Brimonidine-pharmex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRIMONIDINE-PHARMEKS

Composition:

Active substance: brimonidine;

1 ml of solution contains 2 mg of brimonidine tartrate;

Excipients: benzalkonium chloride, polyvinyl alcohol, sodium citrate dihydrate, citric acid monohydrate, sodium chloride, sodium hydroxide or hydrochloric acid (for pH adjustment if necessary), water for injections.

Pharmaceutical form. Eye drops.

Main physicochemical characteristics: clear greenish-yellow solution.

Pharmacotherapeutic group. Anti-glaucoma and miotic agents.

ATC code S01E A05.

Pharmacological Properties

Pharmacodynamics

Brimonidine is an alpha-2 adrenergic agonist that is approximately one thousand times more selective for alpha-2 adrenergic receptors than for alpha-1 adrenergic receptors.

This selectivity accounts for the absence of mydriasis and for reduced microvascular dilation associated with human retinal xenografts.

Topical application of brimonidine tartrate in humans reduces intraocular pressure (IOP) with minimal effects on cardiovascular and pulmonary parameters.

Brimonidine tartrate 0.2% has a rapid onset of action, with peak ocular hypotensive effect achieved within 2 hours after administration. In clinical studies, brimonidine tartrate 0.2% reduced IOP by an average of 4–6 mmHg.

Results from animal and human studies indicate that brimonidine tartrate has a dual mechanism of action. Brimonidine tartrate 0.2% is believed to reduce IOP by decreasing aqueous humor production and increasing uveoscleral outflow.

Clinical trials have shown that brimonidine is effective when used in combination with topical beta-blockers. Short-term studies also demonstrate that brimonidine provides a clinically significant additive effect when combined with travoprost (6 weeks) and latanoprost (3 months).

Pharmacokinetics

After ocular administration of 0.2% brimonidine tartrate twice daily for 10 days, plasma concentrations were low (mean maximum plasma concentration [C_max] was 0.06 ng/mL). Repeated dosing (twice daily for 10 days) resulted in minimal systemic accumulation. The area under the plasma concentration-time curve (AUC_0–12h) at 12 hours was 0.31 ng·h/mL at steady state compared to 0.23 ng·h/mL after the first dose. The mean systemic elimination half-life following topical administration in humans is approximately 3 hours. The extent of plasma protein binding of brimonidine after topical administration in humans is approximately 29%.

In ocular tissues, brimonidine reversibly binds to melanin in vitro and in vivo. After two weeks of ocular administration, brimonidine concentrations in the iris and ciliary body were 3–17 times higher than after a single dose. No accumulation occurs in the absence of melanin.

The significance of binding to melanin is not fully understood. However, biomicroscopic examination of patients treated with brimonidine tartrate 0.2% for up to 1 year revealed no significant ocular adverse reactions. In monkeys receiving doses approximately 4 times the recommended human dose of brimonidine tartrate, no significant ocular toxicity was observed.

In humans, brimonidine is well absorbed and rapidly eliminated after oral administration. A significant portion of the dose (approximately 75%) is excreted in urine as metabolites within 5 days. In vitro studies using animal and human liver preparations indicate that metabolism is primarily mediated by aldehyde oxidase and cytochrome P450. Systemic clearance is believed to be predominantly due to hepatic metabolism. Renal excretion is the major route of elimination for brimonidine and its metabolites.

Geriatric Patients

C_max, AUC, and elimination half-life of brimonidine after a single dose in elderly patients (aged 65 years and older) were similar to those in younger adults, indicating that age does not significantly affect systemic absorption or elimination of the drug.

According to data from a 3-month clinical study that included elderly patients, systemic exposure to brimonidine was very low.

Clinical Characteristics.

Indications.

For lowering elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension:

− as monotherapy in patients for whom topical beta-blocker therapy is contraindicated;

− as part of combination therapy with other medicinal products that reduce intraocular pressure, when target IOP is not achieved with monotherapy.

Contraindications.

• Hypersensitivity to the active substance or to any of the other components of the medicinal product.
• Concomitant use with monoamine oxidase inhibitors and antidepressants affecting noradrenergic transmission (e.g., tricyclic and tetracyclic antidepressants, mianserin).
• Pediatric use under 2 years of age.

Interaction with other medicinal products and other forms of interaction.

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

Although specific interactions of brimonidine with medicinal products have not been studied, the possibility of additive or enhanced effects should be considered when using medicinal products that depress the central nervous system (alcohol, barbiturates, opioids, sedatives, and anesthetics).

Data on plasma catecholamine levels after administration of brimonidine are lacking.

However, caution is advised when prescribing the medicinal product to patients receiving medicinal products that may affect metabolism and increase amine concentrations in plasma (e.g., chlorpromazine, methylphenidate, reserpine).

Clinically insignificant lowering of arterial blood pressure has been observed in some patients after administration of brimonidine tartrate; therefore, concomitant use of brimonidine with antihypertensive agents and cardiac glycosides should be approached with caution.

Monitoring is recommended at the beginning of treatment (or when increasing the dose) during combination therapy with systemic agents (regardless of their pharmaceutical form) that may interact with alpha-adrenergic receptor agonists or affect their efficacy (e.g., isoprenaline, prazosin).

Special precautions for use.

Pediatric population

Treatment of children aged 2 years and older, especially those aged 2 to 7 years and/or with body weight ≤ 20 kg, requires caution and careful monitoring due to the high frequency and degree of somnolence (see section "Adverse reactions").

Cardiac disorders

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

Visual disturbances

Ocular allergic reactions were 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

Brimonidine-Farmeks 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 should be exercised when treating such patients.

Benzalkonium chloride

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

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

Brimonidine-Farmeks should be used with caution in patients with dry eye syndrome or potential corneal damage. Patients should be under supervision 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. Brimonidine-Farmeks should be used during pregnancy only if the potential benefit to the mother outweighs the risk to the fetus. For information on how to minimize systemic absorption, see section "Dosage and method of administration."

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

Ability to influence the ability to drive or operate machinery.

Brimonidine-Farmeks may cause fatigue and/or somnolence, which may negatively affect the ability to drive or operate machinery. In addition, Brimonidine-Farmeks may cause blurred vision or visual disturbances, which may impair the ability to drive or operate machinery, especially at night or under low lighting conditions. Patients should wait until these symptoms have resolved before driving or operating machinery.

Method of Administration and Dosage

Dosage

Recommended dose for adults (including elderly patients)

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

Use in renal and hepatic impairment

The effect of brimonidine has not been studied in patients with hepatic or renal impairment (see section "Special precautions for use").

Method of Administration

As with any ophthalmic drops, to reduce potential systemic absorption, it is recommended to apply pressure on the lacrimal sac located at the medial canthus (punctal occlusion) for approximately 1 minute immediately after instillation of each drop. This helps reduce systemic adverse reactions and enhances local activity. To prevent contamination of the eye or the eye drops, avoid contact between the dropper tip and any surface.

If multiple topical ophthalmic agents are required, an interval of 5–15 minutes should be maintained between their administration.

Children

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

Brimonidine-Pharmex is not recommended for children under 12 years of age and is contraindicated in children under 2 years of age (see sections "Contraindications", "Special precautions for use", and "Adverse reactions"). 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)

Information regarding accidental ingestion of brimonidine by adults is very limited. The only reported adverse effect to date has been hypotension, which was accompanied by rebound hypertension.

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

Overdose of other alpha-2 agonists taken orally has been associated with symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnea, hypotonia, hypothermia, respiratory depression, and seizures.

Pediatric population

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

Adverse Reactions

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

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

The following adverse reactions of brimonidine are categorized by organ system and frequency. Within each frequency group, reactions are listed in order of decreasing severity. The following terminology is used to define frequency: 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).

Immune system

Uncommon: systemic allergic reactions.

Psychiatric disorders

Uncommon: depression.

Very rare: insomnia.

Nervous system disorders

Very common: headache, drowsiness.

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 eyelid edema, blepharitis, conjunctival edema and eye discharge, eye pain, and lacrimation), photophobia, corneal erosion and staining, dry eyes, conjunctival pallor, visual disturbances, conjunctivitis.

Very rare: iritis, miosis.

Cardiac disorders

Uncommon: increased heart rate / 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 reported during post-marketing use of brimonidine in clinical practice. As these reports are voluntary and the patient population size is unknown, it is not possible to reliably estimate their frequency.

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 in the treatment of congenital glaucoma in newborns and infants, symptoms of brimonidine overdose such as loss of consciousness, lethargy, drowsiness, hypotension, bradycardia, hypothermia, cyanosis, pallor, respiratory depression, and apnea have been observed (see section "Contraindications").

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

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, pharmacists, patients, or their legal representatives should report all 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.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children. After first opening, do not use beyond 28 days.

Packaging.

5 ml or 10 ml in a bottle, 1 bottle with dropper cap in a carton.

Prescription status.

Prescription only.

Manufacturer.

TOV "FARMEKS GROUP".

Manufacturer's address and location of operations.

100, Shevchenka Street, Boryspil, Kyiv Oblast, 08301, Ukraine.