Medogistin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEGOHISTINE® (MEDOHISTINE)

Composition:

Active substance: betahistine dihydrochloride;

1 tablet contains betahistine dihydrochloride 16 mg or 24 mg;

Excipients: lactose monohydrate; corn starch; microcrystalline cellulose; anhydrous citric acid; povidone; crospovidone; hydrogenated vegetable oil.

Pharmaceutical form. Tablets.

Main physicochemical properties:

16 mg tablets: white or almost white, flat, round tablets with beveled edges and a score line, approximately 9 mm in diameter;

24 mg tablets: white or almost white, flat, round tablets with beveled edges and a score line, approximately 10 mm in diameter.

Pharmacotherapeutic group. Agents for treatment of vestibular disorders. ATC code N07CA01.

Pharmacological Properties.

Pharmacodynamics.

The mechanism of action of betahistine is only partially understood. There are several well-supported hypotheses, confirmed by studies in animals and humans.

Effect of betahistine on the histaminergic system. Betahistine has been shown to act as a partial agonist at H1-histamine receptors and as an antagonist 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 a down-regulation process of these H3 receptors.

Betahistine may increase blood flow to the cochlear region and to 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, speeding up and facilitating the process of central vestibular compensation. This effect is characterized by enhanced regulation of histamine turnover and release, mediated through H3 receptor antagonism. In humans, betahistine treatment has also been associated with a reduced recovery time of vestibular function following neuroectomy.

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 on the vestibular system. The efficacy of betahistine has been demonstrated in clinical trials in patients with vestibular vertigo and Ménière’s disease, with a reduction in the severity and frequency of vertigo attacks.

Pharmacokinetics.

Absorption. After oral administration, betahistine is rapidly and almost completely absorbed from 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 (Cmax) of betahistine is lower than when administered on an empty stomach. However, the total extent of absorption is identical in both cases. Thus, 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, the concentration of 2-pyridylacetic acid in plasma (and urine) 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 following oral doses of 8–48 mg, indicating linear pharmacokinetics of betahistine, 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 any component of the drug. Pheochromocytoma.

Interaction with other medicinal products and other forms of interaction.

In vivo studies on interaction with other medicinal products have not been conducted. Based on in vitro data, inhibition of cytochrome P450 enzyme activity is not expected in vivo. 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 administering betahistine concomitantly with MAO inhibitors (including selective MAO-B 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 medicinal product Medogistin®, careful monitoring of patients with bronchial asthma and/or a history of peptic ulcer of the stomach and duodenum is required. The product contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, 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. Animal studies have not shown 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 unknown whether betahistine passes into human breast milk. Betahistine passes into the milk of rats. Effects observed postpartum in animal studies were related only to 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. Animal studies in rats have not revealed any effect on fertility.

Ability to influence reaction speed when driving vehicles or operating machinery.

Betahistine is indicated for the treatment of Ménière's syndrome and 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.

Administration and Dosage.

The daily dose for adults is 24–48 mg, evenly distributed throughout the day.

The dosage should be individually adjusted according to the therapeutic response. Improvement of symptoms may sometimes be observed only after several weeks of treatment. Optimal results are achieved with administration of the drug over several months. There is evidence that initiating treatment at the early stages of the disease may prevent its progression and/or hearing loss at later stages.

The tablets should be swallowed whole with water, independent of food intake.

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

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

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

Children.

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

Overdose.

There have been several reported cases of overdose. In some patients, mild to moderate symptoms (nausea, drowsiness, abdominal pain) were observed 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. Management of overdose should include symptomatic treatment.

Adverse Reactions

The adverse reactions listed below are classified according to the following frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Gastrointestinal disorders.
Common: nausea and dyspepsia.

Nervous system disorders.
Common: headache.

In addition to cases reported during clinical trials, the following adverse events have been reported spontaneously during post-marketing use and in the scientific literature. Based on available data, the frequency cannot be determined and is therefore classified as not known.

Immune system disorders.
Frequency not known: hypersensitivity reactions, e.g. anaphylaxis.

Gastrointestinal disorders.
Frequency not known: mild gastrointestinal complaints (vomiting, abdominal pain, flatulence). These adverse effects usually resolve when the medication is taken with food or after dose reduction.

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

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua/

Shelf life. 3 years.

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

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

Prescription status. Prescription only.

Manufacturer.

1. Medochemie LTD (Central Factory)/
   Medochemie LTD (Central Factory).

2. Farmaceutisch Analytisch Laboratorium Duiven B.V./
   Farmaceutisch Analytisch Laboratorium Duiven B.V.

Manufacturer's name and address.

1. 1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus/
   1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus.

2. Dijkgraaf 30, Duiven, 6921RL, Netherlands/
   Dijkgraaf 30, Duiven, 6921RL, Netherlands.