Betahistine-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Betahistine-Teva (Betahistine-Teva)

Composition:

Active substance: betahistine dihydrochloride;

1 tablet contains 8 mg or 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:

Betahistine-Teva 8 mg: white or almost white, cylindrical, flat tablets with beveled edges on both sides. Embossed "B8" on one side, the other side smooth.

Betahistine-Teva 16 mg: white or almost white, cylindrical, flat tablets with beveled edges on both sides. Embossed "B16" on one side, a break line on the other side.

Betahistine-Teva 24 mg: white or almost white, round, biconvex tablets with a break line on one side.

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

Pharmacological Properties

Pharmacodynamics

The mechanism of action of betahistine is only partially understood. Several plausible hypotheses 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 minimal activity at histamine H₂ 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 and throughout 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 facilitating the process of central vestibular compensation. This effect is characterized by enhanced regulation of histamine turnover and release, mediated via H₃ receptor antagonism. In humans, treatment with betahistine has also been associated with reduced recovery time of vestibular function following neuroectomy.

Betahistine alters neuronal activity in the vestibular nuclei.

It has also been established 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 animal studies, may underlie the positive therapeutic effect of the drug on the vestibular system.

The efficacy of betahistine has been demonstrated in clinical trials involving patients with vestibular vertigo and Ménière’s disease, with reductions 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 plasma and urinary concentrations of the metabolite 2-pyridylacetic acid.

When administered with food, the maximum concentration (C_max) of the drug is lower compared to administration on an empty stomach. 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, plasma (and urinary) concentrations of 2-pyridylacetic acid reach peak levels within 1 hour and decline with a half-life of approximately 3.5 hours.

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

Linearity. The rate of elimination 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 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 on the interaction of betahistine 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 the metabolism of betahistine is inhibited by medicinal products that 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 may theoretically affect the efficacy of one of these agents.

Special precautions for use

During treatment with the drug, patients with bronchial asthma and/or peptic ulcer of the stomach and duodenum (including in medical history) should be carefully monitored.

The drug contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, complete lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy. There are insufficient data on the use of betahistine in pregnant women.

Results of animal studies did not show direct or indirect adverse effects regarding 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 unknown 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 using the drug for the mother should be weighed against the benefits of breastfeeding and the potential risk to the infant.

Fertility. Animal studies in rats did not reveal any effect on fertility.

Ability to influence reaction speed when driving or operating machinery.

Betahistine is indicated for the treatment of Ménière’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 car or operate machinery. According to clinical studies investigating the effect of the drug on the ability to drive and operate machinery, betahistine had no effect or only a negligible effect on this ability.

Dosage and Administration.

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

The dosage should be individually adjusted according to the response. Improvement in symptoms may sometimes be observed only after several weeks of treatment. Optimal results may sometimes be achieved with treatment lasting several months. According to some data, initiating treatment at an early stage of the disease may prevent its progression or hearing loss at later stages.

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

Geriatric patients

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

Patients with renal or hepatic impairment

Specific clinical studies have not been conducted in this patient group; however, based on post-marketing experience with betahistine, dose adjustment is not necessary.

Children

Due to insufficient data on 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 betahistine overdose. Mild to moderate symptoms (nausea, drowsiness, abdominal pain) were observed in some patients after ingestion of doses up to 640 mg. More severe complications (seizures, cardiopulmonary complications) occurred following intentional ingestion of high doses of betahistine, particularly in combination with overdose of other medicinal products.

Treatment. Management of overdose should include standard supportive measures.

Adverse Reactions

The adverse reactions listed below were observed in patients receiving 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 cases reported during clinical trials, the following adverse events 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 side effects usually resolve when the medication is taken with food or after dose reduction.

Skin and subcutaneous tissue disorders

Hypersensitivity reactions involving the skin and subcutaneous tissue have been observed, including angioneurotic edema, urticaria, rash and pruritus.

Shelf life: 3 years.

Storage conditions:

8 mg and 16 mg tablets should be stored at a temperature not exceeding 25 °C, in a place inaccessible to children.
24 mg tablets should be stored in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging:

8 mg and 16 mg tablets: 10 tablets in a blister; 3 blisters in a cardboard box.
24 mg tablets: 10 tablets in a blister; 2 blisters in a cardboard box.

Prescription status: Prescription only.

Manufacturer: Merckle GmbH.

Manufacturer's address and place of business:
Ludwig-Merckle-Straße 3, 89143 Blaubeuren, Germany.