolism of betahistine is inhibited by drugs which inhibit monoamine oxidase (MAO) activity, including MAO subtype B (e.g., selegiline). Caution is recommended when administering betahistine concomitantly with MAO inhibitors (including selective inhibitors of MAO subtype B).

Since betahistine is a histamine analogue, interaction between betahistine and antihistamine agents may theoretically affect the efficacy of either agent.

Special precautions for use

During treatment with this medicinal product, patients with bronchial asthma and/or a history of peptic ulcer of the stomach and duodenum should be carefully monitored.

This medicinal product contains mannitol and may therefore have a mild laxative effect.

Use during pregnancy or breastfeeding.

Pregnancy. There are insufficient data on the use of betahistine in pregnant women. Animal studies have not revealed any direct or indirect adverse effects on reproductive performance when betahistine was administered at doses corresponding to those used in clinical practice.

Betahistine should not be used during pregnancy unless clearly necessary.

Breastfeeding period. It is unknown whether betahistine passes into human breast milk. Betahistine passes into the milk of rats. Effects observed in animal studies after delivery occurred only after administration of very high doses.

The benefit of treatment for the mother should be weighed against the benefits of breastfeeding and the potential risk to the infant.

Fertility. Animal studies in rats have shown no effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

Betahistine is indicated for the treatment of Ménière's syndrome, characterized by the triad of main symptoms: vertigo, hearing loss, and tinnitus, as well as for symptomatic treatment of vestibular vertigo. Both conditions may negatively affect the ability to drive or operate machinery. Clinical study data indicate that betahistine had no effect or only a negligible effect on the patient's ability to perform activities requiring heightened attention and rapid psychomotor reactions.

Dosage and Administration.

Take Betagis tablets orally during or after meals. During treatment, mild gastrointestinal disturbances may occur (see section "Side Effects"), which can be avoided by taking the medication with food.

The dosage and duration of treatment are determined individually by a physician for each patient depending on the indications and severity of the disease.

For adults, the usual dose is 24 mg to 48 mg of betahistine per day (½–1 tablet three times daily).

Improvement is usually observed within 2–3 weeks. Optimal results are achieved with a treatment course lasting several months. Available data indicate that initiating treatment with Betagis at the early stages of the disease may prevent its progression and/or hearing loss in later stages.

Geriatric patients.

Although clinical data in this patient group are limited, extensive experience with betahistine suggests that dose adjustment is not required in elderly patients.

Renal/hepatic impairment.

Specific clinical trials have not been conducted in these patient groups; however, based on the experience with betahistine, dose adjustment is not considered necessary.

Children.

Due to insufficient data on safety and efficacy, the use of betahistine in pediatric practice is not recommended in children (under 18 years of age).

Overdose.

Several cases of betahistine overdose have been reported. Mild to moderate symptoms (nausea, epigastric pain, drowsiness) were observed in some patients after ingestion of up to 640 mg. Serious complications—such as seizures and cardiorespiratory disturbances—may occur following intentional ingestion of high doses of betahistine, especially when combined with overdose of other medicinal products.

Treatment. Management of overdose should include standard supportive measures.

Side effects

Adverse reactions are classified by frequency of occurrence into the following categories: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Immune system disorders.

Hypersensitivity reactions (including anaphylaxis).

Gastrointestinal disorders.

Common: nausea and dyspepsia.

In some cases, mild gastrointestinal disturbances (vomiting, abdominal pain, bloating and flatulence) may occur. These adverse effects usually resolve when the drug is taken with food or after dose reduction.

Nervous system disorders.

Common: headache.

In addition to data from clinical trials, the following adverse events have been reported based on post-marketing experience and scientific literature.

Skin and subcutaneous tissue disorders.

Frequency not known: skin and subcutaneous tissue hypersensitivity reactions, including angioneurotic edema, rash, pruritus, and urticaria.

Shelf life. 3 years.

Storage conditions. Store in a place inaccessible to children, in the original packaging at a temperature not exceeding 25 °C.

Packaging. 10 tablets in a blister; 3 blisters in a cardboard box. 18 tablets in a blister; 5 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. LLC "Pharma Start", Ukraine.

Manufacturer's address and location of its business activity.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.