4.1. Therapeutic indications

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

- As monotherapy in patients in whom topical beta-blocker therapy is contra-indicated.

- As adjunctive therapy to other intraocular pressure lowering medications when the target intraocular pressure is not achieved with a single agent. (See section 5.1)

4.2. Posology and method of administration

Posology

Paediatric population

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

Brimonidine eye drops should not be used in children aged below 12 years and are contraindicated in neonates and infants (less than 2 years of age) (see sections 4.3, 4.4 & 4.9). It is known that severe adverse reactions can occur in neonates. The safety and efficacy of brimonidine has not been established in children.

Adults including the elderly:

One drop into the affected eye(s) twice daily, approximately 12 hours apart. No dosage adjustment is required in elderly patients.

To reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctal occlusion) for one minute immediately after the instillation of each drop.

If more than one topical ophthalmic drug is to be administered, they should be instilled 5 to 15 minutes apart.

Patients with renal and hepatic impairment:

Brimonidine eye drops have not been studied in patients with renal or hepatic impairment (see section 4.4).

Method of administration

Precautions to be taken before handling or administering the medicinal product

4.3. Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1 Contraindicated in neonates and infants.(See section 4.8)

Contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy or those on antidepressants which affect noradrenergic transmission (eg. tricyclic antidepressants and mianserin).

4.4. Special warnings and precautions for use

Paediatric population

Children of 2 years of age and above, especially those in the 2 to 7 age range and/or weighing ≤20 kg, should be treated with caution and closely monitored due to the high incidence and severity of somnolence (see section 4.8).

Caution is required in treating patients with:

- severe or unstable and uncontrolled cardiovascular disease.

- depression

- cerebral or coronary insufficiency

- Raynaud's phenomenon

- orthostatic hypotension

- thromboangiitis obliterans

The use of Brimonidine Eye Drops has not been studied in patients with hepatic or renal impairment, therefore, caution should be exercised when treating such patients.

It is reported that some patients (12.7%) in clinical trials experienced ocular allergic type reaction with brimonidine eye drops (see section 4.8); if allergic reactions are apparent, treatment should be discontinued.

Delayed ocular hypersensitivity reactions have been reported with Brimonidine Eye Drops, with some reported to be associated with an increase in IOP.

Contact lenses

Brimonidine eye drops contain 0.05mg/ml benzalkonium chloride as preservative which may be deposited in soft contact lenses. Hence, Brimonidine eye drops should not be used while wearing these lenses. The lenses should be removed before instillation of the drops and not reinserted earlier than 15 minutes after use.

Benzalkonium chloride has been reported to cause eye irritation, symptoms of dry eyes and may affect the tear film and corneal surface. Should be used with caution in dry eye patients and in patients where the cornea may be compromised. Patients should be monitored in case of prolonged use.

4.5. Interaction with other medicinal products and other forms of interaction

Patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenagic transmission (e.g. tricyclic antidepressants and miaserin), (see section 4.3).

Although specific drug interaction studies have not been conducted, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives or anaesthetics) should be considered.

Although no actual data on the level of circulating catecholamines after administration of brimonidine eye drops are available, caution is advised when using the eye drops in patients who are taking medications which can affect the metabolism and uptake of circulating amines, eg. chlorpromazine, methylphenidate, reserpine.

After application of brimonidine eye drops, clinically insignificant decreases in blood pressure have been reported in some patients. Caution is therefore advised when using drugs such as antihypertenstives and/or cardiac glycosides concomitantly with brimonidine eye drops.

Caution is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with α-adrenergic agonists or interfere with their activity, ie. agonists or antagonists of the adrenergic receptor, eg. isoprenaline, prazosin.

4.6. Fertility, pregnancy and lactation

Pregnancy

The safety of use during human pregnancy has not been established. In animal studies, brimonidine tartrate did not cause any teratogenic effects. In rabbits, brimonidine tartrate at plasma levels higher than are achieved during therapy in humans, has been shown to cause increased preimplantation loss and postnatal growth reduction. Brimonidine eye drops should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk to the foetus.

Breast-feeding

It is not known if brimonidine is excreted in human milk. The compound is excreted in the milk of the lactating rat. Brimonidine eye drops should not be used by women nursing infants.

4.7. Effects on ability to drive and use machines

Brimonidine eye drops may cause fatigue and/or drowsiness which may impair the ability to drive or to use machinery. They may also cause blurred and/or abnormal vision, which may impair the ability to drive or to use machinery, especially at night or in reduced lighting. The patient should wait until these symptoms have cleared before driving or operating machinery.

4.8. Undesirable effects

The most commonly reported ADRs are oral dryness, ocular hyperaemia and burning/stinging, all occurring in 22 to 25% of patients. They are usually transient and not commonly of a nature serious enough to require discontinuation of treatment. Symptoms of ocular allergic reactions have been reported to have occurred in 12.7% of subjects in clinical trials (causing withdrawal in 11.5% of subjects), with onset being between 3 and 9 months in the majority of patients.

The following convention has been used for classification of frequency of undesirable effects:

Very common :

Common :

Uncommon :

Rare :

Very rare :

≥ 1 in 10.

≥ 1 in 100 and <1 in 10.

≥ 1 in 1,000 and <1 in 100.

≥ 1 in 10,000 and <1 in 1,000

< 1 in 10,000.

Not known (cannot be estimated from the available data)

Within each frequency grouping, undesired effects are presented in order of decreasing seriousness.

Cardiac disorders:

Uncommon: Palpitations/arrhythmias (including bradycardia and tachycardia).

Nervous system disorders:

Very common: Headache, drowsiness.

Common: Dizziness, abnormal taste.

Very rare: Syncope

Eye disorders:

Very common : Ocular irritation including allergic reactions (hyperaemia, burning, stinging, pruritis, foreign body sensation, conjunctival follicles); blurred vision, allergic blepharitis, allergic blepharoconjuctivitis, allergic conjunctivitis, ocular allergic reaction and follicular conjunctivitis.

Common: Local irritation (eyelid hyperaemia and oedema, blepharitis, conjunctival oedema and discharge, ocular pain and tearing); photophobia; corneal erosion and staining; ocular dryness; 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: Oral dryness.

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 identified during post-marketing use of Brimonidine eye drops in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Not known:

Eye disorders

Iridocyclitis (anterior uveitis)

Eyelid pruritus

Skin and subcutaneous tissue disorders

Skin reaction including erythema, face oedema, pruritus, rash and vasodilation

In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis apnoea, lethargy, somnolence, pallor and respiratory depression have been reported in neonates and infants receiving brimonidine (see section 4.3).

In a 3 month, phase 3 study in children aged 2 to 7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with brimonidine eye drops as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing ≤20 kg (63%) compared to those weighing >20 kg (25%) (See section 4.4)

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 www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google Play or Apple App Store.

4.9. Overdose

Ophthalmic overdose (Adults):

In those cases received, the events reported have generally been those already listed as adverse reactions

Systemic overdose resulting from accidental ingestion (Adults):

There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension.

Treatment of oral overdose includes supportive and symptomatic therapy; patient's airways should be maintained.

Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure

Paediatric population

Reports of serious adverse effects following inadvertent ingestion of brimonidine eye drops have been published/reported. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated. All subjects were reported to have made a full recovery, usually within 6-24 hours.