Betahistine Dihydrochloride 8mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Betahistine dihydrochloride 8 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 8 mg of betahistine dihydrochloride
3. PHARMACEUTICAL FORM
Round, biplane white or almost white tablets with bevel-edges on both sides. The tablet is marked with ‘B8’ on one side.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Vertigo, tinnitus and hearing loss associated with Meniere’s syndrome.
4.2. Posology and Method of Administration
Adults (including elderly): Initially 16 mg 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.
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.
Route of administration: Oral.
4.3. Contraindications
Phaeochromocytoma. Hypersensitivity to any components of the product.
4.4 Special warnings and precautions for use
Caution is advised in the treatment of patients with a history of peptic ulcer.
Clinical intolerance of betahistine has been shown in a small number of bronchial asthma patients therefore caution should be exercised when treating such patients.
Contains lactose. 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 monoamine-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.
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 [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
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.
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Anti-vertigo preparations. ATC code: N07CA01
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 Hi-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 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 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.
5.3. Preclinical Safety Data
Repeat oral dose toxicity studies in dogs and rats for 6 and 18 months respectively revealed no clinically relevant adverse effects.
Betahistine was not mutagenic in conventional in vitro and in vivo studies of genotoxicity.
Histopathological examination in the 18 months chronic toxicity study indicated no carcinogenic effects. However, specific carcinogenicity studies were not performed with Betahistine.
Limited studies of reproductive toxicity in rats and rabbits showed no teratogenic effects.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Povidone
Microcrystalline cellulose a-lactose monohydrate Silicon dioxide Crospovidone Stearic acid
6.2. Incompatibilities
None.
6.3. Shelf life
36 months.
6.4. Special precautions for storage
Do not store above 25°C. Store in the original container.
6.5 Nature and contents of container
Aluminum foil/PVC/PVDC blister strips in a carton.
The following pack sizes are available:
8 mg packs of 60, 84 or 120 tablets.
6.6. Instruction for use, handling and disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Manx Pharma Limited Taylor Group House Wedgnock Lane Warwick CV34 5YA United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 15833/0017
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
30/12/2005
10 DATE OF REVISION OF THE TEXT
11/06/2014