SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Betahistine 16 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 16 mg Betahistine dihydrochloride For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet.

White to off-white round (diameter 8.5 mm), uncoated tablets debossed with ‘X’ and a break line on one side and ‘88’ on the other side.

The tablet can be divided into equal doses.

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 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

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

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.

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.

Patients with bronchial asthma should be monitored carefully during the treatment with betahistine.

Caution is advised in prescribing betahistine to patients with either urticaria, rashes or allergic rhinitis, because of the possibility of aggravating these symptoms.

Caution is advised in patients with severe hypotension.

4.5 Interaction with other medicinal products and other forms of interaction

There are no proven cases of hazardous interactions. No in-vivo interaction studies have been performed. Based on in-vitro data no in-vivo inhibition on Cytochrome P450 enzymes is expected.

Although an antagonism between Betahistine and antihistamines could be expected on a theoretical basis, no such interactions have been reported.

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.

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.

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

4.6 Fertility, pregnancy and lactation

Pregnancy

There is a very limited amount of data from the use of betahistine in pregnant women. Animal studies, though insuffcient do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). The potential risk for humans is unknown. As a precautionary measure, it is preferable to avoid the use of Betahistine during pregnancy.

Lactation

There is insufficient information on the excretion of betahistine in human milk. There are no animal studies on the excretion of betahistine in milk. Betahistine should not be used during breastfeeding.

4.7 Effects on ability to drive and use machines

Betahistine is indicated for vertigo, tinnitus and hearing loss associated with Meniere’s syndrome which 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).

Gastrointestinal disorders:

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”.

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

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).Other symptoms of betahistine overdose are vomiting, dyspepsia, ataxia and seizures. More serious complications (convulsion, pulmonary or cardiac complications) were observed in cases of intentional overdose of betahistine especially in combination with other overdosed drugs. No specific antidote. Gastric lavage and symptomatic treatment are recommended within one hour after intake.

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: 2.7 Central Nervous System. Antiemetic and anti-vertigo ATC code: N07C A01

The mechanism of action of betahistine is only partially understood.

There are several plausible hypotheses that are supported by animal studies and human data:

Betahistine affects the histaminergic system:

Betahistine acts both as a partial histamine H1-receptor agonist and histamine H3-receptor antagonist also in neuronal tissue, and has negligible H2-receptor activity.

Betahistine increases histamine turnover and release by blocking presynaptic H3-receptors and inducing H3-receptor downregulation.

Betahistine may increase blood flow to the cochlear region as well as to the whole brain:

Pharmacological testing in animals has shown that the blood circulation in the striae vascularis of the inner ear improves, probably by means of a relaxation of the precapillary sphincters of the microcirculation of the inner ear.

Betahistine was also shown to increase cerebral blood flow in humans.

Betahistine facilitates vestibular compensation:

Betahistine accelerates the vestibular recovery after unilateral neurectomy in animals, by promoting and facilitating central vestibular compensation; this effect is characterised by an up-regulation of histamine turnover and release, is mediated via the H3 Receptor antagonism.

In human subjects, recovery time after vestibular neurectomy was also reduced when treated with betahistine.

Betahistine alters neuronal firing in the vestibular nuclei:

Betahistine was also found to have a dose-dependent inhibiting effect on spike generation of neurons in lateral and medial vestibular nuclei.

The pharmacodynamic properties as demonstrated in animals may contribute to the therapeutic benefit of betahistine in the vestibular system.

The efficacy of betahistine was shown in studies in patients with vestibular vertigo and with Meniere's disease as was demonstrated by improvements in severity and frequency of vertigo attacks.

5.2 Pharmacokinetic properties

Absorption

Orally administered betahistine is readily and almost completely absorbed from all parts of the gastro-intestinal tract. After absorption, the drug is rapidly and almost completely metabolized into 2-pyridylacetic acid. Plasma levels of betahistine are very low. Pharmacokinetic analyses are therefore based on 2-PAA measurements in plasma and urine.

Under fed conditions Cmax is lower compared to fasted conditions. However, total absorption of betahistine is similar under both conditions, indicating that food intake only slows down the absorption of betahistine.

Distribution

The percentage of betahistine that is bound by blood plasma proteins is less than 5 %.

Biotransformation

After absorption, betahistine is rapidly and almost completely metabolised into 2-PAA (which has no pharmacological activity).

After oral administration of betahistine the plasma (and urinary) concentration of 2-PAA reaches its maximum 1 hour after intake and declines with a half-life of about 3.5 hours.

Excretion:

2-PAA is readily excreted in the urine. In the dose range between 8 and 48 mg, about 85% of the original dose is recovered in the urine. Renal or fecal excretion of betahistine itself is of minor importance.

Linearity:

Recovery rates are constant over the oral dose range of 8 - 48 mg indicating that the pharmacokinetics of betahistine are linear, and suggesting that the involved metabolic pathway is not saturated.

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

Microcrystalline cellulose Mannitol

Povidone Crospovidone Citric acid anhydrous Colloidal anhydrous silica Talc

Stearic acid

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 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 Polyamide/ Aluminium/ PVC/ Aluminium:

16 mg: 10, 20, 30, 60 & 84 tablets.

White opaque round HDPE bottle with polypropylene closure containing cotton coil: 30 and 1000 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Milpharm Limited

Ares Block, Odyssey Business Park

West End Road

Ruislip HA4 6QD

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 16363/0418

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/08/2014

10    DATE OF REVISION OF THE TEXT

08/08/2014