Bglau

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Bglau (Bglau)

Composition:

Active substance: brimonidine tartrate;

1 ml of solution contains brimonidine tartrate 2 mg;

Excipients: benzalkonium chloride 50% solution; polyvinyl alcohol; sodium chloride; sodium citrate; citric acid, monohydrate; 1 M hydrochloric acid or 1 M sodium hydroxide; water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, water-like, slightly greenish-yellow solution free from visible particles.

Pharmacotherapeutic group. Agents used in ophthalmology. Anti-glaucoma preparations and miotics. Sympathomimetics used in the treatment of glaucoma. Brimonidine. ATC code S01EA05.

Pharmacological properties.

Pharmacodynamics.

Brimonidine is an α-2 adrenergic receptor agonist. Brimonidine has 1000 times greater affinity for α-2 adrenergic receptors than for α-1 adrenergic receptors. As a result, brimonidine does not cause pupillary dilation or capillary constriction in human retinal xenografts.

In humans, brimonidine tartrate administered into the conjunctival sac reduces intraocular pressure (IOP) with minimal effects on the cardiovascular and respiratory systems.

Limited data on the use of the drug in patients with bronchial asthma did not confirm the occurrence of adverse reactions.

Brimonidine tartrate has a rapid onset of action, and its maximum hypotensive effect occurs 2 hours after administration. In clinical studies conducted over one year, brimonidine reduced intraocular pressure by approximately 4–6 mm Hg.

Fluorophotometric studies in animals and humans indicate that brimonidine tartrate has a dual mechanism of action. Brimonidine likely reduces intraocular pressure by decreasing aqueous humor production and enhancing uveoscleral outflow.

Clinical studies confirm that brimonidine can be effectively combined with topically applied beta-blockers. Short-term clinical studies also confirm that brimonidine exerts a significant clinical additive effect when used in combination with travoprost (6 weeks) and latanoprost (3 months).

Pharmacokinetics.

General characteristics

After 10 days of twice-daily ocular administration of a 0.2% solution, low plasma concentrations of brimonidine were observed (Cmax averaged 0.06 ng/mL).

After repeated administration of the drug (twice daily for 10 days), a slight accumulation of the drug in the blood was recorded. The area under the plasma concentration-time curve over 12 hours at steady state (AUC0–12h) was 0.31 ng·h/mL compared to 0.23 ng·h/mL after the first dose. The mean apparent elimination half-life from systemic circulation following topical administration was approximately 3 hours.

After topical administration, brimonidine binds to human plasma proteins by approximately 29%.

In vitro and in vivo, brimonidine reversibly binds to melanin in ocular tissues.

After 2 weeks of topical administration, brimonidine concentrations in the iris, ciliary body, and choroid/retina were 3–17 times higher than after a single dose. No accumulation of the drug was observed in the absence of melanin.

The significance of melanin binding in humans has not been studied. However, no adverse ophthalmological effects have been confirmed in biomicroscopic eye examinations of patients treated with brimonidine for up to 1 year. Signs of toxic effects on the visual organs were also not confirmed in studies in monkeys receiving brimonidine tartrate at doses 4 times higher than the recommended human doses for one year.

After oral administration, brimonidine is rapidly absorbed and then rapidly eliminated from the human body. A significant portion of the dose (approximately 75%) is excreted as metabolites in urine within 5 days; unchanged drug in urine has not been demonstrated. In vitro studies using liver tissue from animals and humans indicate that brimonidine metabolism occurs primarily via aldehyde oxidase and cytochrome P450. Therefore, hepatic metabolism is considered the main elimination pathway.

Kinetic profile

No significant deviations from dose proportionality between brimonidine dose, maximum plasma concentration (Cmax), and AUC were observed after single topical administration of the drug at concentrations of 0.08%, 0.2%, and 0.5%, respectively.

Patient characteristics

Characteristics of elderly patients

Cmax, AUC, and apparent elimination half-life of brimonidine after a single dose are similar in elderly patients (aged 65 years and older) and younger adult patients. Observational data indicate no dependence between age and drug absorption or elimination. Clinical studies lasting 3 months (involving elderly patients) confirmed that systemic exposure to brimonidine was minimal.

Clinical characteristics.

Indications.

Reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

• As monotherapy in patients for whom topical beta-blockers are contraindicated.
• As adjunctive therapy to other intraocular pressure-lowering medications when target pressure cannot be achieved with a single agent.

Contraindications.

Hypersensitivity to brimonidine tartrate or to any of the excipients.

Children under 18 years of age.

Patients receiving treatment with monoamine oxidase inhibitors (MAO inhibitors), as well as antidepressants affecting noradrenergic transmission (e.g. tricyclic antidepressants and mianserin).

Interaction with other medicinal products and other forms of interaction.

Bglau is contraindicated in patients receiving treatment with monoamine oxidase inhibitors (MAO inhibitors), as well as antidepressants affecting noradrenergic transmission (e.g. tricyclic antidepressants and mianserin) (see section "Contraindications").

Although specific studies on the interaction of Bglau with other medicinal products have not been conducted, the possibility of additive or potentiating effects should be considered when used concomitantly with agents that depress the central nervous system (alcohol, barbiturates, opiates, sedatives or anesthetics).

Data on catecholamine levels in blood after administration of brimonidine tartrate are lacking. However, caution should be exercised when prescribing the drug to patients taking medicinal products that may affect the metabolism and uptake of circulating amines, such as chlorpromazine, methylphenidate, and reserpine.

In some patients, clinically insignificant reduction in arterial blood pressure has been observed after administration of Bglau. Caution is recommended when using antihypertensive agents and/or cardiac glycosides concomitantly with Bglau.

Caution is recommended when initiating concomitant therapy (or changing the dose) of systemically acting medicinal products (regardless of dosage form) that may interact with α-adrenergic receptor agonists or interfere with their effects, i.e. adrenergic receptor agonists or antagonists (e.g. isoprenaline and prazosin).

Special precautions for use.

Cardiac disorders

Caution should be exercised when administering the medicinal product to patients with severe or unstable, and uncontrolled cardiovascular disease.

Ocular disorders

In some patients (12.7%), hypersensitivity reactions in the eye area were observed during clinical studies following administration of brimonidine (see section "Adverse reactions").

If allergic reactions occur, brimonidine should be discontinued.

Delayed hypersensitivity reactions have been reported with the use of Bimata. In 0.2% of cases, these reports were associated with increased intraocular pressure.
Vascular disorders

Bimata should be prescribed with caution to patients with depression, cerebral or coronary insufficiency, Raynaud's syndrome, orthostatic hypotension, and thromboangiitis obliterans.

Hepatic and renal impairment

Studies on the use of the medicinal product in patients with hepatic or renal impairment have not been conducted; therefore, caution should be exercised when administering brimonidine to such patients.

Benzalkonium chloride

Each 1 ml of Bimata solution contains 0.05 mg of benzalkonium chloride. Benzalkonium chloride may be absorbed by soft contact lenses and may alter their color. Contact lenses must be removed prior to instillation of the medicinal product and at least 15 minutes should be waited before reinserting them. Benzalkonium chloride has been reported to cause eye irritation and dryness and may affect the tear film and corneal surface. The product should be used with caution in patients with dry eye syndrome and in individuals who may have corneal damage. Patients should be monitored during prolonged use.

Use during pregnancy or breastfeeding.

Pregnancy

The safety of using the medicinal product during pregnancy has not been established. In animal studies, no teratogenic effects of brimonidine tartrate were observed. However, in rabbits, brimonidine tartrate at plasma concentrations higher than those achieved in humans during treatment increased the frequency of pregnancy loss during the pre-implantation period and impaired postnatal development. Bimata should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

It is not known whether brimonidine passes into human breast milk. This medicinal product is excreted in the milk of lactating rats. Bimata should not be administered to women who are breastfeeding.

Ability to influence the speed of reactions while driving or operating machinery.

Brimonidine may cause fatigue and/or drowsiness, which may affect the ability to drive or operate machinery. Brimonidine may also cause visual disturbances and/or blurred vision, which may interfere with the ability to drive or operate machinery, particularly at night or in dim light. Patients should wait until these symptoms have resolved before driving or operating machinery.

Method of Administration and Dosage

Use in adults, including elderly patients

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

As with other ophthalmic drops, to reduce the risk of systemic absorption, it is recommended to press and hold the lacrimal sac at the inner corner of the eye (punctal occlusion) for 1 minute immediately after instillation. This procedure should be performed immediately after instilling each drop.

If more than one ophthalmic medicinal product for local use is being administered, an interval of at least 5–15 minutes between applications is recommended.

Use in renal or hepatic impairment

Studies on the use of brimonidine in patients with hepatic or renal impairment have not been conducted (see section "Special Warnings and Precautions for Use").

Children

This medicinal product is not recommended for use in children under 18 years of age, as the efficacy and safety of brimonidine in this age group have not been established (see section "Contraindications").

Overdose

Overdose following ocular administration (adults)

Overdose in adults has not been observed in ophthalmic practice. However, when brimonidine was used as part of combination therapy for congenital glaucoma, symptoms of overdose such as arterial hypotension, decreased muscle tone, bradycardia, hypothermia, and apnea were reported in neonates.

Systemic overdose due to accidental oral intake (adults)

Limited data are available on accidental oral intake of brimonidine by adult patients. The only reported adverse effect was a reduction in arterial blood pressure. Following this episode of hypotension, a rebound hypertension occurred approximately 8 hours after oral ingestion.

Cases of overdose with other alpha-2 agonists have been reported, resulting in symptoms such as arterial hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmia, miosis, apnea, hypotonia, hypothermia, respiratory depression, and seizures.

Overdose in children

Serious adverse events have been reported following accidental oral ingestion of brimonidine tartrate ophthalmic solution by children. Symptoms observed included central nervous system depression, typically transient coma or decreased level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression, and apnea, requiring hospitalization in intensive care units and intubation when indicated. In most cases, patients fully recovered within 6–24 hours.

Adverse Reactions

The most commonly occurring adverse effects (observed in 22–25% of patients) are dryness of the oral mucosa, conjunctival hyperemia, and a burning/stinging sensation in the eyes. The above-mentioned symptoms are usually temporary and do not require discontinuation of treatment.

Ocular allergic reactions occurred in approximately 12.7% of patients participating in clinical studies (leading to study discontinuation in 11.5% of patients). These reactions mostly occurred between the 3rd and 9th month of treatment.

Within each frequency group, adverse effects are listed in order of decreasing severity. The frequency of adverse effects is classified as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (frequency cannot be estimated from available data).

Immune system disorders

Uncommon: systemic allergic reactions.

Psychiatric disorders

Uncommon: depression.

Very rare: insomnia.

Nervous system disorders

Very common: headache, drowsiness.

Common: dizziness, taste disturbances.

Very rare: loss of consciousness.

Eye disorders

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

Common: local irritation (eyelid swelling and redness, blepharitis, conjunctival edema and discharge, eye pain, and lacrimation), photophobia, corneal epithelial erosion and color change, dry eyes, conjunctival depigmentation, visual disturbances, conjunctivitis.

Very rare: iritis (anterior uveitis), miosis.

Cardiac disorders

Uncommon: increased heart rate/arrhythmia (including bradycardia and tachycardia).

Vascular disorders

Very rare: hypotension, arterial hypertension.

Respiratory, thoracic and mediastinal disorders

Common: upper respiratory tract symptoms.

Uncommon: dryness of the nasal mucosa.

Rare: dyspnea.

Gastrointestinal disorders

Very common: dryness of the oral mucosa.

Common: gastrointestinal disturbances.

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 are spontaneous reports from a population of unknown size, it is not possible to estimate their frequency reliably.

Eye disorders

Not known: iridocyclitis (anterior uveitis), eyelid itching.

Skin and subcutaneous tissue disorders

Not known: skin reactions including erythema, facial swelling, pruritus, rash, and vasodilation.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are encouraged to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 24 months.

The shelf life after first opening the dropper bottle is 28 days.

Storage conditions.

Store below 30 °C. Keep out of the reach of children.

Packaging.

5 ml of solution in a dropper bottle; 1 dropper bottle per cardboard box.

Prescription category. Prescription only.

Manufacturer. Laboratorio Edol - Produtos Farmacêuticos, S.A.

Manufacturer's address and location of operations.

Av. 25 de Abril, No. 6 - 6A, Linda-a-Velha, 2795 - 225, Portugal.