Betaserk®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BETAHISTINE® (BETASERC®)

Composition:

Active substance: betahistine dihydrochloride;

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

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

Pharmaceutical form. Tablets.

Main physico-chemical characteristics:

8 mg tablets: round, flat, white or almost white tablets with bevelled edges, marked with "256" on one side; diameter approximately 7 mm and tablet weight approximately 125 mg.

16 mg tablets: round, biconvex, divisible, white or almost white tablets with bevelled edges, with a score line and marking "267" on both sides of the score on one side; diameter approximately 8.5 mm and weight approximately 250 mg; the tablet can be divided into two equal doses.

24 mg tablets: round, biconvex, divisible, white or almost white tablets with bevelled edges, with a score line and marking "289" on both sides of the score on one side; diameter approximately 10 mm and tablet weight approximately 375 mg; the score line is intended only to facilitate breaking the tablet for ease of swallowing and is not intended for dividing the tablet into two equal doses.

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

Pharmacological properties.

Pharmacodynamics.

The mechanism of action of betahistine has been only partially elucidated. 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 exhibit 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 H3 receptors.

Betahistine may enhance 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 the recovery of vestibular function after unilateral labyrinthectomy in animals by stimulating and facilitating the process of central vestibular compensation. This effect is mediated by enhanced regulation of histamine turnover and release, resulting from H3 receptor antagonism. In humans, treatment with betahistine has also been associated with a reduced recovery time of vestibular function following labyrinthectomy.

Betahistine alters neuronal activity in vestibular nuclei.

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

The pharmacodynamic properties of betahistine, as demonstrated in animal studies, 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, as evidenced 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 the drug is administered with food, the maximum concentration (Cmax) of betahistine 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 (and urinary) concentration 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 betahistine in doses of 8–48 mg, approximately 85% of the initial dose is recovered in the urine. Renal or fecal excretion of unchanged betahistine is negligible.

Linearity.

The rate of elimination remains constant after oral administration of betahistine in 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.

Phaeochromocytoma.

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 drugs which inhibit monoamine oxidase (MAO) activity, including MAO subtype B (e.g., selegiline). Caution is recommended when betahistine is used concomitantly with MAO inhibitors (including B-selective MAO inhibitors).

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

Special precautions for use

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

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 adverse 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 were associated only with very high doses. The benefit of treatment for the mother should be weighed against the advantages of breastfeeding and the potential risk to the infant.

Fertility. Studies in rats have not revealed any effects on fertility.

Ability to influence reaction rate while 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 the symptomatic treatment of vestibular vertigo. Both conditions may negatively affect the ability to drive a vehicle 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.

Method of administration and dosage.

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

The dosage should be individually adjusted depending on the effect. Improvement of symptoms is sometimes observed only after several weeks of treatment. The best results are sometimes achieved with administration of the drug for 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.

Betaserk® can be administered independently of food intake. During treatment, 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 limited, extensive post-marketing experience allows the assumption that dose adjustment in elderly patients is not required.

Renal impairment

Specific clinical trials have not been conducted in this patient group, but according to post-marketing experience, dose adjustment is not necessary.

Hepatic impairment

Specific clinical trials have not been conducted in this patient group, but according to post-marketing experience, dose adjustment is not necessary.

Children

Due to insufficient data on safety and efficacy of Betaserk®, its use is not recommended 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) occurred 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.

Side effects

The following adverse reactions have been observed in patients treated with Betaserc® during placebo-controlled studies, with the following frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000).

Gastrointestinal disorders

Common: nausea and dyspepsia.

In addition to cases reported during clinical trials, the following adverse events have been spontaneously reported during post-marketing use and are known from scientific literature. Based on available data, the frequency cannot be estimated 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 affecting the skin and subcutaneous tissue have been observed, including angioedema, urticaria, rash and pruritus.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging.

8 mg tablets: 15 tablets per blister, 2 blisters per cardboard pack; 30 tablets per blister, 1 blister per cardboard pack; 25 tablets per blister, 4 blisters per cardboard pack;

16 mg tablets: 15 or 21 tablets per blister, 2 blisters per cardboard pack; 20 tablets per blister, 3 blisters per cardboard pack;

24 mg tablets: 10 tablets per blister, 1 or 5 blisters per cardboard pack; 20 tablets per blister, 1, 3 or 5 blisters per cardboard pack; 25 tablets per blister, 2 or 4 blisters per cardboard pack.

Prescription category. Prescription only.

Manufacturer.

Mylan Laboratories SAS, France.

Manufacturer's address and place of business.

Route de Belleville, Lieu dit Maillard, 01400, Chatillon-sur-Chalaronne, France.