BRIMONIDINE VIATRIS 0,2 % (2 mg/ml) Collyre sol Fl/5ml

Eye drops in solution.

Clear solution, pale yellow-green in colour with a pH between 5,5 and 6,5 and an osmolality between 275 and 315 mOsm/kg.

Brimonidine tartrate...............................................................................................................................2,0 mg

Equivalent to brimonidine base...................................................................................................................1,3 mg

For 1 mL of solution.

Excipient with known effect: benzalkonium chloride 0,05 mg/ml

Excipients:

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

• As monotherapy in patients with a contraindication to topical beta-blockers.

• In combination with other intraocular pressure-lowering treatments in cases where monotherapy does not achieve the target IOP (see section Pharmacodynamics).

Dosage

Adults (including elderly patients)

The recommended dose is one drop of BRIMONIDINE VIATRIS twice daily in the affected eye or eyes, the two instillations being spaced approximately 12 hours apart. Use of the eye drops in elderly patients does not require any dose adjustment.

Use in patients with hepatic or renal impairment

Brimonidine has not been studied in patients with renal or hepatic impairment (see section Warnings and precautions).

Paediatric population

No clinical studies have been conducted in adolescents (12 to 17 years).

Brimonidine is not recommended in children under 12 years and is contraindicated in newborns and infants (under two years) (see sections Contraindications, Warnings and precautions and 4.9). Serious adverse effects have been reported in newborns. In children, the safety and efficacy of brimonidine have not been established.

Method of administration

Ophthalmic use.

As is the case with all eye drops, to reduce possible systemic absorption, it is recommended to press the lacrimal sac at the inner canthus (punctal occlusion) for one minute. This should be done immediately after the instillation of each drop.

If several topical ophthalmic products are used, the instillations of the different products must be spaced by 5 to 15 minutes.

• Hypersensitivity to the active substance or to any of the excipients listed in section Composition.

• Newborns and infants (see section Adverse effects).

• Patients receiving treatment with a monoamine oxidase inhibitor (MAOI) or an antidepressant affecting noradrenergic transmission (for example, tricyclic antidepressants and mianserin).

Paediatric population

Children from the age of 2 years, particularly those aged 2 to 7 years and/or weighing less than or equal to 20 kg, must be treated with caution and closely monitored because of the high and severe risk of drowsiness (see section Adverse effects).

Cardiovascular disease

Particular caution is required in patients with severe or unstable and uncontrolled cardiovascular disease.

Allergic reactions

During clinical trials, a few patients (12,7 %) presented an ocular allergy-type reaction with brimonidine (see section Adverse effects for further information). In case of an allergic reaction, treatment with BRIMONIDINE VIATRIS must be stopped.

Ocular hypersensitivity reactions have been observed with brimonidine and, in some cases, they were associated with an increase in intraocular pressure.

Other patients

Brimonidine must be used with caution in patients suffering from depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension or thromboangiitis obliterans.

Patients with renal or hepatic impairment

Brimonidine has not been studied in patients with renal or hepatic impairment; particular attention is required when treating these patients.

Excipients

This medicine contains 0,05 mg of benzalkonium chloride per millilitre of solution.

Benzalkonium chloride may be absorbed by soft contact lenses and change their colour. Patients must remove contact lenses before application and wait at least 15 minutes before reinserting them.

Benzalkonium chloride is known to cause eye irritation and symptoms of dry eye syndrome, and may affect the tear film and the corneal surface. It must be used with caution in patients with dry eye and those at risk of corneal damage. Patients must be monitored in case of prolonged use.

Brimonidine is contraindicated in patients treated with a monoamine oxidase inhibitor (MAOI) and in patients taking antidepressants that may affect noradrenergic transmission (e.g., tricyclic antidepressants and mianserin) (see section Contraindications).

Although no specific study of drug interactions with brimonidine has been conducted, the possibility of an additive or potentiating effect when taking central nervous system depressants (alcohol, barbiturates, opiates, sedatives or anaesthetics) must be considered.

No information is available on the level of circulating catecholamines after administration of brimonidine. Consequently, caution should be exercised with patients taking medicines that may affect the metabolism and uptake of circulating amines (e.g., chlorpromazine, methylphenidate, reserpine).

After instillation of brimonidine, clinically non-significant decreases in blood pressure were observed in a few patients. Caution is advised when BRIMONIDINE VIATRIS is taken concomitantly with antihypertensives and/or cardiac glycosides.

Particular attention is recommended when initiating (or changing the dose of) concomitant systemic treatment (whatever the pharmaceutical form) that may interact with alpha-adrenergic agonists or interfere with their activity, such as adrenergic receptor agonists or antagonists (e.g., isoprenaline, prazosin).

Pregnancy

The safety of use in women during pregnancy has not been established.

In animal studies, brimonidine did not produce a teratogenic effect.

In rabbits, brimonidine, at plasma concentrations higher than those obtained with treatment in humans, caused greater losses during the preimplantation period and a reduction in postnatal growth.

BRIMONIDINE VIATRIS should only be used when the potential benefits to the mother outweigh the potential risks to the foetus.

Breast-feeding

It has not been established whether brimonidine metabolites are excreted in human milk. The product is excreted in the milk of lactating rats.

BRIMONIDINE VIATRIS must not be used during breastfeeding.

BRIMONIDINE VIATRIS has a minor or moderate influence on the ability to drive and use machines.

Brimonidine may cause some tiredness and/or drowsiness that may impair the ability to drive or use machines.

Brimonidine may cause blurred or abnormal vision that may impair the ability to drive or use machines, particularly at night or in reduced light. The patient must wait until these symptoms have resolved before driving or using machines.

The most commonly reported adverse events are dry mouth, ocular hyperaemia, burning sensations and stinging sensations, occurring in 22 to 25 % of patients. They are generally transient and rarely severe enough to require discontinuation of treatment.

In clinical studies, symptoms of allergic reactions appeared in 12,7 % of patients (leading to discontinuation of treatment in 11,5 % of patients) and occurred within 3 to 9 months of treatment in the majority of patients.

Within each frequency group, undesirable effects are presented in order of decreasing seriousness. The frequency of undesirable effects is indicated as follows:

Very common	(≥ 1/10) ;
Common	(≥ 1/100, <1/10) ;
Uncommon	(≥ 1/1 000, <1/100) ;
Rare	(≥ 1/10 000, 1/1 000) ;
Very rare	(< 1/10 000) ;
Frequency not known	(cannot be estimated from the available data).

Immune system disorders

Uncommon 

• systemic allergic reactions

Psychiatric disorders

Uncommon :

• depression

Very rare :

• insomnia

Nervous system disorders

Very common :

• headache

• somnolence

Common :

• dizziness

• abnormal taste

Very rare :

• syncope

Eye disorders

Very common :

• eye irritation (hyperaemia, burning and stinging, pruritus, foreign body sensation and conjunctival follicles)

• blurred vision

• allergic blepharitis, allergic blepharoconjunctivitis, allergic conjunctivitis, allergic ocular reaction, follicular conjunctivitis

Common :

• local irritation (eyelid hyperaemia and oedema, blepharitis, conjunctival oedema and discharge, ocular pain and lacrimation)

• photophobia

• corneal erosion and staining

• dry eye

• conjunctival blanching

• abnormal vision

• conjunctivitis

Very rare :

• iritis (anterior uveitis)

• miosis

Cardiac disorders

Uncommon :

• palpitations/arrhythmia (including bradycardia and tachycardia)

Vascular disorders

Very rare :

• hypertension

• hypotension

Respiratory, thoracic and mediastinal disorders

Common :

• upper respiratory 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

The following adverse reactions were observed during the post-marketing period of brimonidine in clinical practice. The frequency of these reactions remains unknown because the size of the population exposed to brimonidine is undetermined.

Eye disorders

Frequency not known:

• iridocyclitis (anterior uveitis)

• eyelid pruritus

Skin and subcutaneous tissue disorders

Frequency not known :

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

Paediatric population

Manifestations of brimonidine overdose (including loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnea) have been described in newborns and infants receiving this product for the treatment of congenital glaucoma (see section Contraindications).

A high prevalence of somnolence (55 %) was reported in a three-month Phase III study evaluating brimonidine as adjunctive treatment in children aged 2 to 7 years with glaucoma insufficiently controlled by a beta-blocker. This somnolence was severe in 8 % of children and led to treatment discontinuation in 13 %. Its incidence decreased with increasing age, the lowest incidence being observed in the group of children aged 7 years (25 %). This incidence was more strongly influenced by weight, remaining higher in children weighing ≤20 kg (63 %) than in those weighing >20 kg (25 %) (see section Warnings and precautions).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr

Ophthalmic overdose (adult) :

The effects reported are generally those described under adverse reactions.

Systemic overdose resulting from accidental ingestion (adult) :

There is very little information regarding accidental ingestion of brimonidine in adults.

To date, the only adverse effect reported is hypotension. It has been reported that these episodes of hypotension were followed by rebound hypertension.

Treatment of oral overdose consists of symptomatic and supportive treatment; the patient's airways must be maintained.

Reported cases of oral overdose with other alpha-2 stimulants have mentioned symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and convulsions.

Paediatric population

Cases of serious adverse effects following inadvertent ingestion of brimonidine by infants and children have been published or reported. The subjects presented manifestations of CNS depression, typically transient coma or a marked decrease in consciousness, as well as lethargy, drowsiness, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, which required admission to an intensive care unit and intubation in some cases. Complete recovery, usually in 6 to 24 hours, has been reported in all subjects.

Pharmacotherapeutic class: sympathomimetics in the treatment of glaucoma, ATC code: S01E-A-05.

Mechanism of action

Brimonidine is an alpha-2 adrenergic receptor agonist 1 000 times more selective for alpha-2 adrenergic receptors than for alpha-1 adrenergic receptors.

Due to this selectivity, no mydriasis or microvascular vasoconstriction is observed, associated with human retinal xenografts.

Clinical efficacy and safety

Local administration of brimonidine tartrate reduces intraocular pressure (IOP) in humans and affects cardiovascular or pulmonary parameters only minimally.

Limited data in patients with bronchial asthma have not revealed any harmful effect.

Brimonidine has a rapid onset of action, with the maximum ocular hypotensive effect observed two hours after administration. In 2 one-year clinical studies, the mean IOP reductions obtained with brimonidine were approximately between 4 and 6 mmHg.

Fluorophotometric studies conducted in animals and humans suggest that brimonidine tartrate has a dual mechanism of action. Brimonidine is thought to reduce IOP by decreasing aqueous humour formation and by increasing aqueous humour outflow via the uveoscleral pathway.

Clinical studies show that brimonidine is effective when combined with topical beta-blockers. Shorter studies also suggest that brimonidine has a clinically significant additional effect on IOP reduction when combined with travoprost (6 weeks) and with latanoprost (3 months).

Absorption

After ocular administration of a 0,2% solution twice daily for 10 days, plasma concentrations were low (Cmax mean equal to 0,06 ng/mL). A slight accumulation in the blood was observed after multiple instillations (2 times daily for 10 days).

After oral administration in humans, brimonidine is well absorbed.

Distribution

In humans, the plasma protein binding rate of brimonidine after local administration is approximately 29%.

Brimonidine is reversibly bound to melanin in ocular tissues, in vitro and in vivo. After 2 weeks of ocular instillations, brimonidine concentrations in the iris, ciliary body and choroid-retina were 3 to 17 times higher than those observed after a single instillation. There is no accumulation in the absence of melanin.

The extent of binding to melanin in humans is poorly understood. However, no harmful ocular effects were found on biomicroscopic examination of the eyes of patients treated with brimonidine for periods of up to one year; likewise, no significant ocular toxicity was found during a one-year ocular tolerance study in monkeys receiving approximately four times the recommended dose of brimonidine.

Biotransformation

Studies in vitro, using animal and human liver, show that metabolism involves aldehyde oxidase and cytochrome P450 to a large extent. Consequently, systemic elimination appears to be primarily due to hepatic metabolism.

Elimination

After oral administration in humans, brimonidine is rapidly eliminated. The mean apparent half-life in the systemic circulation was approximately 3 hours in humans after local administration.

The major part of the dose (approximately 75 %) was excreted in the urine as metabolites within 5 days; no unchanged product was detected in the urine.

Characteristics in elderly patients :

In elderly patients (subjects aged 65 years or older), the Cmax, the area under the curve (AUC) and the apparent half-life of brimonidine are similar, after a single instillation, to those observed in young adults, indicating that age does not influence the systemic absorption and elimination of the product.

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

Linearity/non-linearity

The area under the plasma concentration/time curve over 12 hours at steady state (AUC0-12h) was equal to 0,31 ng.h/mL, compared with 0,23 ng.h/mL after the first dose. After a single ocular instillation of 0,08 %, 0,2 % and 0,5 % concentrations, no significant deviation from linearity of the absorption kinetics (measured by plasma Cmax and AUC) is observed.

Non-clinical data from conventional safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicity and reproductive function studies revealed no particular risk for humans.

Before first opening: 3 years.

After first opening: use within 28 days.

No special precautions for storage.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

List I

Marketing authorisation (AMM)

CIP 3400938958423 (Fl/5mL).

Price:

3,55 euros (Fl/5ml).

Social Security reimbursement at 65% based on the TFR: 3.55 euros (Fl/5ml).
Collection.