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Betahistine Dihydrochloride 24 Mg Tablets

SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Betahistine dihydrochloride 24 mg tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 24 mg betahistine dihydrochloride.

Each tablet contains 150 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet.

White, flat, round tablet with bevelled edges with a break-line; tablets have inscription ‘BH” on one side of the score and “24” on the other side of the score, both markings on the same side of the tablet. Dimensions (diameter): 10.0 mm.

The tablet can be divided into equal halves.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the treatment of Meniere’s syndrome, symptoms of which may include vertigo, nausea, tinnitus and hearing loss.

4.2 Posology and method of administration

Dosage

Adults:

Initial oral treatment is 8 to 16 mg three times daily, taken preferably with meals.

Maintenance doses are generally in the range 24 - 48 mg daily. Daily dose should not exceed 48 mg. Dosage can be adjusted to suit individual patient needs. Sometimes improvement could be observed only after a couple of weeks of treatment.

Renal impairment

There are no specific clinical trials available in this patient group, but according to post-marketing experience no dose adjustment appears to be necessary.

Hepatic impairment

There are no specific clinical trials available in this patient group, but according to post-marketing experience no dose adjustment appears to be necessary.

Elderly population

Although there are limited data from clinical studies in this patient group, extensive post marketing experience suggests that no dose adjustment is necessary in this population.

Paediatric population

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

Method of administration

Take the tablets preferably with meals or after meals with a glass of water.

4.3 Contraindications

Betahistine is contraindicated in case of:

•    Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

•    Phaeochromocytoma. As betahistine is a synthetic analogue of histamine it may induce the release of catecholamines from the tumor resulting in severe hypertension.

4.4 Special warnings and precautions for use

It is recommended to closely monitor patients with a history of peptic ulcers even though studies in healthy subjects showed no elevation of gastric acid secretion by betahistine dihydrochloride.

Caution should be exercised in patients with:

•    bronchial asthma.

•    urticaria, rashes or allergic rhinitis, because of the possibility of aggravating these symptoms.

•    pronounced hypotension.

•    concomitant treatment with antihistamines (see section 4.5).

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

4.5 Interaction with other medicinal products and other forms of interaction

There are no studies on the interactions with the following medicinal products also used in the treatment of the disorders mentioned in section 4.1: vasodilators, psychotropic medicinal products, in particular sedatives, tranquillisers and neuroleptics, parasympatholytics, and vitamins.

Betahistine should not be concomitantly administered with antihistamines because animal studies have demonstrated that the effect of both could be diminished.

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.

Betahistine is a histamine analogue, concurrent administration of H1 antagonists may cause a mutual attenuation of effect of the active agents.

Note:

If betahistine is to be administered subsequent to the treatment with an antihistamine and this treatment is stopped abruptly, withdrawal symptoms such as sleep disorders and agitation could appear because of the sedative action of antihistamines. Therefore the treatment with the antihistamine should be tapered over approximately 6 days.

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 monoaminooxidase (MAO) including MAO subtype B (e.g. selegiline). Caution is recommended when using betahistine and MAO inhibitors (including MAO-B selective) concomitantly.

4.6 Fertility, pregnancy and lactation

Pregnancy:

There are no adequate data from the use of betahistine in pregnant women.

Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition and postnatal development. The potential risk for humans is unknown. Betahistine should not be used during pregnancy unless clearly 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. 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

Vertigo, tinnitus and hearing loss associated with Meniere's syndrome can negatively affect the ability to drive and use machines. In clinical studies specifically designed to investigate the ability to drive and use machines betahistine had no or negligible effects.

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 and in post-marketing reports: 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); and not known (frequency cannot be estimated from the available data).

Common: nausea & dyspepsia

Nervous system disorders: Common: headache

In addition to those events 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 “not known”.

Cardiac disorders:

Not Known: palpitations, tightness of the chest

Immune system disorders:

Not known: hypersensitivity reactions, e.g. anaphylaxis.

Gastrointestinal disorders:

Not known: Mild gastric complaints (e.g. vomiting, gastrointestinal pain, abdominal distension and bloating). These can normally be dealt with by taking the dose during meals or by lowering the dose.

Skin and subcutaneous tissue disorders

Not known:    cutaneous and subcutaneous hypersensitivity reactions, in particular

angioneurotic oedema, urticarial, rash, and pruritus.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms of overdose:

In case of overdose, the following symptoms, analagous to histamine overdose, might occur: headache, redness of the face, vertigo, tachycardia, hypotension, bronchial spasm, oedema, in particular oedema of the mucosa of the upper respiratory tract (Quincke’s oedema).

Treatment of overdose:

There is no specific antidote to betahistine dihydrochloride. In addition to general measures aimed at betahistine elimination (gastric lavage, administration of activated charcoal), treatment should be symptomatic and supportive.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antivertigo preparations

ATC code: N07CA01

Betahistine is a member of the group of beta - 2 pyridylalkylamines. Betahistine is a structural analogue of the endogenous histamine.

The exact biochemical mode of action of betahistine, and its receptor specificity and affinity, has not been elucidated to date.

Betahistine pharmacodynamic studies in animals showed predominantly H1 -receptor agonist activity of betahistine. On the basis of the animal studies, various hypotheses for the mode of action of betahistine on the vestibular function have been postulated.

5.2 Pharmacokinetic properties

There is insufficient data on the pharmacokinetics of betahistine in humans.

Absorption:

Following oral administration betahistine is rapidly and completely absorbed.

Distribution:

No data is available on tissue distribution in man. There is little or no binding to plasma proteins.

Betahistine undergoes rapid and complete biotransformation, probably hepatic, with evidence for the formation of 2 - pyridylacetaldehyde and 2 - (2 -aminoethyl)pyridine.

Elimination:

It is excreted almost quantitatively in urine as the metabolite 2 - pyridylacetic acid within

24 hours. No unchanged betahistine has been detected.

Betahistine is excreted in breast milk at approximately the same level as are found in plasma.

A randomised, single dose bioequivalence study with Betahistine 24 mg tablets on 36 subjects was carried out in 2009. Test and reference were administered orally after a light breakfast. The primary evaluation parameter was the plasma levels of the metabolite 2 - pyridylacetic acid, see Figure 1 following.

The results confirmed bioequivalence of Betahistine 24 mg tablets with the reference product (93.4 % CI), within narrow limits for the area under the curve (AUC, 90 % -110 %) and within conventional limits for maximal plasma concentration (Cmax, 80 % - 125 %).

Table 1: Summary statistics for the primary pharmacokinetic parameters 2 -

pyridylacetic acid following a single dose (1 tablet) of treatment A (Vertimed 24) or treatment B (reference 24 mg tablets)

Parameter

Test A*

Reference B*

Test / Reference**

Cmax (ng / ml)

818.0 (± 352.3

875.9 (± 352.7)

0.93 (0.87 - 0.99)

AUC0 - 00 (ng / ml.h)

4557.3 (± 2759.0)

4375.4 (± 2091.1)

1.00 (0.95 - 1.07)

T1 / 2 (h)

3.15 (± 0.78)

3.10 (± 0.78)

1.02 (0.96 - 1.08)

* Arithmetic mean (± SD)

5.3 Preclinical safety data

There are no findings from preclinical chronic toxicity studies that suggest any increased risk associated with use in humans. Betahistine has been inadequately investigated for its toxicity in relation to reproduction. No adequate mutagenicity or carcinogenicity studies are available.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate Maize starch

Cellulose microcrystalline, E 460 Citric acid, anhydrous, E 330 Povidone K 25, E 1201 Crospovidone type A, E 1202 Hydrogenated vegetable oil

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blisters of PVC / PE / PVDC - aluminium.

Packs of 14, 20, 24, 28, 30, 48, 50, 60, 84, 90, 96, and 100 tablets are available. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Morningside Healthcare Ltd 115 Narborough Road Leicester LE3 0PA

8    MARKETING AUTHORISATION NUMBER(S)

PL 20117/0238

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/06/2015

10    DATE OF REVISION OF THE TEXT

29/06/2015