Avero

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AVERO (AVERO)

Composition:

Active substance: betahistine dihydrochloride;

1 tablet contains 8 mg, 16 mg or 24 mg of betahistine dihydrochloride;

Excipients: povidone K 90, microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silicon dioxide, crospovidone, stearic acid.

Pharmaceutical form. Tablets.

Main physicochemical properties:

8 mg tablets: white or almost white, round, flat, bevelled on both sides, with a raised marking "В8" on one side of the tablet and smooth on the other side;

16 mg tablets: white or almost white, round, flat, bevelled on both sides, with a raised marking "В16" on one side of the tablet and a division line on the other side;

24 mg tablets: white or almost white, round, biconvex, with a line on one side.

Pharmacotherapeutic group. Agents for treatment of vestibular disorders. Betahistine.

ATC code N07C A01.

Pharmacological Properties

Pharmacodynamics

The mechanism of action of betahistine is only partially understood. Several plausible hypotheses have been confirmed by data from studies conducted in animals and humans.

Effect of betahistine on the histaminergic system

Betahistine has been shown to exhibit partial agonistic activity at H1-receptors and antagonistic activity at H3-receptors of histamine in nervous tissue, with negligible activity at histamine H2-receptors. Betahistine increases histamine turnover and release by blocking presynaptic H3-receptors and inducing a down-regulation process of these H3-receptors.

Betahistine may increase blood flow in the cochlear region as well as in the entire brain

Pharmacological studies in animals have demonstrated improved circulation in the vessels of the stria vascularis of the inner ear, possibly due to relaxation of precapillary sphincters in the microcirculatory system of the inner ear. Betahistine has also been shown to increase cerebral blood flow in humans.

Betahistine promotes vestibular compensation

Betahistine accelerates the recovery of vestibular function after unilateral neurectomy in animals by stimulating and supporting the process of central vestibular compensation. This effect is characterized by enhanced regulation of histamine turnover and release and is mediated via H3-receptor antagonism. In humans, treatment with betahistine has also been associated with a reduced recovery time of vestibular function following neurectomy.

Betahistine alters neuronal activity in the vestibular nuclei

It has also been established that betahistine exerts a dose-dependent inhibitory effect on the generation of action potentials in neurons of the lateral and medial vestibular nuclei.

The pharmacodynamic properties of betahistine, as demonstrated in animals, may provide a positive therapeutic effect of the drug on the vestibular system.

The efficacy of betahistine has been demonstrated in clinical studies in patients with vestibular vertigo and Ménière’s disease, showing a reduction in the severity and frequency of vertigo attacks.

Pharmacokinetics

Absorption

After oral administration, betahistine is rapidly and almost completely absorbed throughout the gastrointestinal tract. Following absorption, the drug is quickly and almost entirely metabolized to form the metabolite 2-pyridylacetic acid. The plasma concentration of betahistine itself is very low. Therefore, all pharmacokinetic analyses are performed by measuring the plasma and urinary concentrations of the metabolite 2-pyridylacetic acid.

When administered with food, the maximum concentration (Cmax) of the drug is lower than when administered fasting. However, the total absorption of betahistine is identical in both cases, indicating that food intake only delays the absorption process.

Distribution

The percentage of betahistine bound to plasma proteins is less than 5%.

Biotransformation

After absorption, betahistine is rapidly and almost completely metabolized to 2-pyridylacetic acid (which has no pharmacological activity).

After oral administration of betahistine, the plasma (and urinary) concentration of 2-pyridylacetic acid reaches its maximum within 1 hour and declines with a half-life of approximately 3.5 hours.

Elimination

2-Pyridylacetic acid is rapidly excreted in the urine. After administration of betahistine in doses of 8–48 mg, approximately 85% of the initial dose is recovered in the urine. Renal or fecal excretion of unchanged betahistine is negligible.

Linearity

The elimination rate remains constant after oral administration of betahistine in doses of 8–48 mg, indicating linear pharmacokinetics and suggesting that the metabolic pathway involved is not saturable.

Clinical characteristics.

Indications.

Meniere's disease and Meniere's syndrome, characterized by three main symptoms:

• vertigo, sometimes accompanied by nausea and vomiting;
• hearing loss (deafness);
• tinnitus.

Symptomatic treatment of vestibular vertigo of various origins.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Phaeochromocytoma.

Interaction with other medicinal products and other forms of interaction.

In vivo studies specifically designed to investigate interactions with other medicinal products have not been conducted. Based on in vitro data, inhibition of cytochrome P450 enzyme activity in vivo is not expected.

In vitro data indicate that the metabolism of betahistine is inhibited by medicinal products that inhibit monoamine oxidase (MAO) activity, including MAO subtype B (e.g., selegiline). Caution is recommended when betahistine is used concomitantly with MAO inhibitors (including B-selective MAO inhibitors).

Since betahistine is a histamine analogue, interaction between betahistine and antihistamine medicinal products could theoretically affect the efficacy of one or both agents.

Special precautions for use

During treatment with the medicinal product, patients with bronchial asthma and/or a history of peptic ulcer disease of the stomach and duodenum should be carefully monitored.

The medicinal product should be prescribed with caution to patients with urticaria, skin rashes, or allergic rhinitis due to the risk of exacerbation of these symptoms.

The medicinal product should be prescribed with caution in patients with severe hypotension.

Lactose

Avero contains lactose:

• The 8 mg tablet contains 70 mg of lactose.
• The 16 mg tablet contains 140 mg of lactose.
• The 24 mg tablet contains 210 mg of lactose.

Patients with rare hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding

Pregnancy. There are insufficient data on the use of betahistine in pregnant women.

Animal studies have not shown direct or indirect harmful effects with regard to reproductive toxicity at doses corresponding to those used in clinical practice. Betahistine should not be used during pregnancy except in cases of clear medical necessity.

Breastfeeding period. It is unknown whether betahistine passes into human breast milk. Betahistine passes into the milk of rats. Effects observed postnatally in animal studies were related only to very high doses. The benefit of treatment for the mother should be weighed against the benefits of breastfeeding and the potential risk to the infant.

Fertility. Studies in rats have not shown any effect on fertility.

Ability to influence the reaction rate when driving or operating machinery.

Betahistine is indicated for the treatment of Ménière's syndrome, characterized by the triad of vertigo, hearing loss, and tinnitus, as well as for symptomatic treatment of vestibular vertigo. Both conditions may negatively affect the ability to drive or operate machinery. According to clinical study data investigating the effect of the medicinal product on the ability to drive and operate machinery, betahistine has no effect or only a negligible effect on this ability.

Method of administration and dosage.

The daily dose for adults is 24–48 mg, evenly distributed throughout the day. Tablets should be swallowed with water.

The dose should be individually adjusted according to the effect. Improvement in symptoms is sometimes observed only after several weeks of treatment. The best results are sometimes achieved with administration of the drug over several months. According to some data, initiating treatment at an early stage of the disease may prevent its progression or hearing loss at later stages.

Avero can be administered independently of food intake. During treatment, mild gastrointestinal disturbances (listed in section "Adverse Reactions") may occur, which can be alleviated by taking the drug with food.

Geriatric patients

Although clinical data in this patient group are limited to date, extensive post-marketing experience allows the assumption that dose adjustment in elderly patients is not required.

Renal impairment

Specific clinical trials have not been conducted in this patient group, but according to post-marketing experience, dose adjustment is not necessary.

Hepatic impairment

Specific clinical trials have not been conducted in this patient group, but according to post-marketing experience, dose adjustment is not necessary.

Children

Due to insufficient data on safety and efficacy, Avero is not recommended for use in children (under 18 years of age).

Overdose

There have been several reported cases of overdose. Mild to moderate symptoms (nausea, drowsiness, abdominal pain) were observed in some patients after taking doses up to 640 mg. More severe complications (seizures, cardiopulmonary complications) occurred following intentional ingestion of high doses of betahistine, particularly in combination with overdose of other medicinal products.

Management of overdose

Treatment of overdose should include standard supportive measures.

Side effects

The adverse reactions listed below were observed in patients treated with Avero during placebo-controlled clinical studies, with the following frequency: 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 events reported during clinical trials, the following adverse reactions have been reported spontaneously during post-marketing use and are known from scientific literature. Based on available data, the frequency cannot be estimated and is therefore classified as unknown.

Immune system disorders

Hypersensitivity reactions, e.g. anaphylaxis.

Gastrointestinal disorders

Reports of mild gastrointestinal disturbances (vomiting, gastrointestinal pain, abdominal distension and flatulence). These side effects usually resolve when the medication is taken with food or after dose reduction.

Skin and subcutaneous tissue disorders

Hypersensitivity reactions involving the skin and subcutaneous tissue have been observed, including angioedema, urticaria, rash and pruritus.

Shelf life.

3 years.

Storage conditions.

Keep out of the reach of children.

Store in the original packaging in a dry place protected from moisture.

Store at a temperature not exceeding 25 °C.

Packaging.

Tablets 8 mg: 10 tablets in a blister; 3 blisters in a cardboard box.

Tablets 16 mg: 10 tablets in a blister; 3 blisters in a cardboard box. 15 tablets in a blister; 2 blisters in a cardboard box.

Tablets 24 mg: 10 tablets in a blister; 3 or 6 blisters in a cardboard box. 15 tablets in a blister; 2 or 4 blisters in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Pharmaceutical Works «POLPHARMA» S.A.

Manufacturer's address and place of business.

Production Department in Nowa Deba, 2 Metalowca Str., 39-460 Nowa Deba, Poland.