Metformin Generis

1. Name of the medicinal product

Betahistine dihydrochloride 16 mg tablets

2. Qualitative and quantitative composition

Each tablet contains

Betahistine dihydrochloride 16 mg

Excipient(s) with known effect:

Each tablet contains 100 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

White, round, flat, 9.0. mm tablets with bevelled edges with the inscription 'BF' on one side and a breakline on the other side.

The tablet can be divide into two equal halves.

4. Clinical particulars

4.1 Therapeutic indications

Betahistine is indicated for treatment of Ménière'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.

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.

4.3 Contraindications

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:

• hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

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.

Clinical intolerance to Betahistine may occur in bronchial asthma patients (see section 4.5 and 4.8) - 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.

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.

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.

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.

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 are insufficient data on the use of betahistine in pregnant women. Animal studies, though insufficient do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant therapeutic exposure. (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

It is not known whether betahistine is excreted in breast milk in humans. Betahistine is excreted in rat milk. The effects post-partum seen in animal studies were limited to very high doses. The importance of taking the medicine by the mother must be weighed against the benefits of breastfeeding and the potential risk for the child.

Fertility

Animal studies show no influence on fertility in rats.

4.7 Effects on ability to drive and use machines

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.

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).

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 (see section 4.4)

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.

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

5.1 Pharmacodynamic properties

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.

5.2 Pharmacokinetic properties

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.

5.3 Preclinical safety data

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.

 

 

 

Posology

Adults (with normal renal function, GFR> 90 mL/min):

Monotherapy and combination with other oral antidiabetic agents:

- The usual starting dose is 500mg (5ml) or 850mg (8.5ml) Metformina Generis 1000 mg Comprimidos hydrochloride 2 or 3 times daily given during or after meals.

- After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. In patients receiving a high Metformina Generis 1000 mg Comprimidos hydrochloride dose (2 to 3 grams per day), it is possible to replace two Metformina Generis 1000 mg Comprimidos hydrochloride 500mg doses (5ml) with one Metformina Generis 1000 mg Comprimidos hydrochloride 1000mg (10ml) dose. The maximum recommended dose of Metformina Generis 1000 mg Comprimidos is 3g (30ml) daily, taken as 3 divided doses.

- If transfer from another oral antidiabetic agent is intended, discontinue the other agent and initiate Metformina Generis 1000 mg Comprimidos at the dose indicated above.

Combination with insulin:

Metformina Generis 1000 mg Comprimidos and insulin may be used in combination therapy to achieve better blood glucose control. Metformina Generis 1000 mg Comprimidos hydrochloride is given at the usual starting dose of 500mg (5ml) or 850mg (8.5ml) 2-3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

Patients with renal impairment

A GFR should be assessed before initiation of treatment with Metformina Generis 1000 mg Comprimidos containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

Metformina Generis 1000 mg Comprimidos may be used in patients with moderate renal impairment, stage 3a (creatinine clearance [CrCl] 45-59 ml/min or estimated glomerular filtration rate [eGFR] 45-59 ml/min/1.73m2) only in the absence of other conditions that may increase the risk of lactic acidosis and with the following dose adjustments:

GFR mL/min

Total maximum daily dose

(to be divided into 2-3 daily doses)

Additional considerations

60-89

3000 mg

Dose reduction may be considered in relation to declining renal function.

45-59

2000 mg

Factors that may increase the risk of lactic acidosis (see 4.4) should be reviewed before considering initiation of Metformina Generis 1000 mg Comprimidos.

The starting dose is at most half of the maximum dose.

30-44

1000 mg

<30

-

Metformina Generis 1000 mg Comprimidos is contraindicated.

Metformina Generis 1000 mg Comprimidos is contraindicated in patients with severe renal failure (GFR <30 mL/min).

Elderly:

Due to the potential for decreased renal function in elderly subjects, the Metformina Generis 1000 mg Comprimidos dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Paediatric population

Monotherapy and combination with insulin

- Metformina Generis 1000 mg Comprimidos hydrochloride can be used in children from 10 years of age and adolescents.

- The usual starting dose is 500mg (5ml) or 850mg (8.5ml) once daily, given during meals or after meals.

- After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of Metformina Generis 1000 mg Comprimidos is 2g (20ml) daily, taken as 2 or 3 divided doses.

Method of administration

Metformina Generis 1000 mg Comprimidos oral solution is for oral administration.