Alpha-bryon®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AЛFA-BRION® (ALFA-BRION)

Composition:

Active substance: brimonidine tartrate;

1 ml of solution contains brimonidine tartrate 2.0 mg, equivalent to brimonidine 1.3 mg;

Excipients: benzalkonium chloride; polyvinyl alcohol; sodium chloride; sodium citrate; citric acid monohydrate; sodium hydroxide; hydrochloric acid diluted; water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear greenish-yellow liquid.

Pharmacotherapeutic group. Sympathomimetics for the treatment of glaucoma. ATC code S01E A05.

Pharmacological properties.

Pharmacodynamics.

Brimonidine is an alpha-2 adrenergic agonist that is 1000 times more selective for alpha-2 adrenergic receptors than for alpha-1 adrenergic receptors. This selectivity accounts for the absence of mydriasis and microvascular vasoconstriction associated with human retinal xenotransplants.

Topical application of brimonidine tartrate reduces intraocular pressure (IOP) in humans, with minimal effects on cardiovascular and pulmonary parameters. Limited data are available on the use of brimonidine in patients with bronchial asthma, in whom no adverse effects were observed.

Brimonidine has a rapid onset of action, with peak ocular hypotensive effect observed 2 hours after administration. In two one-year studies, brimonidine reduced IOP by approximately 4–6 mm Hg.

Fluorophotometric studies in animals and humans indicate that brimonidine tartrate has a dual mechanism of action. Brimonidine is believed to reduce IOP by decreasing aqueous humor production and enhancing uveoscleral outflow.

Studies show that brimonidine is effective when used in combination with topical beta-blockers. Short-term studies also indicate that brimonidine has a clinically significant additive effect when combined with travoprost (6 weeks) and latanoprost (3 months).

Pharmacokinetics.

After instillation of the 0.2% solution of brimonidine twice daily for 10 days, plasma concentrations were low (mean Cmax was 0.06 ng/mL). With repeated administration (twice daily for 10 days), there was minimal accumulation of the drug in blood. The area under the pharmacokinetic curve over 12 hours at steady state (AUC 0–12 h) was 0.31 ng×h/mL compared to 0.23 ng×h/mL after the first dose. After topical administration, the mean elimination half-life from systemic circulation was approximately 3 hours.

Plasma protein binding of brimonidine after topical administration is approximately 29%.

Brimonidine reversibly binds to melanin in ocular tissues, in vitro and in vivo. After 2 weeks of ocular instillation, brimonidine concentrations in the iris, ciliary body, and choroid-retina were 3–17 times higher than after a single dose. Accumulation does not occur in the absence of melanin. The significance of melanin binding is not known.

Biomicroscopic examination of eyes in patients who received brimonidine for one year revealed no significant ocular adverse reactions. Furthermore, no significant ocular toxicity was observed during a one-year ocular safety study in monkeys receiving approximately four times the recommended dose of brimonidine tartrate.

After oral administration, brimonidine is well absorbed and rapidly eliminated. The majority of the dose (approximately 75%) is excreted as metabolites in urine within 5 days; unchanged brimonidine was not detected in urine.

In vitro studies using liver tissue from animals and humans indicate that metabolism is primarily mediated by aldehyde oxidase and cytochrome P450. Therefore, systemic elimination is primarily related to hepatic metabolism.

After single doses of 0.08%, 0.2%, and 0.5% brimonidine, no significant deviation in plasma Cmax and AUC proportional to dose was observed.

Geriatric patients.

After a single dose, plasma Cmax, AUC, and elimination half-life of brimonidine in geriatric patients (aged 65 years and older) did not differ from those in younger patients. This indicates that age does not affect systemic absorption or elimination of the drug. Data from studies including geriatric patients show that systemic exposure to brimonidine was very low.

Clinical characteristics.

Indications.

Alphagan® is indicated for reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension:

− as monotherapy — when therapy with topical beta-blockers is contraindicated;

− as part of combination therapy with other medicinal products that reduce intraocular pressure — when target IOP is not achieved with a single agent.

Contraindications.

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

Concomitant use with monoamine oxidase inhibitors (MAOIs) and antidepressants affecting noradrenergic transmission (e.g., tricyclic antidepressants and mianserin).

Do not use in children under 2 years of age.

Interaction with other medicinal products and other forms of interaction.

Alphagan® is contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs) and in patients taking antidepressants affecting noradrenergic transmission (e.g., tricyclic antidepressants and mianserin) (see section "Contraindications").

Although specific interactions of brimonidine with medicinal products have not been studied, the possibility of enhanced effect should be considered when central nervous system depressants (alcohol, barbiturates, opioids, sedatives, and anesthetics) are used concomitantly.

Data on plasma catecholamine levels after administration of brimonidine are lacking. However, brimonidine should be administered with caution in patients receiving medicinal products that affect the metabolism and uptake of circulating amines (e.g., chlorpromazine, methylphenidate, reserpine).

Clinically insignificant lowering of blood pressure has been observed in some patients after administration of brimonidine. Caution is recommended when administering brimonidine concomitantly with antihypertensive agents and/or cardiac glycosides.

Caution is recommended when prescribing (or changing the dose of) concomitant systemic agents (regardless of their pharmaceutical form) that may interact with alpha-adrenergic receptor agonists or affect their efficacy (e.g., agonists or antagonists of adrenergic receptors — isoprenaline, prazosin).

Special precautions for use.

Pediatric population

Children aged 2 years and older, especially those aged 2 to 7 years and/or with body weight ≤ 20 kg, should be treated with caution and under close supervision due to the high frequency and degree of somnolence (see section "Adverse reactions").

Cardiac disorders

Caution should be exercised when treating patients with severe, unstable, or uncontrolled cardiovascular diseases.

Visual disturbances

Ocular allergic reactions have been observed in some patients (12.7%) in clinical trials following administration of brimonidine (see section "Adverse reactions"). If allergic reactions occur, treatment with brimonidine should be discontinued.

Delayed hypersensitivity reactions in the eye have been reported with 0.2% brimonidine, some of which were associated with increased IOP.

Vascular disorders

Alpha-Brion® should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's syndrome, orthostatic hypotension, or thromboangiitis obliterans.

Hepatic and renal impairment

The effect of brimonidine in patients with hepatic or renal impairment has not been studied; caution is advised when treating such patients.

Benzalkonium chloride

The preservative benzalkonium chloride contained in the medicinal product may cause eye irritation, symptoms of dry eye, and may affect the tear film and corneal surface. Contact lenses must be removed prior to instillation and at least 15 minutes should elapse after instillation before reinserting them.

Benzalkonium chloride is known to alter the color of soft contact lenses. Contact between the medicinal product and soft contact lenses should be avoided.

Alpha-Brion® should be used with caution in patients with dry eye syndrome or potential corneal damage. Patients should be monitored during prolonged treatment.

Use during pregnancy or breastfeeding.

Pregnancy. The safety of brimonidine use during pregnancy has not been established. In animal studies, brimonidine tartrate did not produce teratogenic effects. However, in rabbits, brimonidine tartrate at plasma levels higher than those achieved during human therapy caused increased preimplantation loss and reduced postnatal growth. Alpha-Brion® should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. For information on how to minimize systemic absorption, see section "Dosage and administration".

Breastfeeding. It is unknown whether brimonidine is excreted in human breast milk. Brimonidine tartrate is excreted in milk in rats. Alpha-Brion® should not be used in women who are breastfeeding infants.

Ability to affect reaction speed when driving or operating machinery.

Alpha-Brion® may cause fatigue and/or somnolence, which could impair the ability to drive or operate machinery. Alpha-Brion® may also cause blurred vision and visual disturbances that could impair the ability to drive or operate machinery, especially at night or under low lighting conditions. Patients should wait until these symptoms resolve before driving or operating machinery.

Dosage and Administration

Dosage

Recommended dose for adults (including elderly patients)

The recommended dose is 1 drop in the affected eye(s) twice daily, approximately 12 hours apart. Dose adjustment is not required in elderly patients.

Use in renal or hepatic impairment

The effect of brimonidine has not been studied in patients with hepatic or renal impairment (see section "Special Warnings and Precautions for Use").

Administration method

As with any ophthalmic drops, to reduce potential systemic absorption, it is recommended to apply digital pressure to the lacrimal sac located at the medial canthus (punctal occlusion) for one minute immediately after instilling each drop. This reduces systemic side effects and enhances local activity. To prevent contamination of the eye or the eye drops, avoid contact between the dropper tip and any surface.

If more than one topical ophthalmic agent is required, the different medications should be administered at least 5–15 minutes apart.

Children

Clinical studies in adolescents (aged 12 to 17 years) have not been conducted.

Alph-Brion® is not recommended for use in children under 12 years of age and is contraindicated in children under 2 years of age (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Side Effects"). Serious adverse reactions have been reported in neonates. The safety and efficacy of brimonidine in children aged 2 to 12 years have not been established.

Overdose

Overdose in ophthalmic use (adults)

All events observed in known cases of overdose have already been described as adverse reactions.

Systemic overdose due to accidental ingestion (adults)

Available information on accidental oral ingestion of brimonidine in adults is very limited. The only reported adverse effect to date has been hypotension. Episodes of rebound hypertension following hypotension have also been reported.

Treatment of oral overdose includes supportive and symptomatic therapy; maintaining airway patency is essential.

Overdose of other alpha-2 agonists taken orally is known to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnea, hypotension, hypothermia, respiratory depression, and seizures.

Pediatric population

Serious adverse effects have been reported in children following accidental ingestion of brimonidine. Symptoms of central nervous system depression have been observed, including transient coma or decreased level of consciousness, lethargy, somnolence, hypotension, bradycardia, hypothermia, pallor, respiratory depression, and apnea, sometimes requiring intensive treatment with intubation. All reported patients fully recovered within 6–24 hours.

Adverse Reactions

The most commonly reported adverse reactions with brimonidine are dry mouth, ocular hyperemia, and burning/stinging, occurring in 22–25% of patients. These are generally transient and do not require discontinuation of treatment.

In clinical studies, symptoms of ocular allergic reactions occurred in 12.7% of patients (11.5% of patients discontinued brimonidine due to this reason). Such reactions typically occurred between months 3 and 9 of treatment.

The adverse reactions listed below are categorized by system organ class and frequency. Within each frequency group, reactions are listed in order of decreasing severity. The following frequency terminology is used: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and not known (data obtained primarily from spontaneous reports during post-marketing surveillance, so the frequency cannot be estimated reliably).

Immune system disorders

Uncommon: systemic allergic reactions.

Psychiatric disorders

Uncommon: depression.

Very rare: insomnia.

Nervous system disorders

Very common: headache, somnolence.

Common: dizziness, taste disturbance.

Very rare: syncope.

Eye disorders

Very common: eye irritation (hyperemia, inflammation, burning, stinging, itching, foreign body sensation, conjunctival follicles), blurred vision, allergic blepharitis, allergic blepharoconjunctivitis, allergic conjunctivitis, ocular allergic reaction, and follicular conjunctivitis.

Common: local irritation (hyperemia and swelling of eyelids, blepharitis, conjunctival swelling and eye discharge, eye pain, and lacrimation), photophobia, corneal erosion and staining, dry eye, conjunctival pallor, visual disturbance, conjunctivitis.

Very rare: iritis, miosis.

Cardiac disorders

Uncommon: palpitations/arrhythmias (including bradycardia and tachycardia).

Vascular disorders

Very rare: hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders

Common: respiratory symptoms.

Uncommon: dry nose.

Rare: dyspnea.

Gastrointestinal disorders

Very common: dry mouth.

Common: gastrointestinal disorders.

General disorders and administration site conditions

Very common: fatigue.

Common: asthenia.

The following adverse reactions have been identified during post-marketing use of brimonidine in clinical practice. Because these reactions were reported voluntarily and the patient population size is unknown, frequency cannot be estimated.

Eye disorders: iridocyclitis (anterior uveitis), eyelid itching.

Skin and subcutaneous tissue disorders: skin reactions including erythema, facial swelling, itching, rash, and vasodilation.

In cases where brimonidine was used as part of treatment for congenital glaucoma in neonates and infants, symptoms of brimonidine overdose have been reported, such as loss of consciousness, lethargy, somnolence, hypotension, bradycardia, hypothermia, cyanosis, pallor, respiratory depression, and apnea (see section "Contraindications").

In a study of children aged 2 to 7 years with glaucoma inadequately controlled by beta-blockers, a high incidence of somnolence (55%) was observed when brimonidine was used as adjunctive therapy. The adverse reaction was severe in 8% of children and led to discontinuation of treatment in 13% of cases. The incidence of somnolence decreased with increasing age (lowest in 7-year-olds at 25%) but was more strongly associated with body weight, increasing in children with body weight ≤ 20 kg (63%) compared to those with body weight > 20 kg (25%) (see section "Special precautions").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

The shelf life of the product after first opening of the container is 28 days.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach and sight of children.

Packaging. 5 ml in a bottle; 1 bottle per pack.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.