Rimonid

INSTRUCTION for medical use of the medicinal product RIMONID (RIMONID)

Composition:

Active substance: brimonidine;

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

Excipients: benzalkonium chloride; polyvinyl alcohol; sodium chloride; trisodium citrate dihydrate; citric acid monohydrate; sodium hydroxide and/or hydrochloric acid (for pH adjustment); water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical characteristics: clear, greenish-yellow solution, practically free from visible particles.

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 complications 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% is characterized by 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.

Studies in animals and humans 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 studies have confirmed that brimonidine is effective when used in combination with beta-blockers for ophthalmic use. Short-term clinical studies also confirm that brimonidine significantly enhances clinical effect when combined with travoprost (6 weeks) and latanoprost (3 months).

Pharmacokinetics

After ocular administration of the 0.2% solution twice daily for 10 days, plasma concentrations were low (mean Cmax — 0.06 ng/mL). Repeated dosing (twice daily for 10 days) resulted in minimal accumulation in blood. The area under the plasma concentration-time curve over 12 hours at steady state (AUC0–12 h) was 0.31 ng·h/mL compared to 0.23 ng·h/mL after the first dose. The mean systemic elimination half-life following topical administration in humans was approximately 3 hours.

The extent of brimonidine binding to plasma proteins 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. Accumulation does not occur 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 did not reveal any significant ocular adverse reactions. In monkeys receiving doses approximately four times higher than the recommended dose of brimonidine tartrate, no 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 tissues indicate that its metabolism is primarily mediated by aldehyde oxidase and cytochrome P450. Systemic clearance is believed to be predominantly due to hepatic metabolism.

Elderly patients

Cmax, 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 affect systemic absorption and elimination of the drug.

Clinical characteristics.

Indications.

Open-angle glaucoma or elevated intraocular pressure (IOP):

• Brimonidine as monotherapy in patients for whom the use of topical beta-blockers is contraindicated;
• Brimonidine as part of combination therapy with other agents to reduce IOP when monotherapy is insufficient.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Concomitant use with monoamine oxidase inhibitors and antidepressants affecting noradrenergic transmission (e.g., tricyclic antidepressants, mianserin).
• Pediatric use (under 18 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 (e.g., alcohol, barbiturates, opioids, sedatives, and anesthetics).

Data on plasma catecholamine levels after brimonidine administration are lacking.

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

In some patients, a clinically insignificant reduction in blood pressure has been observed after administration of brimonidine tartrate; therefore, caution is advised when using brimonidine concomitantly with antihypertensive agents and cardiac glycosides.

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

Rimonid should be used with caution in patients with severe, unstable, or uncontrolled cardiovascular diseases.

Dosage adjustment is not required for elderly patients.

In some patients who received brimonidine tartrate 0.2%, allergic reactions of the eye have been observed. If an allergic reaction occurs, the use of the medication should be discontinued.

Use with caution in patients with depression, cerebral insufficiency, coronary insufficiency, Raynaud's syndrome, orthostatic hypotension, and thromboangiitis obliterans.

The effect of the medicinal product in patients with hepatic or renal insufficiency has not been studied; therefore, caution should be exercised when administering it to patients with these conditions.

Rimonid contains the preservative benzalkonium chloride, which may cause eye irritation. Benzalkonium chloride is absorbed by soft contact lenses. When using soft (hydrophilic) contact lenses, they should not be worn for at least 15 minutes after instillation of the medication.

If more than one topical ophthalmic agent is being used, the interval between applications should be 5–15 minutes.

Use during pregnancy or breastfeeding

Safety studies of brimonidine tartrate use in pregnant women have not been conducted; therefore, Rimonid should not be used during pregnancy.

It is not known whether brimonidine passes into breast milk; therefore, the drug should not be used during breastfeeding.

Ability to affect reaction rate when driving or operating machinery

Brimonidine may cause dizziness, drowsiness, and visual disturbances, which could impair the ability to drive or operate machinery. Such activities should not be undertaken earlier than 15 minutes after instillation of the drops, and only after vision has cleared.

Method of Administration and Dosage

For use in adults (including elderly patients), it is recommended to instill one drop into the affected eye twice daily, with an interval of 12 hours between doses.

Dosage adjustment in elderly patients is not required.

As with any ophthalmic drops, it is recommended to apply gentle pressure to the lacrimal sac area in the inner corner of the eye for one minute to reduce systemic absorption. This should be performed immediately after instillation of each drop. If more than one type of ophthalmic drop is prescribed, the drops should be administered with an interval of 5–15 minutes between each.

Children

The efficacy and safety of brimonidine in children have not been established; therefore, Rimonid should not be used in pediatric patients.

Overdose

Local overdose in ophthalmic use

Cases of local overdose have not been reported in adults.

Systemic overdose following accidental oral ingestion

There have been two reported cases of adverse effects following accidental oral ingestion of 9–10 drops of brimonidine in adult patients. In these cases, significant reduction in arterial blood pressure was observed. In one patient, an increase in arterial blood pressure occurred approximately 8 hours after ingestion. Within 24 hours, both patients fully recovered. Another patient who orally ingested an unknown quantity of the drug experienced no adverse effects. Serious adverse effects have been reported in children following accidental oral ingestion of brimonidine. Symptoms observed included central nervous system (CNS) depression, transient coma or loss of consciousness, arterial hypotension, bradycardia, hypothermia, and apnea, requiring intensive therapy including intubation. In all pediatric cases, full recovery occurred within 6–24 hours.

Following oral overdose of other alpha-2 agonists, symptoms reported include arterial hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmia, miosis, apnea, hypothermia, respiratory depression, and seizures.

Treatment is symptomatic.

Adverse Reactions

During clinical studies, the most common adverse reactions of brimonidine were eye pain and ocular irritation, occurring in approximately 1–2% of patients.

The adverse reactions listed below are categorized by organ systems. Within each group, adverse events are listed in decreasing order of severity. Frequency is defined as follows: very common (˃ 1/10); common (≥ 1/10 to < 1/10); uncommon (≥ 1/100 to < 1/10); rare (≥ 1/1000 to < 1/100); very rare (< 1/10000).

Cardiovascular disorders.

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

Nervous system disorders.

Very common: headache, somnolence.

Common: dizziness, taste disturbances.

Very rare: syncope.

Eye disorders.

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

Common: local irritation (eyelid hyperemia, eyelid edema, blepharitis, eye pain and lacrimation, conjunctival discharge, conjunctival edema), photophobia, erosion, dry eyes, conjunctival pallor, visual disturbance, conjunctivitis.

Very rare: iritis (anterior uveitis), miosis.

Respiratory, thoracic and mediastinal disorders.

Common: upper respiratory tract symptoms.

Uncommon: nasal dryness.

Rare: dyspnea.

Gastrointestinal disorders.

Very common: dry mouth.

Common: gastrointestinal symptoms.

Vascular disorders.

Very common: arterial hypertension, hypotension.

General disorders and administration site conditions.

Very common: fatigue.

Common: asthenia.

Immune system disorders.

Uncommon: systemic allergic reactions.

Psychiatric disorders.

Uncommon: depression.

Very rare: insomnia.

During post-marketing use of brimonidine in clinical practice, the following adverse reactions have been reported (frequency unknown, as they were reported spontaneously in a population of unknown size).

Eye disorders:

iridocyclitis (anterior uveitis), eyelid pruritus.

Skin and subcutaneous tissue disorders:

skin reactions including erythema, facial edema, pruritus, rash, and vasodilation.

Reporting of suspected adverse reactions after a medicinal product is authorized is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or 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.

Storage period after opening the bottle — 28 days.

Storage conditions. Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging.

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

Prescription status. Prescription only.

Manufacturer. Micro Labs Limited.

Manufacturer's address and location of operations.

Plot No. 113-116, Phase IV, KIADB, Bommasandra Industrial Area, Jigani Link Road, Anekal Taluk, Bangalore 560 099, India.