ADVERT-16

NAME OF THE MEDICINAL PRODUCT
ADVERT- 16 mg tablets

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 16mg betahistine dihydrochloride.

Therapeutic indications
Betahistine is indicated for the treatment of vertigo, tinnitus, hearing loss and nausea associated with Ménière´s syndrome.

Posology and method of administration

Dosage for Adults (including the elderly):
Initial oral treatment is 8 to 16 mg three times daily, taken with food.
Maintenance doses are generally in the range 24 - 48 mg daily. Dosage can be adjusted to suit individual patient needs.

Children:
Betahistine tablets are not recommended for use in children. Betahistine efficacy and safety have not been studied in children and adolescents below the age of 18 years.

Contraindications
Betahistine is contraindicated in patients with phaeochromocytoma. As betahistine is a synthetic analogue of histamine it may induce the release of catecholamines from the tumor resulting in severe hypertension.

Also contraindicated are the following:
- Known hypersensitivity to betahistine hydrochloride and/or any other excipient.
- Concurrent use with antihistamines.

Special warnings and precautions for use
Caution is advised in the treatment of patients with peptic ulcer or a history of peptic ulceration, because of the occasional dyspepsia encountered in patients on betahistine.
Caution should be exercised in patients with bronchial asthma.
Caution is advised in prescribing betahistine to patients with either urticaria, rashes of allergic rhinitis, because of the possibility of aggravating these symptoms.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interaction with other medicinal products and other forms of interaction
There are no proven cases of hazardous interactions.
There is a case report of an interaction with ethanol and a compound containing pyrimethamine with dapsone and another of potentiation of betahistine with salbutamol.
As betahistine is an analogue of histamine, interaction with antihistamines is theoretically possible, but none have been reported.

Pregnancy and lactation
The safety of betahistine in pregnancy has not been fully established, but tests conducted on pregnant rabbits have shown no evidence of teratological effects. Caution is therefore advised when administering betahistine during pregnancy.

Betahistine is excreted in breast milk in concentration similar to those found in plasma. The toxic effects of betahistine in neonates at these concentrations are not known. The use of betahistine should therefore be avoided in patients who are breast feeding.

Effects on ability to drive and use machines
Rare reports of drowsiness associated with betahistine have been made. Patients should be advised that if they are affected in this way they should avoid activities requiring concentration, such as driving and operating machinery.

Undesirable effects

Immune system disorders
Very rare: skin rashes and pruritus.

Hepatobiliary disorders
Very rare: liver injury after long exposure.

Nervous system disorders
Not known (cannot be estimated from the available data): headaches, and occasional drowsiness.

Gastrointestinal disorders
Rare: gastro-intestinal upset, nausea, dyspepsia.

Overdose
The symptoms of betahistine overdose are nausea, vomiting, dyspepsia, ataxia and seizures at higher doses. No specific antidote. Gastric lavage and symptomatic treatment are recommended.

Pharmacodynamic properties
Betahistine is an antivertigo preparation, which belongs to the group of miscellaneous drugs that act on the nervous system.

Betahistine´s H1-agonist activity at histamine receptors in peripheral blood vessels has been demonstrated in man by the abrogation of betahistine-induced vasodilation with the histamine antagonist diphenhydramine. Betahistine has minimal effects on gastric acid secretion (an H2-receptor mediated response).

The efficacy of betahistine in the treatment of vertigo 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.

Single oral doses of betahistine of up to 32 mg in normal subjects produced maximal suppression of induced vestibular nystagmus 3 to 4 hours post-dose, with larger doses being more effective in reducing the nystagmus duration.

Pulmonary epithelial permeability in man is increased by betahistine. This is derived from a reduction in the time of clearance from the lung to blood of a radioactive marker. This action is prevented by oral pre-treatment with terfenadine, a known H1- receptor blocker.

Whilst histamine has positive inotropic effects on the heart, betahistine is not known to increase cardiac output and its vasodilator effect may produce a small fall in blood pressure in some patients.

In man, betahistine has little effect on exocrine glands

Pharmacokinetic properties

Absorption
Betahistine is completely absorbed after oral administration, and for fasting subjects, peak plasma concentrations of 14C-labelled betahistine are attained approximately one hour after oral administration.

Distribution
After oral administration of betahistine, its levels in plasma are very low. Therefore, the pharmacokinetic assessment of this drug is based on plasma concentration data of the only known metabolyte, 2-pyridylacetic acid. Little or no binding occurs with human plasma proteins.

Metabolism and elimination
Elimination of betahistine primarly occurs by metabolism in the liver. Subsequently, the metabolites are mainly eliminated by renal excretion. 85-90% of the radioactivity of an 8mg dose appears in 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.

Preclinical safety data
Repeated dose toxicity studies of six months duration in dogs and 18 months duration in albino rats revealed no clinically relevant harmful effects at dose levels in the range 2.5 to 120 mg.kg –1. Betahistine is devoid of mutagenic potential and there was no evidence of carcinogenicity in rats. Tests conducted on pregnant rabbits showed no evidence of teratological effects.

Shelf life
The shelf-life of ADVERT- 16 mg tablets is 2 years when stored in the original packing.

Special precautions for storage
Store in the original package.

Nature and contents of container
Alu-Alu packing

Available in packs of 10 tablets.