Vestibo

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

Composition:

Active substance: betahistine;

One tablet contains 8 mg, 16 mg, or 24 mg of betahistine dihydrochloride;

Excipients: povidone, microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silicon dioxide, crospovidone, stearic acid.

Pharmaceutical form. Tablets.

Main physicochemical properties:

8 mg tablets: cylindrical, flat, white or almost white tablets with bevelled edges on both sides; embossed "V8" on one side, the reverse side plain;

16 mg tablets: cylindrical, flat, white or almost white tablets with bevelled edges on both sides; embossed "V16" on one side, the reverse side with a score line;

24 mg tablets: round, biconvex, white or almost white tablets (Snap-Tab) with a break line on one side.

Pharmacotherapeutic group. Drugs for the treatment of vestibular disorders. Betahistine. ATC code N07CA01.

Pharmacological properties.

Pharmacodynamics.

The mechanism of action of betahistine is only partially understood. There are several plausible hypotheses that have been supported by data from studies conducted in animals and humans.

Effect of betahistine on the histaminergic system. Betahistine has been shown to act as a partial agonist at H1-receptors and as an antagonist at H3-receptors of histamine in nervous tissue, with negligible activity at H2-receptors. Betahistine increases histamine turnover and release by blocking presynaptic H3-receptors and inducing down-regulation of H3-receptors.

Betahistine may increase blood flow in the cochlear region and 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 recovery of vestibular function after unilateral labyrinthectomy in animals by stimulating and supporting 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 has also been associated with reduced recovery time of vestibular function after labyrinthectomy.

Betahistine alters neuronal activity in the vestibular nuclei. It has also been demonstrated that betahistine exerts a dose-dependent inhibitory effect on spike generation in neurons of the medial and lateral 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, confirmed by a reduction in the severity and frequency of vertigo attacks.

Pharmacokinetics.

Absorption. After oral administration, betahistine is rapidly and almost completely absorbed throughout the gastrointestinal tract. Following absorption, the drug 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 concentration of the metabolite 2-pyridylacetic acid in plasma and urine.

When administered with food, the maximum concentration (Cmax) of the drug is lower than when administered fasting. However, the overall absorption of betahistine 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 plasma concentration (and in urine) of 2-pyridylacetic acid reaches its maximum within 1 hour and declines with a half-life of approximately 3.5 hours.

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

Linearity. The elimination rate remains constant after oral administration of 8–48 mg of betahistine, 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 the active substance 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 interactions with other medicinal products have not been conducted. Based on in vitro data, inhibition of cytochrome P450 enzyme activity in vivo is not expected.

In vitro data indicate that metabolism of betahistine is inhibited by medicinal products 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 MAO-B inhibitors).

Since betahistine is a histamine analogue, interaction between betahistine and antihistamine medicinal products could theoretically affect the efficacy of one or both agents.

Special precautions for use

Patients with bronchial asthma and/or a history of peptic ulcer disease of the stomach and duodenum should be carefully monitored during treatment with this medicinal product.

The preparation contains lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy. There are insufficient data on the use of betahistine in pregnant women. Animal studies have not shown any direct or indirect harmful effects with regard to reproductive toxicity at doses corresponding to those used in clinical practice. Betahistine should not be used during pregnancy except in cases of clear necessity.

Breastfeeding period. It is not known whether betahistine passes into human breast milk. Betahistine passes into the milk of rats. Effects observed postpartum in animal studies occurred only at 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. Studies in rats have not revealed any effect on fertility.

Ability to influence the reaction rate when driving vehicles or operating machinery.

Betahistine is indicated for the treatment of Meniere's syndrome, characterized by a 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 a vehicle or operate machinery. Clinical studies investigating the effect of the drug on the ability to drive and operate machinery have shown that betahistine has no effect or only a negligible effect on this ability.

Method of administration and dosage.

The daily dose for adults is 24–48 mg, evenly divided and administered throughout the day. Tablets should be swallowed with water.

The dose should be individually adjusted depending on the effect. Symptom improvement may sometimes be observed only after several weeks of treatment. The best results may sometimes be achieved with drug administration over several months. According to some data, initiating treatment at the early stage of the disease may prevent its progression or hearing loss at later stages.

Betahistine can be administered independently of food intake. During drug administration, mild gastrointestinal disturbances (listed in the section "Adverse Reactions") may occur, which can be alleviated by taking the drug with food.

Geriatric patients

Although clinical data in this patient group are currently limited, extensive post-marketing experience allows the assumption that dose adjustment in elderly patients is not required.

Renal impairment

No specific clinical trials have been conducted in this patient group, but according to post-marketing experience, dose adjustment is not necessary.

Hepatic impairment

No specific clinical trials have been conducted in this patient group, but according to post-marketing experience, dose adjustment is not necessary.

Children

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

Overdose

There have been several reported cases of overdose. Mild to moderate symptoms (nausea, drowsiness, abdominal pain) were observed in some patients after intake of doses up to 640 mg. More severe complications (seizures, cardiopulmonary complications) were observed following intentional ingestion of high doses of betahistine, particularly in combination with overdose of other medicinal products.

Treatment of overdose. Management of overdose should include standard supportive measures.

Adverse Reactions

The adverse reactions listed below were observed in patients treated with betahistine during placebo-controlled clinical trials, with the following frequencies: 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).

Gastrointestinal disorders

Common: nausea and dyspepsia.

In addition to the events reported during clinical trials, the following adverse reactions have been reported spontaneously during post-marketing use and are known from scientific literature. Based on available data, the frequency cannot be estimated reliably and is therefore classified as unknown.

Immune system disorders

Hypersensitivity reactions, e.g., anaphylaxis.

Gastrointestinal disorders

Reports of mild gastrointestinal disturbances (vomiting, gastrointestinal pain, abdominal distension, and flatulence). These adverse effects usually resolve when the medication is taken with food or after dose reduction.

Skin and subcutaneous tissue disorders

Skin and subcutaneous hypersensitivity reactions have been observed, including angioedema, urticaria, rash, and pruritus.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

Tablets 8 mg: 10 tablets in a blister, 3 blisters in a carton;

Tablets 16 mg: 10 tablets in a blister, 3 blisters in a carton;

Tablets 24 mg: 10 tablets in a blister, 2 blisters in a carton;

6 blisters in a carton – for manufacturer Balkanpharma-Dupnitsa AD;

15 tablets in a blister, 4 blisters in a carton – for manufacturer Catalent Germany Schorndorf GmbH, Germany.

Prescription status. Prescription only.

Manufacturers.

Catalent Germany Schorndorf GmbH.

Balkanpharma-Dupnitsa AD.

Manufacturers' locations and addresses of their business sites.

Steinbeisstrasse 1 and 2, 73614 Schorndorf, Germany.

Samokovsko shose str. 3, Dupnitsa, 2600, Bulgaria.