Brimonord (Drops) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

S01ED51 (Timolol in combination with other drugs)

Active Substances

Timolol (Rec.INN registered by WHO)

Brimonidine (Rec.INN registered by WHO)

Dosage Form

Brimonord

Eye drops 2 mg+5 mg/1 ml: dropper bottles 5 ml or 10 ml

Dosage Form, Packaging, and Composition

Eye drops as a clear greenish-yellow solution.

Excipients: benzalkonium chloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, 1M hydrochloric acid solution or 1M sodium hydroxide solution, purified water.

5 ml – polyethylene dropper bottles (1) with dropper caps – cardboard boxes.
10 ml – polyethylene dropper bottles (1) with dropper caps – cardboard boxes.

Clinical-Pharmacological Group

Antiglaucoma drug

Pharmacotherapeutic Group

Drugs used in ophthalmology, antiglaucoma drugs and miotics, beta-blockers, combinations with timolol

Pharmacological Action

Mechanism of action

A combined medicinal product containing 2 active substances: brimonidine – an adrenomimetic that has a stimulating effect on α₂-adrenergic receptors, and Timolol – a β-adrenergic receptor blocker. Both active substances reduce intraocular pressure (IOP) through combined interaction, leading to a significantly more pronounced hypotensive effect compared to the effect of each component separately.

Brimonidine is an agonist of α-adrenergic receptors, with 1000 times greater selectivity for α₂-adrenergic receptors compared to α₁-adrenergic receptors. This selectivity is expressed in the absence of mydriasis and vasoconstriction of the microcirculatory bed vessels. The hypotensive action of brimonidine is provided by reducing the production of intraocular fluid and increasing its outflow through the uveoscleral pathway.

Timolol is a non-selective beta-adrenergic blocker, devoid of intrinsic sympathomimetic and membrane-stabilizing activity. Timolol reduces IOP by reducing the production of intraocular fluid. The exact mechanism of action is not established; it may be associated with the inhibition of cyclic adenosine monophosphate (cAMP) synthesis and is caused by endogenous stimulation of β-adrenergic receptors.

Pharmacokinetics

Brimonidine

Absorption

When instilling a 0.2% solution as eye drops, the concentration of brimonidine in blood plasma is very low.

Distribution

The mean C_max of brimonidine in blood plasma after application of the fixed combination brimonidine/Timolol is 0.0327 ng/ml.

The binding of brimonidine to blood plasma proteins is about 29%.

Metabolism

Brimonidine undergoes minimal metabolism in the eye tissues. In vitro studies on animal and human liver cells have shown that aldehyde oxidase and cytochrome P450 are largely involved in the metabolism process. Therefore, systemic elimination is determined primarily by the metabolism of the drug in the liver.

Elimination

The T_1/2 of brimonidine after topical application is, on average, about 3 hours. The main part of the drug (about 74% of the dose absorbed into the systemic circulation) is excreted by the kidneys in the form of metabolites within 5 days; the unchanged drug is not detected in the urine.

Timolol

Absorption

80% of timolol applied as eye drops enters the systemic circulation through absorption via the conjunctival vessels, nasal mucosa, and lacrimal tract. After instillation of eye drops, C_max in the aqueous humor of the eye is reached within 1-2 hours.

Distribution

The mean C_max of timolol in blood plasma after application of the fixed combination brimonidine/Timolol is 0.406 ng/ml.

Timolol is minimally bound to blood plasma proteins.

Metabolism

Timolol partially undergoes biotransformation in the liver.

Elimination

The T_1/2 of timolol in blood plasma is 7 hours. Timolol and its metabolites are excreted by the kidneys.

Indications

For adults aged 18 years and older to reduce intraocular pressure in

• Open-angle glaucoma;
• Ocular hypertension (with insufficient effectiveness of local therapy with beta-blockers).

ICD codes

Dosage Regimen

Adults

1 drop 2 times/day in the morning and evening with a 12-hour interval.

The dose should not exceed 1 drop into the conjunctival sac 2 times/day.

If a dose is missed, treatment should be continued with the next scheduled dose. The duration of treatment is determined by the doctor.

Children

The safety and efficacy of the drug Brimonord in children and adolescents aged 0 to 18 years have not been established. The drug Brimonord is contraindicated in children aged 0 to 18 years.

Method of administration

The drug is intended for topical administration as instillations into the conjunctival cavity of the affected eye (eyes).

The drug Brimonord can be used with other ophthalmic drugs to reduce IOP. If the patient uses more than 2 drugs, a 5-minute break should be taken between instillations. When used in complex therapy with eye ointments, eye ointments should be applied last.

As with the use of other eye drops, to reduce possible systemic absorption, brief pressure on the lacrimal sac in the area of the lacrimal sac projection at the inner corner of the eye or eyelid closure for 2 minutes is recommended. This should be done immediately after instilling each drop.

Do not touch the tip of the dropper bottle to any surface to avoid contamination of the dropper bottle and its contents. The bottle must be tightly closed after each use.

Adverse Reactions

According to 12-month clinical studies, the most frequent adverse reactions were conjunctival injection (about 15% of patients) and burning sensation of the eye mucosa (about 11% of patients). In most cases, the severity of these symptoms was mild; therapy discontinuation was required only in 3.4% and 0.5% of cases, respectively.

Tabulated summary of adverse reactions

During clinical studies and post-registration use of the fixed combination brimonidine/Timolol, the following adverse reactions have been reported with the following frequency: very common (≥1/10), common (≥1/100 but <1/10), uncommon (≥1/1000 but <1/100), rare (≥1/10000 but <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Additional adverse reactions observed with the use of one of the active substances and potentially occurring with the use of the drug Brimonord

Brimonidine

Timolol

Like other topically applied ophthalmic drugs, the drug Brimonord is absorbed into the systemic circulation. The absorption of timolol may cause adverse effects similar to those observed with systemically acting beta-blockers.

The frequency of adverse reactions after topical ophthalmic application is lower than with systemic use.

Additional adverse reactions observed with the use of ophthalmic beta-blockers, which may also be observed with the use of the drug Brimonord, are listed below.

Adverse reactions noted with the use of eye drops containing phosphates

Very rarely, in connection with the use of eye drops containing phosphates, cases of corneal calcification have been noted in some patients with significant corneal damage.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk ratio of the drug. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to brimonidine, timolol, or to any of the excipients included in the drug;
• Increased respiratory reactivity, including bronchial asthma and episodes of bronchial obstruction, including in the anamnesis, severe chronic obstructive pulmonary disease (COPD);
• Sinus bradycardia, sick sinus syndrome, sinoatrial block, atrioventricular block II and III degree without an implanted artificial pacemaker, heart failure, cardiogenic shock;
• Concomitant therapy with MAO inhibitors, tricyclic and tetracyclic antidepressants (including mianserin).

Use in Pregnancy and Lactation

Pregnancy

No controlled studies have been conducted on the use of the fixed combination brimonidine/Timolol in pregnant women.

Brimonidine

There are insufficient data on the use of brimonidine in pregnant women. Animal studies have revealed reproductive toxicity of high doses of the drug for the maternal organism. The degree of risk to humans is not established.

Timolol

Animal studies have established reproductive toxicity when using doses of the drug significantly exceeding those recommended for clinical use. However, epidemiological studies have not revealed congenital malformations of the fetus, but the risk of intrauterine growth retardation is known with oral administration of drugs from the beta-blocker group. In addition, symptoms characteristic of the beta-blocker group (bradycardia, decreased blood pressure, dyspnea, and hypoglycemia) were observed in newborns in cases where beta-blockers were used by the mother until delivery.

In this regard, if the drug Brimonord is prescribed during pregnancy until the moment of delivery, medical monitoring of the newborn’s condition is necessary during the first days of life.

The drug Brimonord can be used during pregnancy only in the absence of alternative treatment methods.

Breastfeeding period

Brimonidine

The possibility of brimonidine penetration into human breast milk has not been established. It is known that it is excreted in the milk of rats.

Timolol

Beta-blockers penetrate into breast milk. However, when using timolol as eye drops in therapeutic doses, the development of clinical symptoms in children is unlikely due to the lack of a sufficient amount of the drug that has penetrated into breast milk.

Breastfeeding should be discontinued during treatment.

Use in Hepatic Impairment

The use of the drug has not been sufficiently studied in patients with hepatic insufficiency.

Use in Renal Impairment

The use of the drug has not been sufficiently studied in patients with renal insufficiency. In patients with severe renal impairment on hemodialysis, treatment with timolol is accompanied by a pronounced decrease in blood pressure.

Pediatric Use

The drug Brimonord is contraindicated in children aged 0 to 18 years.

Special Precautions

Circulatory disorders

Patients with serious peripheral circulatory disorders (e.g., severe Raynaud’s disease or Raynaud’s syndrome) should use the drug with caution.

Diabetes mellitus

Beta-blockers should be used with caution in patients with existing signs of spontaneous hypoglycemia or patients with unstable diabetes mellitus, as beta-blockers can mask the signs and symptoms of hypoglycemia.

Metabolic acidosis and pheochromocytoma

The drug Brimonord should be used with caution in patients with metabolic acidosis and with pheochromocytoma (without prior treatment).

Hepatic and renal disorders

The use of the drug has not been sufficiently studied in patients with renal and hepatic insufficiency.

In patients with severe renal impairment on hemodialysis, treatment with timolol is accompanied by a pronounced decrease in blood pressure.

Cardiac disorders

Given the negative impact on intracardiac conduction time, beta-blockers should be used with caution by patients with atrioventricular block I degree.

Cardiac reactions, sometimes fatal, associated with heart failure have been reported after the use of timolol. In patients with cardiovascular diseases (e.g., coronary artery disease, Prinzmetal’s angina, and heart failure) and arterial hypotension, the possibility of therapy with beta-blockers should be critically assessed and the possibility of therapy with other active substances should be considered. Patients with cardiovascular diseases should be monitored for signs of worsening of these diseases, as well as adverse reactions.

As with systemic beta-blockers, if patients with coronary artery disease require discontinuation of therapy, the drug should be withdrawn gradually to avoid arrhythmias, myocardial infarction, or sudden death.

Respiratory system disorders

In patients with mild/moderate COPD, the drug should be used with caution.

After the use of some ophthalmic beta-blockers, respiratory reactions have been reported, including death due to bronchospasm in patients with asthma.

Other beta-adrenergic blocking agents

The effect on IOP is a known effect of systemic beta-blockade, and it may be enhanced when Timolol is used in patients already receiving a systemic beta-blocker. The response to treatment in such patients should be carefully monitored. The use of two topically acting beta-blockers is not recommended.

Anaphylactic reactions

While using beta-blockers, patients with a history of atopy or severe anaphylactic reactions to a wide range of allergens may be prone to a more severe reaction upon repeated challenge with such allergens and may not respond to the usual dose of adrenaline used to treat anaphylactic reactions.

Corneal Diseases and Choroidal Detachment

Patients with corneal diseases should use the drug with caution, because ophthalmic beta-blockers can cause dry eye syndrome.

In cases of using drugs that reduce the production of intraocular fluid (for example, Timolol, acetazolamide), choroidal detachment has been observed after surgeries to improve the outflow of intraocular fluid.

Surgical Anesthesia

Ophthalmic beta-blocking drugs can block systemic beta-agonist effects, for example, those of epinephrine. The anesthesiologist must be informed that this patient is receiving Timolol.

Pharmacokinetic studies of the fixed combination brimonidine/Timolol in patients with angle-closure glaucoma have not been conducted.

It is unacceptable to touch the tip of the dropper bottle to any surfaces to avoid infecting the eye and the contents of the dropper bottle.

Like all topical ophthalmic drugs, Brimonord can be systemically absorbed. The absorption of timolol can cause undesirable effects similar to those observed with systemically acting beta-blockers.

If allergic reactions occur, treatment with Brimonord should be discontinued.

The shelf life of the drug after first opening the dropper bottle is 28 days. After this period has expired, the dropper bottle should be discarded, even if it still contains a residual amount of the drug. This is necessary to avoid the risk of infection. Patients are recommended to write the date of opening the bottle on the cardboard packaging.

Excipients

Brimonord contains the preservative benzalkonium chloride, which can irritate the eyes. In patients with corneal disease and “dry” eye syndrome using a drug containing benzalkonium chloride as a preservative, the development of ulcerative toxic keratopathy or punctate keratopathy is possible. During long-term therapy with Brimonord in such patients, the condition of the cornea should be monitored.

Direct contact of the drug with soft contact lenses should be avoided. Patients using contact lenses should remove the lenses before applying the drug and put them back in no earlier than 15 minutes later. Brimonord may change the color of soft contact lenses.

Effect on the Ability to Drive Vehicles and Operate Machinery

Brimonord has a minor effect on the ability to drive vehicles and operate machinery. During treatment with Brimonord, transient visual impairment (blurring), episodes of weakness and drowsiness may occur, which may have an adverse effect if the patient’s work involves potentially hazardous activities. If these symptoms occur, one should refrain from performing hazardous activities.

Overdose

In rare reports of overdose of the fixed combination brimonidine/Timolol in adults, there were no adverse outcomes. Treatment of overdose includes supportive and symptomatic therapy; the patient’s airway should be maintained.

Brimonidine

Overdose with Topical Application

The adverse event reports received mainly corresponded to the events described as adverse reactions.

Overdose with Accidental Ingestion

There is extremely limited information regarding the accidental ingestion of brimonidine in adults. The only adverse event noted to date is arterial hypotension. It was noted that the episode of arterial hypotension was followed by “rebound” arterial hypertension. In overdose caused by drugs of the alpha₂-adrenomimetic group, the following symptoms have been reported: decreased blood pressure, asthenia, vomiting, drowsiness, sedative effect, bradycardia, arrhythmias, miosis, apnea, hypothermia, respiratory depression, convulsions.

Timolol

Symptoms of systemic overdose with timolol: bradycardia, decreased blood pressure, bronchospasm, headache, dizziness, cardiac arrest. A study has shown that Timolol is not completely eliminated by hemodialysis.

Children

In cases of accidental ingestion of brimonidine by pediatric patients, these individuals experienced the following symptoms: CNS depression, short-term confusion, coma or depressed consciousness, sleep, drowsiness, muscle hypotonia, bradycardia, hypothermia, pale skin, respiratory depression and apnea, which necessitated urgent hospitalization in the emergency therapy department, and in some cases, tracheal intubation was performed. Full functional recovery was reported in all reported cases within 6 to 24 hours.

Drug Interactions

Specific studies on the drug interactions of the fixed combination brimonidine/Timolol have not been conducted. Nevertheless, the possibility of an enhanced effect of drugs that depress the CNS (alcohol, barbiturates, opiate derivatives, sedatives, or general anesthetics) when used concomitantly with Brimonord should be considered.

There is a possibility of an additive effect leading to arterial hypotension and/or marked bradycardia in case of simultaneous use of ophthalmic beta-blocker solutions with orally taken calcium channel blockers, beta-blockers, antiarrhythmic drugs (including amiodarone), digitalis glycosides, parasympathomimetics, or guanethidine. In addition, very rare (<1 in 10,000) cases of arterial hypotension have been observed after the use of brimonidine. Therefore, caution is recommended when using Brimonord in combination with systemic antihypertensive drugs.

Mydriasis occurring with the simultaneous use of ophthalmic beta-blockers and epinephrine has been occasionally observed. Beta-blockers may enhance the hypoglycemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycemia.

Potentiation of the hypotensive reaction to the abrupt withdrawal of clonidine during the administration of beta-blockers is possible.

Potentiation of systemic beta-blockade (e.g., in the form of decreased heart rate, depression) has been observed with the combined use of CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) and timolol.

Concomitant use of a beta-blocker and anesthetic agents may attenuate compensatory tachycardia and increase the risk of arterial hypotension, so the anesthesiologist must be informed that the patient is using Brimonord.

Caution should be exercised when using Brimonord concomitantly with iodine-based contrast agents or with intravenously administered lidocaine.

Cimetidine, hydralazine, and alcohol may increase the plasma concentration of timolol.

There are no data on the level of circulating catecholamines after the use of Brimonord. Nevertheless, caution is recommended in patients taking medications that can affect the metabolism and uptake of circulating amines, for example, chlorpromazine, methylphenidate, reserpine.

There are no data on the level of circulating catecholamines after the use of the fixed combination brimonidine/Timolol.

Caution is recommended at the start of use (or when changing the dose) of concomitant systemic agents (regardless of dosage form) that may interact with α-adrenergic agonists or affect their activity, i.e., when using adrenergic receptor agonists or antagonists (e.g., isoprenaline, prazosin) or alter their therapeutic potential. Although specific drug interaction studies have not been conducted with the fixed combination brimonidine/Timolol, the theoretical possibility of an additive intraocular pressure-lowering effect should be considered when used concomitantly with prostamides, prostaglandins, carbonic anhydrase inhibitors, and pilocarpine.

Brimonidine is contraindicated in patients receiving treatment with MAO inhibitors, as well as in patients receiving treatment with antidepressants that affect noradrenergic transmission (e.g., tricyclic antidepressants and mianserin). Patients who have been treated with MAO inhibitors should wait 14 days after discontinuation of treatment before starting therapy with Brimonord.

Storage Conditions

The drug should be stored in the original packaging (bottle in a carton) to protect from light at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

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

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.