Vertigo, tinnitus and hearing loss associated with Ménière's syndrome.

Adults, including the elderly: Initially 16mg three times daily, taken preferably with meals. Maintenance
doses are generally in the range 24 to 48 mg daily. Dosage should be altered according to clinical
response.
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 dihydrochloride is considered to be unsafe in patients with porphyria
Betahistine dihydrochloride should be administered with caution to patients with bronchial asthma (due
to clinical intolerance) or a history of peptic ulcer.
Betahistine dihydrochloride is not recommended for use in children.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose
malabsorption should not take this medicine.

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.
Betahistine dihydrochloride should not be used concurrently with antihistamines (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 are insufficient with respect to effects on pregnancy, embryonal/foetal development,
parturition and postnatal development. The potential risk for humans is unknown. 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 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 dihydrochloride-treated patients in placebo-controlled clinical trials (very common (≥ 1/10);
very common (_1/10); common (_1/100 to <1/10); uncommon (≥ /1,000 to < 1/100); rare (≥ /10,000 to
< 1/1,000); very rare (<1/10,000))
Gastrointestinal disorders
Common: nausea and dyspepsia
Nervous systems 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 systems 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

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.
There is no specific antidote to betahistine dihydrochloride. Gastric lavage and symptomatic treatment is
recommended. Treatment of overdose should include standard supportive measures.

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 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 dihydrochloride is a histamine-like drug in which pharmacological activity can be attributed
to a specific effects and/or more direct influences on recovery mechanisms the vestibular nuclei. It has
weak agonist activity at histamine H1receptors and moderate antagonist activity at H3; receptors. The
antagonist action of betahistine dihydrochloride at the H3: receptor can be expected to potentiate the release of presynaptic histamine in vivo by blocking the auto-inhibitory feedback at histaminergic
terminals, its action on medial vestibular nucleus cells is to significantly reduce their responsiveness to
histamine. This action of betahistine dihydrochloride occurs at post-synaptic H1 receptors, since
betahistine dihydrochloride lacks any effect at H2 receptors. The effects of betahistine dihydrochloride
are thus consistent with a partial agonist action at these receptors, with betahistine dihydrochloride
having little excitatory action on its own but reducing the excitatory responses to histamine by
occupying H1 receptor sites.

The reduced response of the medial vestibular nucleus cells to histamine in the presence of betahistine
dihydrochloride may be the result of the activation of H2 receptor-coupled second-messenger pathways
alone rather than the normal activation of both H1 and H2 second-messenger systems together. Thus,
simultaneous stimulation of the H1 and H2 receptor pathways is known to cause a large amplification of
the cellular cAMP response, above that caused by stimulation of the H2 receptor pathway alone. The
reduction in the amplitude and total duration of the histamine-induced excitation in medial vestibular
nucleus cells in the presence of betahistine dihydrochloride is suggestive of such a mechanism. This
partial agonist action of betahistine dihydrochloride at H1 receptor may be an important part of its
mechanism of action.
• 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:
Betahistine dihydrochloride is readily and almost completely absorbed after oral administration from all
parts of the gastro-intestinal tract, and peak plasma concentrations of 14C-labelled betahistine
dihydrochloride are attained one hour after oral administration to fasting subjects.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.
Betahistine dihydrochloride is eliminated by the kidney with 85 - 90% of the radioactivity of an 8 mg
dose appearing in the urine over 56 hours. Maximum excretion rates are reached within 2 hours of
administration. Plasma levels of the parent drug are below the limits of detection of the assay.
Bioavailability has therefore been assessed from urinary excretion of its main metabolite, 2-
pyridylacetic acid.

There is no evidence for presystemic metabolism. Biliary excretion is not important as a route of
elimination of either the drug or its metabolites in the rat and is unlikely to be so in man.
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.

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 25mg/kg showed Betahistine to be well tolerated with no definitive toxicities.
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.
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.

Microcrystalline cellulose PH 101
Mannitol
Citric Acid Monohydrate
Colloidal Silicon Dioxide-Aerosil 200
Talc
Stearic Acid
Purified Water

Not applicable

Do not store above 30° C.

Primary Packaging: Blisters consists of Aluminium foil and clear PVC / PVDC.
Secondary Packaging: Carton and PIL

Not applicable.