Eliqraya xr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ELIBRIA XR (Elibria XR)

Composition:

Active ingredient: betahistine dihydrochloride;

One prolonged-release tablet contains betahistine dihydrochloride 32 mg;

One prolonged-release tablet contains betahistine dihydrochloride 48 mg;

Excipients: microcrystalline cellulose pH 102; silicified microcrystalline cellulose; pregelatinized corn starch; hypromellose K100 M PR CR; hypromellose K100 LV; povidone 30; colloidal silicon dioxide; sodium stearyl fumarate; sodium starch glycolate (type M); lactose monohydrate; yellow dye.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical characteristics: round tablet, smooth on both sides, with one white and one orange side.

Pharmacotherapeutic group. Agents for the treatment of vestibular disorders. Betahistine. ATC code: N07CA01.

Pharmacological Properties

Pharmacodynamics

The exact mechanism of action of betahistine is only partially understood.

There are several well-supported hypotheses, confirmed by data from animal and human studies:

Betahistine affects the histaminergic system: it exhibits partial agonist activity at histamine H₁ receptors and antagonist activity at H₃ histamine receptors in nervous tissue, with negligible activity at H₂ receptors. Betahistine increases histamine turnover and release by blocking presynaptic H₃ receptors and inducing upregulation of H₃ receptors.

Betahistine may enhance blood flow both to the cochlear region and to the brain overall: pharmacological studies in animals have demonstrated that betahistine improves blood flow to the inner ear, likely through a relaxing effect on precapillary sphincters in the microcirculatory system of the inner ear. It has also been shown that betahistine increases cerebral blood flow in humans.

Betahistine promotes vestibular compensation: it accelerates recovery of vestibular function after vestibular neurectomy in animals, facilitating vestibular compensation. This effect, characterized by regulation of histamine release and turnover, is mediated via H₃ receptor antagonism. In humans, the recovery time following vestibular neurectomy was shortened with betahistine treatment.

Betahistine modulates neuronal activity in the vestibular nuclei: betahistine has been shown to exert a dose-dependent inhibitory effect on neuronal potential generation in the lateral and medial vestibular nuclei. The pharmacodynamic properties of betahistine, as demonstrated in animals, may provide a positive therapeutic effect in the vestibular system. The efficacy of betahistine has been demonstrated in clinical studies in patients with vestibular vertigo and Ménière’s disease, shown by a reduction in the severity and frequency of vertigo attacks.

Pharmacokinetics

Absorption and metabolism. Elibria XR is a highly soluble and highly permeable medicinal product, with rapid and nearly complete absorption from the gastrointestinal tract. Betahistine is also rapidly metabolized by the liver, as quickly as it is absorbed. Its main metabolite is 2-pyridylacetic acid (2-PAA). 2-PAA is pharmacologically inactive but can be easily quantified using appropriate analytical methods. Maximum concentration of 2-PAA after administration of betahistine in immediate-release form is reached in slightly over half an hour. Maximum concentration of 2-PAA after administration of Elibria XR occurs approximately 1.5 hours after intake.

Distribution. The percentage of betahistine bound to plasma proteins is less than 5%. At the same time, it is a hydrophilic molecule. Therefore, it does not remain circulating in plasma and cannot be widely distributed into tissues. As a result, it is rapidly metabolized. The volume of distribution of its metabolite, 2-PAA, was 20 liters for immediate-release formulations. The volume of distribution of the same metabolite, measured after single-dose administration of the prolonged-release formulation, ranged from 30 to 47 liters according to study data.

Elimination. Due to the above characteristics, betahistine and its metabolites have a very short elimination half-life in plasma. The literature reports a half-life of the active substance of 3 to 4 hours. Elibria XR, in all evaluated studies, demonstrated a longer half-life ranging from 4.12 to 5.13 hours. The elimination of betahistine and its metabolites occurs predominantly via the urine.

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

Clinical characteristics

Indications

Meniere's disease or Meniere's syndrome characterized by the triad of symptoms:

• vertigo (with nausea and vomiting);
• hearing loss or decreased hearing;
• tinnitus.

Symptomatic treatment of vertigo of vestibular origin.

Contraindications

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

Pheochromocytoma.

Interaction with other medicinal products and other forms of interaction

There are no in vivo data on the interaction of the medicinal product Elibria XR with other medicinal products. Based on in vitro data, inhibition of cytochrome P450 enzyme activity is not expected. In vitro data indicate that the metabolism of betahistine may be inhibited by medicinal products which inhibit monoamine oxidase (MAO), including MAO subtype B (e.g., selegiline). Concomitant use of Elibria XR and MAO inhibitors (including selective MAO-B inhibitors) is therefore recommended with caution. Since betahistine is a histamine analogue, interaction between betahistine and antihistamine medicinal products could theoretically affect the efficacy of either agent.

Special precautions for use

Patients with bronchial asthma and/or a history of peptic ulcer of the stomach and duodenum should be carefully monitored during treatment with Elibria XR.

Since the medicinal product contains lactose, it should not be administered to patients with rare hereditary disorders of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption syndrome.

Elibria XR contains the yellow dye crocus yellow, which may occasionally cause allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy. There are insufficient data on the use of betahistine in pregnant women. Animal studies have not shown any direct or indirect adverse effects on reproductive toxicity at doses corresponding to those used in clinical practice. Betahistine should not be used during pregnancy except in cases of clear necessity.

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

Fertility. Studies in rats have not revealed any effects on fertility.

Ability to influence reaction speed when driving or operating machinery

Betahistine is indicated for the treatment of Ménière's syndrome, characterized by a triad of main symptoms: vertigo, hearing loss, and tinnitus, as well as for symptomatic treatment of vestibular vertigo. Both conditions may negatively affect the ability to drive a vehicle or operate machinery. According to clinical studies investigating the effect of the drug on the ability to drive and operate machinery, betahistine had no effect or only a negligible effect on this ability.

Dosage and Administration

The recommended doses of the medicinal product Elibria XR for treatment of adults range from 32 to 48 mg per day. Prolonged-release Elibria XR tablets should be taken once daily at the same time each day, regardless of food intake.

The tablets should be taken orally with water. Tablets must be swallowed whole: they should not be chewed, broken, or crushed.

Dosage should be individually adjusted according to the therapeutic response.

Since triggering factors that increase the risk of Ménière’s disease attacks predominantly occur during periods when the patient is active, it is recommended to take the medication before the start of daily activities. This approach ensures maintenance of adequate plasma concentrations of the drug during the most vulnerable periods, thus contributing to effective symptom control in Ménière’s disease.

Improvement may sometimes only become apparent after several weeks of treatment. In some cases, optimal results are achieved after several months. Evidence suggests that early initiation of treatment may prevent disease progression and/or hearing loss at later stages of the disease.

The total active substance release period is 24 hours.

Elderly patients. The release of Elibria XR over a 24-hour period is similar to that of immediate-release formulations administered two or three times daily. Although clinical data in this patient group are limited, extensive post-marketing experience with betahistine indicates that dose adjustment is not necessary in elderly individuals.

Renal and hepatic impairment. There are no specific clinical studies conducted in these patient groups. However, based on post-marketing experience with betahistine and considering that the release of Elibria XR occurs over 24 hours and is similar to that of immediate-release formulations taken two or three times daily, dose adjustment is not required.

Missed dose

If a dose of Elibria XR is missed, it may be taken within 6 hours after the usual administration time. If it is not possible to resume dosing within 6 hours, the missed dose should be skipped and the next dose taken at the usual time. When this occurs, caution is recommended due to the possible occurrence of vertigo attacks; activities that could become hazardous during episodes of vertigo—such as driving or operating machinery—should be avoided.

Elibria XR tablets must not be broken, crushed, or chewed.

Children

Elibria XR is not recommended for individuals under 18 years of age due to insufficient data on safety and efficacy.

Overdose

Cases of overdose are rare. Some patients experienced mild symptoms (nausea, drowsiness, and abdominal pain) after taking doses up to 640 mg of betahistine. More severe complications (seizures, cardiac and pulmonary complications) were observed in cases of intentional overdose, particularly when combined with overdose of other medicinal products. Management of overdose should include standard supportive measures.

Adverse Reactions

In placebo-controlled clinical trials, the following adverse reactions were reported in patients receiving betahistine, with frequencies as specified below: very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10000 to <1/1000); very rare (<1/10000).

Common frequent reactions:

Gastrointestinal disorders: nausea and dyspepsia.

Nervous system disorders: headache.

In addition to the above adverse reactions reported during clinical trials, the following adverse reactions have been spontaneously reported in scientific literature during post-marketing use of betahistine. The frequency of these reactions cannot be estimated from the available data and is therefore classified as "unknown".

Immune system disorders: hypersensitivity reactions (e.g., anaphylaxis).

Gastrointestinal disorders: mild gastrointestinal disturbances (e.g., vomiting, abdominal pain, bloating and flatulence). These adverse reactions can usually be avoided by administering the dose with food or by reducing the dose.

Skin and subcutaneous tissue disorders: skin and subcutaneous hypersensitivity reactions, including angioedema, urticaria, rash, and pruritus.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life: 24 months.

Storage conditions:

Store at temperatures from 15 °C to 30 °C in the original packaging to protect from moisture and light. Keep out of reach and sight of children.

Packaging

10 tablets in a blister; 3 blisters per carton.

Prescription category

Prescription only.

Manufacturer

Ache Laboratorios Farmaceuticos S.A.

Ache Laboratorios Farmaceuticos S.A.

Manufacturer's address and location of operations

Rodovia Presidente Dutra KM 222,2, Guarulhos Sao Paulo, Brazil.

Rodovia Presidente Dutra KM 222,2, Guarulhos Sao Paulo, Brazil.

Marketing Authorization Holder

UAB "Farmlyga" / JSC "Farmliga"

Address of the Marketing Authorization Holder

Antakalnio g. 48A-304, Vilnius, Republic of Lithuania