Betahistine

Betahistine Dihydrochloride 8mg Tablets

Each tablet contains Betahistine dihydrochloride 8 mg

Excipient(s) with known effect: Each tablet contains 50 mg lactose

For a full list of excipients, see section 6.1.

Tablets for oral administration

Flat white tablets, with bevelled edge. Markings: R3 on one side scoreline on the reverse.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

Betahistine is indicated for the treatment of vertigo, tinnitus and hearing loss associated with Ménière's syndrome.

Posology:

Adults

(including the elderly);

Initially two tablets three times daily taken preferably with meals. Maintenance doses are generally in the range 24-48 mg daily.

Paediatric population: not recommended for use in children below 18 years due to insufficient data on safety and efficacy.

Geriatric 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 patient population.

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.

Betahistine is contraindicated in patients with a phaeochromocytoma and hypersensitivity to betahistine dihydrochloride or any of the excipients listed in section 6.1.

Caution is advised in the treatment of patients with a history of peptic ulcer. Clinical intolerance to betahistine dihydrochloride in bronchial asthma patients has been shown in a relatively few patients. These patients need to be carefully monitored during the therapy.

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, interaction of betahistine with antihistamines may in theory affect the efficacy of one of these drugs.

Pregnancy:

There are no adequate data from the use of betahistine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant therapeutic exposure. As a precautionary measure, it is preferable to avoid the use of betahistine during pregnancy.

Lactation:

It is not known whether betahistine is excreted in human milk. Betahistine is excreted in rat milk. Effects seen post-partum in animal studies were limited to very high doses. The importance of the drug to the mother should be weighed against the benefits of nursing and the potential risks for the child.

Fertility:

Animal studies did not show effects on fertility in rats.

Vertigo, tinnitus and hearing loss associated with Ménière'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.

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

Gastrointestinal disorders:

Common: nausea and 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:

Hypersensitivity 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.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

Pharmacotherapeutic group :Antivertigo preparation. ATC Code: NO7CA01

The mechanism of action of betahistine is only partly 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 characterized 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 Ménière's disease as was demonstrated by improvements in severity and frequency of vertigo attacks

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 metabolized 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 faecal 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.

Chronic toxicity:

Adverse effects in the nervous system were seen in dogs and baboons after intravenous doses at and above 120 mg/kg.

Chronic oral toxicity testing for 18 months in rats at a dose of 500 mg/kg and 6 months in dogs at a dose of 25 mg/kg showed betahistine to be well tolerated with no definitive toxicities.

Mutagenic and carcinogenic potential:

Betahistine does not have mutagenic potential.

In an 18 months chronic toxicity study in rats betahistine up to a dose of 500 mg/kg did not show any evidence for carcinogenic potential.

Reproduction toxicity:

Effects in reproductive toxicity studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Lactose monohydrate

Citric acid anhydrous

Microcrystalline cellulose

Maize starch

Crospovidone

Povidone K25

Sodium stearyl fumarate

Not applicable

2 Years

Do not store above 30°C.

Betahistine Dihydrochloride 8mg Tablets are packed in PVC/PE/PVDC with backing of aluminium foil blister packs contained in a cardboard carton.

Pack sizes: 84, 100 and 120 Tablets. Not all pack size may be marketed.

No special requirements

Flamingo Pharma (UK) Ltd.

1^st Floor, Kirkland house,

11-15 Peterborough Road Harrow,

Middlesex,

HA1 2AX,

United Kingdom

PL 43461/0049

22/03/2018

07/10/2019