BRIMAZED 2 mg/ml Collyre sol récip unidose 60unid

Eye drops at 2 mg/mL in solution (clear, slightly yellow-greenish).
Single-dose containers of 0,35 mL, box of 60.

For 1 mL of eye drops in solution :

Brimonidine tartrate: 2,0 mg
Quantity corresponding to brimonidine base: 1,3 mg

One drop contains 0,06-0,07 mg of brimonidine tartrate.

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.
• As adjunctive therapy to other intraocular pressure-lowering medicinal products in cases where monotherapy does not achieve the target IOP (see section Pharmacodynamics).

Dosage

Recommended dosage in adults (including elderly patients)

The recommended dosage is one drop of BRIMAZED twice daily in the affected eye(s), the two instillations being spaced about 12 hours apart. Use of the eye drops in elderly patients does not require any dosage adjustment.

Use in cases of renal or hepatic impairment

BRIMAZED 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).

BRIMAZED is not recommended in children under 12 years and is contraindicated in newborns and infants (under 2 years) (see sections Contraindications, Warnings and precautions, Overdose). Serious adverse reactions have been reported in newborns. The safety and efficacy of BRIMAZED in children aged 2 to 12 years have not been established.

Method of administration

Ophthalmic use.

As with all eye drops, in order to reduce possible systemic absorption, it is recommended to compress the lacrimal sac at the level of the canthus inner (occlusion point) for one minute. This should be done immediately after the instillation of each drop. This may result in a decrease in systemic adverse effects and an increase in local activity.

To avoid contamination of the eye or the eye drops, do not allow the tip of the single-dose container to come into contact with any surface.

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

• Hypersensitivity to the active substance or to any of the excipients listed in section Composition.
• Newborns and infants (under 2 years) (see section Adverse effects),
• Patients receiving monoamine oxidase inhibitor (MAOI) treatment and patients taking antidepressants that affect noradrenergic transmission (for example tricyclic antidepressants and mianserin).

Cardiac disorders

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

Eye disorders

During clinical trials, a few patients (12,7 %) experienced an allergic-type ocular reaction with a brimonidine eye drop containing preservative in multidose solution (see section Adverse effects). In case of an allergic reaction, treatment with BRIMAZED must be discontinued.

Delayed ocular hypersensitivity reactions have been reported with a brimonidine eye drop containing preservative in multidose solution, some of which were associated with an increase in intraocular pressure.

Vascular disorders

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

Renal and hepatic impairment

BRIMAZED has not been studied in patients with hepatic or renal impairment. Particular attention is required when treating these patients.

Paediatric population

Children aged two years or older, in particular 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 incidence and severity of somnolence (see section Adverse effects).

BRIMAZED is contraindicated in patients treated with monoamine oxidase inhibitors (MAOIs) and in patients treated with antidepressants that affect 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 an eye drop containing brimonidine. Consequently, vigilance is required in patients taking medicines that may affect the metabolism and uptake of circulating amines (e.g. chlorpromazine, methylphenidate, reserpine).

After instillation of an eye drop containing brimonidine, some patients showed decreases in blood pressure that were not clinically significant. Vigilance is required when BRIMAZED 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 during pregnancy in women 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 with treatment in humans, caused greater losses during the preimplantation period and a reduction in postnatal growth. BRIMAZED should only be used when the potential benefit to the mother outweighs the potential risk to the foetus. To reduce systemic absorption, see section Dosage and administration.

Breast-feeding

It is not known whether brimonidine is excreted in human milk. The product is excreted in the milk of lactating rats. BRIMAZED must not be used during breastfeeding.

BRIMAZED may cause some fatigue and/or drowsiness that may impair the ability to drive or use machines. BRIMAZED 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 for these symptoms to disappear before driving or using machines.

Summary of the safety profile

The most commonly reported adverse events for an eye drop containing brimonidine with preservative 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, for an eye drop containing brimonidine with preservative, 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 category, adverse effects are presented in order of decreasing seriousness. To classify the frequency of adverse effects the following terminology has been used: 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).

Table of adverse reactions

The following adverse effects have been reported for an eye drop containing brimonidine with preservative and may also occur with BRIMAZED without preservative:

* These undesirable effects have been reported in clinical practice following the marketing of an eye drop containing brimonidine with preservative. Knowing that they were reported on the basis of spontaneous notifications, an estimate of their frequency could not be made.

In cases where brimonidine was used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, drowsiness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in newborns and infants who had received brimonidine (see section Contraindications).

In a phase III study lasting 3 months, in children aged 2 to 7 years, with uncontrolled glaucoma under beta-blockers, a high prevalence (55%) of somnolence was reported with a brimonidine eye drop with preservative in multidose solution used in combination. In 8% of children, it was severe and led to treatment discontinuation in 13% of cases. The incidence of somnolence decreased with increasing age, being minimal in the group of subjects aged 7 years (25%), but it was more related to weight, appearing more frequently in children weighing less than or equal to 20 kg (63%) than in those weighing more than 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 reactions via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/.

Ophthalmic overdose (adults)

In such cases, the reported events have generally been listed among the undesirable effects.

Systemic overdose resulting from accidental ingestion (adults)

There is very little information regarding accidental ingestion of brimonidine in adults. The only undesirable 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. The respiratory tract must be monitored.

Reported cases of oral overdose with other alpha-2 stimulants have been associated with the following symptoms: hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and convulsion.

Paediatric population

Notifications of serious undesirable effects following accidental ingestion of a brimonidine eye drop with preservative 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, drowsiness, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, requiring admission to intensive care with intubation if necessary. Complete recovery was reported in all subjects, generally within 6 to 24 hours.

Pharmacotherapeutic class: Ophthalmological drugs, Antiglaucoma sympathomimetics, ATC code: S01EA 05.

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.

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; the maximum ocular hypotensive effect is observed two hours after administration of a brimonidine eye drop in solution with preservative. In 2 one-year clinical studies, the mean IOP reductions obtained with an eye drop containing brimonidine with preservative 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 additional effect in combination with travoprost (6 weeks) and latanoprost (3 months).

General characteristics

After ocular administration of a brimonidine tartrate eye drop solution at 0,2 % with preservative twice a day for 10 days, plasma concentrations were low (C_max mean equal to 0,06 ng/mL). A slight accumulation in the blood was observed after multiple instillations (2 times a day for 10 days). The area under the plasma concentration/time curve over 12 hours at steady state (AUC_{0-12 h}) 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 general circulation was approximately 3 hours in humans after local administration.

In humans, the rate of binding of brimonidine to plasma proteins 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 known. However, no harmful ocular effect was found on biomicroscopic examination of the eyes of patients treated with a brimonidine eye drop with preservative 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 five days; no unchanged product was detected in the urine. Studies in vitro, using animal and human liver, show that metabolism largely involves aldehyde oxidase and cytochrome P450. Consequently, systemic elimination appears to be due primarily to hepatic metabolism.

Kinetic profile

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

Characteristics in patients

Characteristics in elderly patients

In elderly patients (subjects aged 65 years or older), the C_max, 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 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.

Non-clinical data from conventional safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenesis and reproductive function studies did not reveal any particular risk for humans.

4 years

Do not use more than 3 months after opening the aluminium sachet.

Store in the original package, protected from light.

The contents of a single-dose container must be used immediately after opening.

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