Betakule

Betakule is indicated for treatment of Ménière's syndrome, symptoms of which may include vertigo, tinnitus, hearing loss and nausea

Betahistine is indicated for treatment of Ménière's syndrome, symptoms of which may include vertigo, tinnitus, hearing loss and nausea.

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:

Betakule 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.

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.

There is no data available for patients with hepatic impairment.

There is no data available for patients with renal impairment.

There is limited data in the elderly, betahistine should be used with caution in this population.

Children and adolescents:

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

Betakule is contraindicated in patients with phaeochromocytoma. As Betakule is a synthetic analogue of histamine it may induce the release of catecholamines from the tumor resulting in severe hypertension.

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.

Also contraindicated are the following:

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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 Betakule.

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

Caution is advised in prescribing Betakule 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.

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.

Clinical intolerance to Betahistine may occur in bronchial asthma patients - These patients should therefore 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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Betakule is indicated for vertigo, tinnitus and hearing loss associated with Ménière'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, Betakule had no or negligible effects.

Vertigo, tinnitus and hearing loss associated with Ménière's syndrome can negatively affect the ability to drive and use machines.

Betahistine is regarded to have no or negligible effects on the ability to drive and use machines as no effects potentially influencing this ability were found to be related to betahistine in clinical studies.

The following undesirable effects have been experienced with the below indicated frequencies in Betakule-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).

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.

“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).

Immune system disorders:

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

Nervous system disorders:

Common: headache, occasional drowsiness

Cardiac disorders

Not known: palpitations

Respiratory disorders

Not known: Bronchospasms may occur in patients with bronchial asthma

Gastrointestinal disorders:

Common: dyspepsia ^*, nausea

Skin and subcutaneous tissue disorders

Not known: cutaneous and subcutaneous hypersensitivity reactions, in particular angioneurotic oedema, urticarial, rash, and pruritus

^*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.”

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 Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard.

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

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.

Pharmacotherapeutic group: 2.7 Central Nervous System. Antiemetic and anti-vertigo

ATC code: N07C A01

The mechanism of action of Betakule is only partially understood.

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

Betakule affects the histaminergic system:

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

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

Betakule 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.

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

Betakule facilitates vestibular compensation:

Betakule 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 Betakule.

Betakule alters neuronal firing in the vestibular nuclei:

Betakule 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 Betakule in the vestibular system.

The efficacy of Betakule 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.

Pharmacotherapeutic group: antivertigo preparation,

ATC code: N07C A01

The mechanism of action of betahistine is known partially. Betahistine has a very strong affinity as an antagonist for histamine H₃ receptors and a weak affinity as an agonist for histamine H₁ receptors. The active ingredient is a specific histamine agonist with virtually no H₂-activity.

Betahistine has two modes of action. Primarily, it has a direct stimulating (agonistic) effect on H₁ receptors located on blood vessels in the inner ear. It appears to act on the precapillary sphincter in the stria vascularis of the inner ear, thus reducing the pressure in the endolymphatic space.

In addition, betahistine has a powerful antagonistic effects at H₃ receptors, and increases the levels of neurotransmitters released from the nerve endings. The increased amounts of histamine released from histaminergic nerve endings stimulates H₁ receptors, thus augmenting the direct agonistic effects of betahistine on these receptors. This explains the potent vasodilatory effects of betahistine in the inner ear. This explains the efficacy of betahistine in the treatment of vertigo.

Taken together these properties contribute to its therapeutic benefits in Ménière's syndrome. Ménière's syndrome is characterised by attach of vertigo, tinnitus, nausea, headache, hearing loss. The efficacy of betahistine may be due to its ability to modify the circulation of the inner ear or due to a direct effect on neurons of the vestibular nucleus.

Whilst histamine has positive inotropic effects on the heart, betahistine is not known to increase cardiac output and its vasodilator effect may produce a small fall in blood pressure in some patients.

In man, betahistine has little effect on exocrine glands.

Absorption

Orally administered Betakule 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 Betakule 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 Betakule is similar under both conditions, indicating that food intake only slows down the absorption of Betakule.

Distribution

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

Biotransformation

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

After oral administration of Betakule 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 Betakule itself is of minor importance.

Linearity:

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

Absorption

Betahistine is rapidly and completely absorbed after oral administration of the drug in tablets, and peak plasma concentrations of ¹⁴C-labelled betahistine are attained after approximately one hour of oral administration for fasting subjects.

Distribution

Little or no binding occurs with human plasma proteins.

Metabolism and Elimination

Elimination of betahistine takes place mainly by metabolism and the metabolites are subsequently eliminated mainly by renal excretion

Following the absorption, the drug is metabolized rapidly in the metabolite and almost completely in metabolite 2-pyridylacetic acid.

After oral administration of betahistine, its plasma levels are very low. Therefore, the assessment of the pharmacokinetics of betahistine is based on the plasma concentration data of the only metabolite 2-pyridylacetic acid. The concentration of 2-pyridylacetic acid reaches its maximum at 1 hour after intake and declines with half approximately 3.5 hours. The 2-pyridylacetic acid is excreted almost quantitatively in urine within 24 hours after administration. In the dose range between 8 and 48 mg, about 85% of the original dose was recovered in the urine. No unchanged betahistine has been detected in urine.

85-90% of the radioactivity of an 8 mg dose appears in the urine over 56 hours, with maximum excretion rates reached within 2 hours of administration.

There is no evidence of presystemic metabolism and biliary excretion is not thought to be an important route of elimination for the drug or any of its metabolites. However betahistine is subject to metabolism in the liver.

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. Betakule 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.

Chronic toxicity

Adverse reactions affecting the central nervous system were seen in dogs and baboons after intravenous doses of 120 mg / kg and higher.

Studies on chronic oral toxicity over a period of 18 months in rats with a dose of 500 mg / kg and for 6 months in dogs with a dose of 25 mg / kg indicate that betahistine is well tolerated without definitive toxicity.

Mutagenic and carcinogenic potential Betahistine has no mutagenic potential.

In an 18-month chronic toxicity study in rats with a dose up to 500 mg / kg, there was no evidence of carcinogenic potential.

Reproductive toxicity

During reproductive toxicity studies, effects were only seen at exposures considered to be well above the maximum human exposure, indicating minimal relevance during clinical use.

No special requirements.

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