VAZOSERK FORT

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VASOSERCFORT (VASOSERCFORT)

Composition:

Active substance: betahistine;

1 tablet contains 16 mg of betahistine dihydrochloride;

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

Pharmaceutical form. Tablets.

Main physico-chemical properties: white, round tablets with a break 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. Available data are from studies conducted in animals and in 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 increase blood flow to the cochlear region as well as to the entire brain Pharmacological studies in animals have demonstrated improved circulation in the stria vascularis vessels 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 neurectomy in animals, thereby speeding up 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 also reduced the time required for vestibular function recovery after neurectomy.

Betahistine alters neuronal activity in vestibular nuclei

It has also been established that betahistine exerts a dose-dependent inhibitory effect on spike generation 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, shown by reduction in 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 betahistine itself are very low; therefore, all pharmacokinetic analyses are performed by measuring concentrations of the metabolite 2-pyridylacetic acid in plasma and urine.

When administered with food, the maximum concentration (Cmax) 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

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

After oral administration of betahistine, the concentration of 2-pyridylacetic acid in plasma (and urine) reaches its maximum within 1 hour after dosing 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 administration of 8–48 mg of the drug, indicating linear pharmacokinetics of betahistine, and suggesting that the metabolic pathway involved is not saturated.

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 interactions.

In vivo studies on the interaction 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 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.

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

Use during pregnancy or breast-feeding.

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

Results of animal studies are inadequate to assess the impact on pregnancy progression, embryonic/foetal development, labour, or postnatal development. The potential risk for humans is unknown. Betahistine should not be used during pregnancy except in cases of clear necessity.

Lactation (breast-feeding). It is unknown whether betahistine passes into human breast milk. Studies in animals on the passage of betahistine into milk have not been conducted. The benefit of treatment for the mother should be weighed against the advantages of breast-feeding and the potential risk to the infant.

Effects on ability to drive and use machines.

Betahistine is indicated for the treatment of Ménière's syndrome, characterised by the triad of 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. According to clinical studies evaluating 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 divided and taken throughout the day: ½–1 tablet three times daily.

The drug should preferably be taken during meals or shortly after eating. The dose should be individually adjusted according to the therapeutic response. Improvement in symptoms may only become evident after 2–3 weeks of treatment. Optimal results are achieved with administration of the drug over several months. There is evidence that initiating treatment early in the disease course may prevent progression and/or prevent hearing loss at later stages.

Geriatric Patients

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

Renal Impairment

No specific clinical trials have been conducted in patients with renal impairment; however, based on post-marketing experience, dose adjustment is not necessary.

Hepatic Impairment

No specific clinical trials have been conducted in patients with hepatic impairment; however, according to post-marketing experience, dose adjustment is not required.

Children

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

Overdose

There have been a few 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) have been reported following intentional ingestion of high doses of betahistine, particularly when combined 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 studies, 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.

Nervous system disorders

Common: headache.

In addition to cases 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, gastro-intestinal 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

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

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.

15 tablets in a blister; 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ABDI IBRAHIM Ilac Sanai ve Ticaret A.S.

Manufacturer's address.

Orhan Gazi Mahallesi Tunc Caddesi No. 3, Esenyurt/Istanbul, Turkey.