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

Eye drops in solution.

Clear solution, pale yellow-green in colour.

One millilitre of solution contains:

Brimonidine tartrate...................................................................................................................................2 mg

Equivalent to 1,3 mg of brimonidine

Excipient with known effect:

Each mL of solution contains 0.05 mg of benzalkonium chloride.

Excipients:

Reduction of 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 medicinal products that lower intraocular pressure in cases where monotherapy does not achieve the target IOP (see section Pharmacodynamics).

Dosage

Recommended dose in adults (including elderly patients)

The recommended dosage is one drop of brimonidine twice daily in the affected eye(s), the two instillations being spaced approximately 12 hours apart.

Elderly patients :

Use of the eye drops in elderly patients does not require any dosage adjustment.

Insuffisance rénale ou hépatique

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

Population paediatric

No clinical study has been conducted in adolescents (12 to 17 years).

Brimonidine is not recommended in children under 12 years and is contraindicated in neonates and infants (under 2 years) (see sections Contraindications, Warnings and precautions and Overdose). Serious adverse reactions have been reported in neonates. In children, the safety and efficacy of brimonidine have not been established.

Method of administration

As with all eye drops, to reduce possible systemic absorption, it is recommended to press the lacrimal sac at the inner canthus (punctum occlusion) for one minute. This should be done immediately after the instillation of each drop. If several topical ophthalmic medicines are used, the instillations of the different medicines should be separated 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) and patients on antidepressants affecting noradrenergic transmission (for example tricyclic antidepressants and mianserin)

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

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

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

Delayed ocular hypersensitivity reactions have been reported with brimonidine, some of which were associated with an increase in IOP.

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

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

Excipients :

Benzalkonium chloride may be absorbed by soft contact lenses and discolour them. Contact with soft contact lenses should be avoided. Contact lenses should be removed before using the eye drops and should not be reinserted for at least 15 minutes.  

Benzalkonium chloride may also cause eye irritation, eye dryness, affect the tear film and the corneal surface. This product should be used with caution if the patient suffers from dry eye syndrome or corneal disorders.

Patients should be regularly monitored in case of prolonged use.

Brimonidine is contraindicated in patients treated with monoamine oxidase inhibitors (MAOIs) and in patients treated with antidepressants affecting noradrenergic transmission (e.g. tricyclic antidepressants and mianserin) (See section Contraindications).

Although there are no specific studies on drug interactions with brimonidine, the possibility of an additive or potentiating effect when taking central nervous system (CNS) depressants (alcohol, barbiturates, opiates, sedatives or anaesthetics) must be taken into account.

No information is available regarding the level of circulating catecholamines after instillation of brimonidine. However, vigilance is advised in patients taking medicines that may affect the metabolism and uptake of circulating amines (e.g. chlorpromazine, methylphenidate, reserpine).

After instillation of brimonidine, some patients showed clinically non-significant decreases in blood pressure. Vigilance is advised when brimonidine is taken concomitantly with antihypertensives and/or cardiac glycosides.

Particular attention is recommended when initiating (or changing the dosage 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 tartrate did not produce a teratogenic effect. In rabbits, brimonidine tartrate, at plasma concentrations higher than those obtained during treatment in humans, caused greater losses during the preimplantation period and a reduction in postnatal growth. Brimonidine should only be used during pregnancy when the potential benefits to the mother outweigh the potential risks to the foetus.

Breast-feeding

It has not been established whether brimonidine is excreted in human breast milk. The product is excreted in the milk of lactating rats. Brimonidine must not be used during breastfeeding.

Brimonidine has a minor or moderate influence on the ability to drive vehicles 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 and/or abnormal vision that may impair the ability to drive vehicles or use machines, particularly at night or in low light. The patient should wait for these symptoms to disappear before driving or using machines.

The most commonly reported undesirable effects 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.

Undesirable effects are presented in decreasing order of seriousness within each frequency group. The following terminology is used to classify the occurrence of undesirable effects:

Very common: (≥1/10);
Frequent: (≥1/100 to <1/10);
Uncommon: (≥1/1 000 to < 1/100);
Rare: (≥1/10 000 to 1/1 000);
Very rare: (<1/10 000);
Unknown: (cannot be estimated from the available data).

Cardiac disorders

Uncommon:

• palpitations/arrhythmia (including bradycardia and tachycardia).

Nervous system disorders

Very common:

• headache

• somnolence.

Common:

• dizziness

• abnormal taste.

Very rare:

• syncope.

Eye disorders

Very common:

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

• blurred vision.

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

Common:

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

• photophobia

• corneal erosion and corneal staining.

• dry eye

• conjunctival blanching

• abnormal vision

• conjunctivitis.

Very rare:

• iritis (anterior uveitis)

• miosis.

Respiratory, thoracic and mediastinal disorders

Common:

• upper respiratory symptoms.

Uncommon:

• nasal dryness.

Rare:

• dyspnoea.

Gastrointestinal disorders

Very common:

• dry mouth.

Common:

• gastrointestinal symptoms.

Vascular disorders

Very rare:

• 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.

The following adverse reactions have been reported in clinical practice following the marketing of brimonidine. Since they were spontaneously reported from a population of unknown size, an estimate of their frequency could not be made.

Eye disorders

Unknown frequency:

• iridocyclitis (anterior uveitis).

• eyelid pruritus.

Skin and subcutaneous tissue disorders

Unknown frequency:

• skin reaction including erythema, facial oedema, pruritus, rash and vasodilation.

Manifestations of brimonidine overdose, including loss of consciousness, hypotension, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea) have been described in newborns and infants receiving brimonidine 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 an add-on treatment in children aged 3 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 as age increased, the lowest incidence being observed in the group of children aged 7 years (25 %). This incidence was more strongly influenced by weight, occurring more frequently 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 (Adults):

In such cases, the events reported were generally those listed among the adverse effects.

Systemic overdose resulting from accidental ingestion (Adults):

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

The only adverse effect reported to date is hypotension. This hypotensive episode was followed by reactive hypertension.

Treatment of an oral overdose relies on symptomatic and supportive measures; maintenance of airway patency should be ensured.

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

Paediatric population:

Notifications of serious adverse effects following accidental ingestion of brimonidine by children have been published or reported. Subjects presented with symptoms of central nervous system (CNS) depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, requiring admission to intensive care units with intubation where applicable. Complete recovery was reported in all subjects, generally within 6 to 24 hours.

Pharmacotherapeutic class: ANTIGLAUCOMA SYMPATHOMIMETICS. ATC code: S01EA05

Brimonidine is an alpha-2 adrenergic receptor agonist, 1000 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.

Topical 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. It is thought that brimonidine lowers IOP by reducing aqueous humour formation and by increasing aqueous humour outflow via the uveoscleral pathway.

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

General characteristics

After ocular administration of a 0,2 % solution twice daily for 10 days, plasma concentrations were low (Cmaxmean equal to 0,06 ng/ml). A slight accumulation in the blood was observed after multiple instillations (2 times daily for 10 days). 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. The mean apparent half-life in the systemic circulation was approximately 3 hours in humans after topical administration.

In humans, the plasma protein binding rate of brimonidine after topical 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 significance of melanin binding in humans is poorly understood. However, no adverse ocular effects were found on slit-lamp biomicroscopic examination of 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 tartrate.

After oral administration in humans, brimonidine is well absorbed and rapidly eliminated. 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. In vitro studies using animal and human liver show that metabolism largely involves aldehyde oxidase and cytochrome P450. Consequently, systemic elimination appears to be mainly due to hepatic metabolism.

Kinetic profile:

After a single ocular instillation of 0,08 %, 0,2 % and 0,5 % concentrations, no significant deviation from linearity of absorption kinetics (measured by the Cmax plasma and AUC) is observed.

Characteristics in patients

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

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

Before first opening: 4 years.

After first opening: use within 28 days.

No special precautions for storage.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400938959482 (Fl/5ml).

Price:

3,55 euros (Fl/5ml).

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