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Betahistine hydrochloride.

Each uncoated tablet contains: Betahistine hydrochloride BP 16 mg. Excipients: q.s.
Betahistine hydrochloride is a white to almost white crystalline powder, which is very hygroscopic. The product is very soluble in water, freely soluble in methanol and 96% ethanol, and slightly soluble in isopropanol. The pKa values are 3.5 and 9.7. Betahistine hydrochloride is an antivertigo drug. It is commonly prescribed patients with balance disorders or to alleviate vertigo symptoms associated with Meniere's disease. The drug increases histamine endogenous production and also functions as a weak histamine receptor H1 agonist and H3 receptor antagonist. Betahistine chemically is 2-[2-(methylamino)ethyl]pyridine, and is formulated as the dihydrochloride salt. Its structure closely resembles that of phenethylamine and histamine.

Pharmacology: Pharmacodynamics: The mechanism of action of betahistine is known partially. Betahistine has a very strong affinity as an antagonist for histamine H3 receptors and a weak affinity as an agonist for histamine H 1 receptors. Betahistine has two modes of action. Primarily, it has a direct stimulating (agonistic) effect on H1 receptors located on blood vessels in the inner ear. It appears to act on the precapillary sphincter in the stria vascularis of the inner ear, thus reducing the pressure in the endolymphatic space.
In addition, betahistine has a powerful antagonistic effects at H3 receptors, and increases the levels of neurotransmitters released from the nerve endings. The increased amounts of histamine released from histaminergic nerve endings stimulates H1 receptors, thus augmenting the direct agonist ic effects of betahistine on these receptors. This explains the potent vasodilatory effects of betahistine in the inner ear. This explains the efficacy of betahistine in the treatment of vertigo. Taken together these properties contribute to its therapeutic benefits in Meniere's syndrome. Meniere's syndrome is characterised by attack of vertigo, tinnitus, nausea, headache, hearing loss. The efficacy of betahistine may be due to its ability to modify the circulation of the inner ear or due to a direct effect on neurons of the vestibular nucleus.
Pharmacokinetics: In man, orally administered doses of betahistine hydrochloride are rapidly and completely absorbed from the gastrointestinal tract. The drug is rapidly metabolized to one major metabolite - 2-pyridylacetic acid - and excreted in the urine. Studies with radiolabelled betahistine have demonstrated a plasma half life of 3.4 hours and a urinary half life of 3.5 hours for the radio-label. Urinary excretion of the label was about 90% complete within 24 hours of administration.
Absorption: Betahistine is completely absorbed after oral administration, and peak plasma concentrations of C-labelled betahistine are attained after approximately one hour of oral administration for fasting subjects.
Distribution: Little or no binding occurs with human plasma proteins.
Metabolism and Elimination: Elimination of betahistine takes place mainly by metabolism and the metabolites are subsequently eliminated mainly by renal excretion. Following the absorption, the drug is metabolized rapidly in the metabolite and almost completely in metabolite 2-pyridylacetic acid. After oral administration of betahistine, its plasma levels are very low. Therefore, the assessment of the pharmacokinetics of betahistine is based on the plasma concentration data of the only metabolite 2-pyridylacetic acid. The concentration of 2-pyridylacetic acid reaches its maximum at I hour after intake and declines with half approximately 3.5 hours. The 2-pyridylacetic acid easily excreted in urine. In the dose range between 8 and 48 mg, about 85% of the original dose was recovered in the urine.85-90% of the radioactivity of an 8 mg dose appears in the urine over 56 hours, with maximum excretion rates reached within 2 hours of administration. There is no evidence of presystemic metabolism and biliary excretion is not thought to be an important route of elimination for the drug or any of its metabolites. However betahistine is subject to metabolism in the liver.

Meniere's Syndrome as defined by the following core symptoms: vertigo (with nausea/vomiting), hearing loss (hardness of hearing), tinnitus.

The recommended starting dose is 8 to 16 mg taken three times a day. The maximum recommended daily dose is 48 mg. The tablets may be taken with or without food. However, if gastrointestinal upset occurs, it is recommended that the tablets be taken with meals. The dosage should be individually adapted according to the response. Improvement can sometimes only be observed after a couple of weeks of treatment.

There have been a few cases of overdosage reported. Although in most cases no overdose symptoms were reported, some patients have experienced mild to moderate symptoms of overdosage including nausea, dry mouth, epigastric pain and sleepiness at doses above 200 mg. A case of convulsion was reported at a dose of 728 mg. In all cases recovery was complete. Treatment should include standard supportive measures. Contact the Poisons Information Centre for advice on management of overdosage.

Betahistine hydrochloride tablets are contraindicated as follows: during pregnancy and lactation, in children less than 18 years, in patients suffering from phaeochromocytoma, in patients with active peptic ulcer or a history of this condition, in patients with hypersensitivity to any component to the product (see Description).

Patients with bronchial asthma need to be carefully monitored during therapy. Caution should be taken in the treatment of patients receiving antihistamines (see Interactions).
Effects on Fertility: Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.
Carcinogenicity/Mutagenicity: No animal data is available on the carcinogenic or mutagenic potential of betahistine.
Effect on Ability to Drive and Use Machines: Betahistine is presumed to be safe or unlikely to produce an effect on the ability to drive or use machinery.
Use in Pregnancy: Category B2: Betahistine hydrochloride should not be used during pregnancy (see Contraindications) since there is insufficient data on the use of this drug during pregnancy to evaluate possible harmful effects. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of foetal damage.
Use in Lactation: Betahistine hydrochloride should not be used during lactation (see Contraindications).
Use in Children: Due to lack of clinical experience, betahistine hydrochloride should not be used in children less than 18 years (see Contraindications).

Most of the reported adverse reactions pertain to the skin, gastrointestinal tract, body as a whole, nervous system, respiratory system and cardiovascular system. Events are listed within body system and categorised by frequency according to the following definitions: Common (frequency ≥1 and <1%); Rare (frequency ≥0.01% and <0.1%); Very rare (frequency <0.01%).
Skin and subcutaneous tissue disorders: Rare: various types of rash, pruritis and urticaria/angioneurotic oedema.
These reactions are probably related to the histamine like structure of betahistine.
There was a single case of Stevens Johnson syndrome.
Body as a whole: Common: headache. Rare: tiredness and malaise.
Gastrointestinal system: Common: nausea and dyspepsia. Rare: vomiting, diarrhoea, abdominal distension, bloating and epigastric pain have been reported. These symptoms were usually mild. Gastrointestinal disturbances may be relieved by reducing the dose or by taking betahistine with meals.
Nervous system: Rare: dizziness. Very rare: convulsions, somnolence, confusion and hallucinations.
Some of these symptoms may also be observed as part of the disease condition and are usually resolved without changes to the treatment schedule.
Patients with neurological events usually presented with confounding factors.
Cardiovascular system: Very rare: vasodilation, postural hypotension and tachycardia.
Respiratory system: Very rare: dyspnoea, asthma and bronchospasms (see Precautions).
Immune system disorders: Hypersensitivity reactions, e.g. anaphylaxis have been reported.

In vitro data indicate an inhibition of betahistine metabolism by drugs that inhibit monoamineoxidase (MAO) including MAO subtype B (e.g. selegiline). Caution is recommended when using betahistine and MAO inhibitors (including MAO-B selective) concomitantly. An antagonism between antihistamines could be expected on a theoretical basis. However, no such interactions have been reported.

Store at temperatures not exceeding 30°C. Store in a dry place and protect from light.

Antivertigo Drugs

N07CA01 - betahistine ; Belongs to the class of antivertigo preparations.

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