Bimanoxx®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BIMANOX® (BIMANOX®)

Composition:

Active substance: brimonidine tartrate;

1 ml of solution contains 2 mg of brimonidine tartrate, equivalent to 1.32 mg of brimonidine;

Excipients: benzalkonium chloride 50% solution; polyvinyl alcohol 40-88; sodium citrate dihydrate; citric acid monohydrate; sodium chloride; sodium hydroxide/hydrochloric acid; purified water.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear yellowish-green liquid, practically free from foreign particles.

Pharmacotherapeutic group. Anti-glaucoma and miotic agents.

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 results in the absence of pupillary dilation and vasoconstriction in the microvessels associated with human retinal pigment epithelium.

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

Bimantox® has a rapid onset of action, reaching peak ocular hypotensive effect 2 hours after administration, reducing IOP on average by 4–6 mm Hg.

Bimantox® is believed to reduce IOP by decreasing aqueous humor production and increasing uveoscleral outflow.

Studies demonstrate that Bimantox® is effective in combination with topically applied beta-blockers and shows clinically significant additive effects when combined with travoprost and latanoprost.

Pharmacokinetics.

After ophthalmic administration of the 0.2% solution twice daily for 10 days, plasma concentrations were low (mean Cmax was 0.06 ng/mL).

Minimal accumulation in blood was observed after multiple (twice daily for 10 days) instillations. The area under the plasma concentration-time curve (AUC) over 12 hours at steady state (AUC 0–12h) was 0.31 ng·h/mL compared to 0.23 ng·h/mL after the first dose. The mean apparent elimination half-life in systemic circulation was approximately 3 hours following topical administration.

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

Brimonidine reversibly binds to melanin in ocular tissues in vitro and in vivo. Two weeks after ocular instillation, brimonidine concentrations in the iris, ciliary body, choroid, and retina were 3–17 times higher than after a single dose.

Accumulation does not occur in the absence of melanin.

The clinical significance of melanin binding in humans has not been fully elucidated. However, no significant adverse ocular reactions have been reported.

Clinical characteristics.

Indications.

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

• Monotherapy in patients for whom topical beta-blockers are contraindicated.
• As part of combination therapy with other IOP-lowering agents when monotherapy does not achieve the desired effect.

Contraindications.

Hypersensitivity to brimonidine tartrate or to any of the excipients of the medicinal product.

Pregnancy or breastfeeding. Pediatric age.

Patients receiving therapy with monoamine oxidase inhibitors (MAO inhibitors), and patients taking antidepressants affecting noradrenergic transmission (e.g., tricyclic antidepressants and mianserin).

Interaction with other medicinal products and other forms of interaction.

The medicinal product Bimanoxx® is contraindicated in patients receiving treatment with MAO inhibitors and in patients taking antidepressants that affect noradrenergic transmission (e.g., tricyclic antidepressants and mianserin). Although specific interaction studies with other medicinal products have not been conducted for Bimanoxx®, the possibility of additive or potential effects with CNS depressants (alcoholic beverages, barbiturates, opioids, sedatives or analgesics) should be considered.

Data on circulating catecholamine levels after administration of Bimanoxx® are not available. However, caution is recommended when using the medicinal product in patients taking drugs that may affect the metabolism and uptake of circulating amines, such as chlorpromazine, methylphenidate, reserpine.

Clinically insignificant lowering of blood pressure has been observed in some patients after administration of the product. Caution should be exercised when using antihypertensive agents and/or cardiac glycosides in combination with Bimanoxx®.

Careful initiation (or dose adjustment) of concomitant systemic medicinal products (regardless of dosage form) that may interact with alpha-adrenergic agonists—i.e., adrenergic receptor agonists or antagonists (e.g., isoprenaline, prazosin)—is recommended.

When using more than one topical ophthalmic agent, the products should be administered with an interval of 5 minutes.

Special precautions for use

Caution should be exercised when treating patients with severe or unstable and uncontrolled cardiovascular diseases. Allergic reactions affecting the eyes have been observed in some patients treated with Bimanoxx®. If allergic reactions occur, treatment with Bimanoxx® should be discontinued.

Bimanoxx® should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension, or thromboangiitis obliterans. Patients with these conditions should be closely monitored, and if their condition worsens, the medication should be discontinued.

Bimanoxx® has not been studied in patients with hepatic or renal impairment; therefore, treatment of such patients should be carried out with caution.

Patients should be advised that if they undergo eye surgery or develop an intercurrent illness (e.g., trauma or infection), they should immediately consult their physician regarding the continued use of the multi-dose dropper bottle.

The preservative in Bimanoxx® – benzalkonium chloride – may cause eye irritation.

Patients wearing soft contact lenses should remove them before instilling Bimanoxx®. Contact lenses may be reinserted 15 minutes after administration. The medication may discolor soft contact lenses.

Use during pregnancy or breastfeeding

Pregnancy

The safety of Bimanoxx® during pregnancy in humans has not been established. In animal studies, brimonidine tartrate did not show teratogenic effects. Bimanoxx® may be prescribed to pregnant women only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

It is unknown whether brimonidine is excreted in human breast milk. Bimanoxx® should not be used in women who are breastfeeding infants.

Ability to influence reaction speed when driving or operating machinery

The use of Bimanoxx® may be accompanied by visual disturbances; therefore, patients should refrain from driving or operating machinery until visual acuity is restored. The medication may cause episodes of weakness and/or drowsiness in some patients. If a patient's occupation involves potentially hazardous activities, they should be warned in advance about possible reductions in attention and psychomotor reaction speed.

Dosage and Administration.

Apply topically. Instill 1 drop of Bimacox® into the conjunctival sac of the affected eye twice daily, with an interval of approximately 12 hours. Dose adjustment in elderly patients is not required. Bimacox® may be used concomitantly with other ophthalmic agents intended to reduce IOP. If the patient is using other ophthalmic drops simultaneously, an interval of at least 5 minutes should be maintained between administrations. As with any other ophthalmic drops, to minimize potential systemic absorption, it is recommended to press on the lacrimal sac at the medial canthus of the eye (nasolacrimal occlusion) for 1 minute after instillation.

Children.

Safety and efficacy of brimonidine in children have not been established.

Overdose.

Overdose in ophthalmic use.

There have been no reports of overdose with this medication.

Systemic overdose following accidental oral ingestion.

A single adverse effect has been reported—hypotension, followed by rebound hypertension. Limited data are available on adverse effects following accidental oral ingestion of brimonidine in adult patients. The only reported adverse reaction is arterial hypotension. Approximately 8 hours after drug intake, an increase in arterial blood pressure was observed.

Serious adverse effects have been reported in children following accidental oral ingestion of brimonidine. Symptoms observed included CNS depression, transient coma or loss of consciousness, arterial hypotension, bradycardia, hypothermia, and apnea, requiring intensive therapy with intubation. Within 6–24 hours, all patients fully recovered.

Following oral overdose of other alpha-2 agonists, cases of the following symptoms have been reported: arterial hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmia, miosis, apnea, hypothermia, respiratory depression, and seizures. Management of overdose includes supportive and symptomatic therapy, with careful monitoring and maintenance of airway patency.

Adverse Reactions

Within each frequency group, adverse effects are listed in reverse order of severity. The following terminology is used to classify the frequency of adverse effects: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data).

The most commonly reported adverse reactions during use of the medicinal product are dry mouth, eye hyperemia, and burning/stinging sensations, occurring in 22–25% of patients. These are usually transient and often not severe, and therefore typically do not require discontinuation of treatment.

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: syncope

Eye disorders
Very common: eye irritation (ocular hyperemia, burning and stinging sensation, itching, foreign body sensation, conjunctival follicles), blurred vision, allergic blepharitis, allergic blepharoconjunctivitis, allergic conjunctivitis, allergic conjunctivitis and follicular conjunctivitis; common: local irritation (hyperemia and swelling of eyelids, blepharitis, conjunctival swelling and discharge, conjunctival swelling, eye pain, and lacrimation), photophobia, erosion, conjunctival staining, dry eyes, conjunctival pallor, visual disturbances, conjunctivitis; very rare: iritis, miosis

Cardiac disorders
Not known: increased heart rate/arrhythmia (including bradycardia and tachycardia)

Vascular disorders
Very rare: arterial hypertension, arterial hypotension

Respiratory, thoracic and mediastinal disorders
Common: upper respiratory tract symptoms; uncommon: nasal dryness; rare: dyspnea

Gastrointestinal disorders
Very common: dry mouth; common: gastrointestinal symptoms

General disorders and administration site conditions
Very common: fatigue; common: asthenia

Skin and subcutaneous tissue disorders
Skin reactions including erythema, facial swelling, pruritus, rash, and vasodilation

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via 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 dropper bottle is 28 days.

Storage conditions.
No special storage conditions required. Keep out of reach and sight of children.
Do not use more than 28 days after first opening of the container.

Packaging.
5 ml in a dropper bottle, 1 dropper bottle per cardboard box.

Prescription status.
Prescription only.

Manufacturer.
Jadran-Galenski Laboratorij d.d.

Manufacturer's address and place of business.
Svilno 20, 51000 Rijeka, Croatia