Document: spc-doc_PL 28444-0009 change

• spc-doc_PL 00142-0502
• spc-doc_PL 00289-1545
• spc-doc_PL 04569-0349
• spc-doc_PL 15833-0018
• spc-doc_PL 20075-0315
• spc-doc_PL 28444-0009

---

SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Betahistine Dihydrochloride 16 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

One Betahistine Dihydrochloride 16 mg Tablet contains 8 mg Betahistine dihydrochloride

One Betahistine Dihydrochloride 16 mg Tablet contains 140 mg lactose monohydrate.

For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Tablet.

White or almost white, round tablet. Embossed B16 on one side, scored reverse.

The tablet can be divided into equal halves.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Betahistine is indicated for treatment of Meniere’s syndrome, symptoms of which may include vertigo, tinnitus, hearing loss and nausea.

4.2    Posology and method of administration

Dosage

Adults:

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.

Sometimes improvement could be observed only after a couple of weeks of treatment. Children and adolescents:

Betahistine tablets are not recommended for use in children and adolescents below age 18 due to lack of data on safety and efficacy.

Elderly:

Although there is limited data from clinical studies in this patient group, postmarketing experience suggests that there is no dosage adjustment required in elderly patients.

Impaired Renal Function:

There is no available data from clinical studies, however on the basis of postmarketing experience an adaptation of the dose is not required in patients with renal impairment.

Impaired Liver Function:

There is no available data from clinical studies, however on the basis of postmarketing experience an adaptation of the dose is not required in patients with renal impairment.

4.3 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:

• hypersensitivity to the active substance or to any of the excipients.

4.4 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. These patients need to be carefully monitored during the therapy.

Caution is advised in patients with severe hypotension.

This product contains lactose. Therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

No in-vivo interaction studies have been performed. Based on in-vitro data no in-vivo inhibition on cytochrome P450 enzymes is expected.

In vitro data indicate an inhibition of betahistine metabolism by drugs that inhibit monoamino-oxidase (MAO) including MAO subtype B (e.g. selegiline). Caution is recommended when using betahistine and MAO inhibitors (including MAO-B selective) concomitantly.

As betahistine is an analogue of histamine, an interaction with antihistamines is theoretically possible affecting the efficacy of the drugs, but none have been reported.

4.6    Pregnancy and lactation

Pregnancy:

There is insufficient data on the use of betahistine during pregnancy in humans. Animal studies have found no evidence of harmful effects on embryonic and foetal development, pregnancy, birth and the postnatal development.

Betahistine should not be used during pregnancy, unless strictly necessary.

Lactation:

It is not known whether betahistine is excreted in human milk. There are no animal studies on the excretion of betahistine in milk. A risk to the infant cannot be excluded. The importance of the drug to the mother should be weighed against the benefits of nursing and the potential risks for the child.

4.7    Effects on ability to drive and use machines

Betahistine has no or negligible effects on the ability to drive and use machines as no effects potentially influencing this ability were found to be related to betahistine in clinical studies.

4.8 Undesirable effects

The following undesirable effects have been experienced with the below indicated frequencies in betahistine-treated patients in placebo-controlled clinical trials:

Where:

Very common: more than 1 in 10 patients (> 1/10)

Common: more than 1 in 100 patients and less than 1 in 10 patients (>1/100 - <1/10)

Uncommon: more than 1 in 1,000 patients and less than 1 in 100 patients (>1/1,000 -<1/100)

Rare: more than 1 in 10,000 patients and less than 1 in 1,000 patients (>1/10,000 -<1/1,000)

Very rare: less than 1 in 10,000 patients, including isolated cases (<1/10,000)

Nervous system disorders:

Common: headaches

The occurrence of headaches in placebo controlled patients (5.9% out of a sample of 457 patients) was similar to that of patients treated with betahistine (5.1% from a sample of 468 patients).

Gastrointestinal disorders:

Common: nausea, dyspepsia

In addition to those side effects reported during clinical trials, the following undesirable effects have been reported spontaneously during post-marketing use and in scientific literature. A frequency cannot be estimated from the available data and is therefore classified as ‘unknown’.

Immune system disorders:

Allergic reactions, e.g. anaphylaxis, have been reported

Gastrointestinal disorders:

Mild gastric complaints (e.g. vomiting, gastrointestinal pain, abdominal distension and bloating) have been observed. These can normally be dealt with by taking the dose during meals or by lowering the dose.

Skin and subcutaneous tissue disorders:

Cutaneous and subcutaneous hypersensitivity reactions have been reported, in particular angioneurotic oedema, urticaria, rash and pruritus.

4.9 Overdose

A few overdose cases have been reported. Some patients experienced mild to moderate symptoms with doses up to 640 mg (e.g. nausea, somnolence abdominal pain). More serious complications (e.g. convulsion, pulmonary or cardiac complications) were observed in cases of intentional overdose of betahistine especially in combination with other overdosed drugs. Treatment of overdose should include standard supportive measures.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: antivertigo preparation, ATC code: N07C A01

Betahistine’s Hj-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).

Mechanism of action of betahisitine in Meniere’s syndrome is unclear. 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

5.2 Pharmacokinetic properties

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

Elimination of betahistine takes place mainly by metabolism and the metabolites are subsequently eliminated mainly by renal excretion. 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. 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.

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. Little or no binding occurs with human plasma proteins, however betahistine is subject to metabolism in the liver. Approximately 80-90% of the administered dose is excreted in the urine.

5.3 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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Povidone K90 Microcrystalline cellulose Lactose monohydrate Colloidal anhydrous silica Crospovidone Stearic acid.

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years

6.4    Special precautions for storage

Store in the original package and keep the blister in the outer carton in order to protect from light and moisture.

This medicinal product does not require any special temperature storage conditions.