Brimonidine Tartrate 2 mg/ml Eye drops, solution

One ml solution contains 2.0 mg brimonidine tartrate, equivalent to 1.3 mg of brimonidine.

Excipient(s): Contains benzalkonium chloride 0.05 mg/ml.

For a full list of excipients, see section 6.1.

Eye drops, solution.

Clear, greenish-yellow to light greenish-yellow solution.

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 contraindicated.

− As adjunctive therapy to other intraocular pressure lowering medications when the target IOP is not achieved with a single agent (see Section 5.1).

Posology

Recommended dosage in adults (including the elderly)

The recommended dose is one drop of Brimonidine Tartrate 2 mg/ml Eye drops, solution in the affected eye(s) twice daily, approximately 12 hours apart. No dosage adjustment is required for the use in elderly patients.

As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctal occlusion) for one minute. This should be performed immediately following the instillation of each drop.

If more than one topical ophthalmic drug is to be used, the different drugs should be instilled 5-15 minutes apart.

Use in renal and hepatic impairment

Brimonidine Tartrate 2 mg/ml Eye drops, solution has not been studied in patients with hepatic or renal impairment (see section 4.4).

Paediatric population

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

Brimonidine Tartrate 2 mg/ml Eye drops, solution is not recommended for use in children below 12 years and is contraindicated in neonates and infants (less than 2 years of age) (see sections 4.3, 4.4 and 4.9). It is known that severe adverse reactions can occur in neonates.

The safety and efficacy of Brimonidine Tartrate 2 mg/ml Eye drops, solution have not been established in children.

Method of administration

Brimonidine Tartrate 2 mg/ml Eye drops, solution comes as eye drops. Always wash your hands before applying eye drops. Your prescription label tells you how many drops to use at each dose. If you use Brimonidine Tartrate 2 mg/ml Eye drops, solution with another eye drop, wait 5-15 minutes before applying the second eye drop.

Apply your eye drops in the following way:

1. Tilt your head back and look at the ceiling.

2. Gently pull the lower eyelid down until there is a small pocket.

3. Squeeze the upturned dropper bottle to release a drop into your eye.

4. Whilst keeping the affected eye closed, press your finger against the corner of the closed eye (the side where the eye meets the nose) and hold for 1 minute.

Avoid touching the dropper tip against your eye or anything else.

Replace and tighten the cap straight after use.

− Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

− Neonates and infants (see section 4.8).

− Patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and mianserin).

Paediatric population

Children of 2 years of age and above, especially those in the 2-7 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).

Cardiac disorders

Caution should be exercised in treating patients with severe or unstable and uncontrolled cardiovascular disease.

Ocular

It is reported that some (12.7%) patients in clinical trials experienced an ocular allergic type reaction with brimonidine eye drops (see section 4.8 for details). If allergic reactions are observed, treatment with Brimonidine Tartrate 2 mg/ml Eye drops should be discontinued.

Delayed ocular hypersensitivity reactions have been reported with brimonidine eye drops 0.2%, with some reported to be associated with an increase in IOP.

Other Information

Brimonidine Tartrate 2 mg/ml Eye drops should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension or thromboangiitis obliterans.

Brimonidine Tartrate 2 mg/ml Eye drops has not been studied in patients with hepatic or renal impairment; caution should be used in treating such patients.

The preservative in Brimonidine Tartrate 2 mg/ml Eye drops, benzalkonium chloride, may cause eye irritation. Avoid contact with soft contact lenses. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion. Known to discolour soft contact lenses.

Brimonidine Tartrate 2 mg/ml Eye drops is contraindicated in 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 interactions studies have not been conducted with Brimonidine Tartrate 2 mg/ml Eye drops the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.

No data on the level of circulating catecholamines after brimonidine eye drops, administration are available. Caution, however, is advised in patients taking medications which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine.

After the application of Brimonidine eye drops, clinically insignificant decreases in blood pressure were noted in some patients.

Caution is advised when using drugs such as antihypertensives and/or cardiac glycosides concomitantly with Brimonidine Tartrate 2 mg/ml 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 i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin).

Fertility

No impairment of fertility and reproduction was reported in rats.

No data on the effects of Brimonidine on human fertility are available.

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 Tartrate 2 mg/ml Eye drops should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the foetus.

Lactation

It is not known if brimonidine is excreted in human milk. The compound is excreted in the milk of the lactating rat. Brimonidine Tartrate 2 mg/ml Eye drops should not be used by women nursing infants.

Brimonidine Tartrate 2 mg/ml Eye drops may cause fatigue and/or drowsiness, which may impair the ability to drive or operate machinery. Brimonidine Tartrate 2 mg/ml Eye drops may 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 using machinery.

Summary of the safety profile

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 severity requiring discontinuation of treatment.

Symptoms of ocular allergic reactions occurred in 12.7% of subjects (causing withdrawal in 11.5% of subjects) in clinical trials with the onset between 3 and 9 months in the majority of patients.

Summary of adverse reactions

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following terminologies have been used in order to classify the occurrence of undesirable effects: Very Common (≥1/10); Common (≥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), not known (cannot be estimated from the available data).

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

− blurred vision

− allergic blepharitis, allergic blepharoconjunctivitis, 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

− 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 vasodilatation

Description of selected adverse reactions

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, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants receiving brimonidine (See section 4.3).

In a 3-month, phase 3 study in children aged 2-7 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

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 by paediatric subjects have been published or 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.

Pharmacotherapeutic group: Sympathomimetics in glaucoma therapy, ATC code = S01EA05

Mechanism of action

Brimonidine is an alpha-2 adrenergic receptor agonist that is 1000-fold more selective for the alpha-2 adrenoceptor than the alpha-1 adrenoreceptor.

This selectivity results in no mydriasis and the absence of vasoconstriction in microvessels associated with human retinal xenografts.

Pharmacodynamic effects

Topical administration of brimonidine tartrate decreases intraocular pressure (IOP) in humans with minimal effect on cardiovascular or pulmonary parameters.

Limited data are available for patients with bronchial asthma showing no adverse effects.

Brimonidine Tartrate 2 mg/ml Eye drops, solution has a rapid onset of action, with peak ocular hypotensive effect seen at two hours post-dosing. In two 1 year studies, brimonidine eye drops lowered IOP by mean values of approximately 4-6 mmHg.

Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action. It is thought that brimonidine may lower IOP by reducing aqueous humour formation and enhancing uveoscleral outflow.

Clinical efficacy and safety

Clinical trials show that brimonidine eye drops is effective in combination with topical beta-blockers. Shorter term studies also suggest that brimonidine eye drops has a clinically relevant additive effect in combination with travoprost (6 weeks) and latanoprost (3 months).

a) General characteristics

After ocular administration of a 0.2% solution twice daily for 10 days, plasma concentrations were low (mean Cmax was 0.06 ng/ml). There was a slight accumulation in the blood after multiple (2 times daily for 10 days) instillations. The area under the plasma concentration-time curve over 12 hours at steady state (AUC_{0- 12h}) was 0.31 ng·hr/ml, as compared to 0.23 ng·hr/ml after the first dose. The mean apparent half-life in the systemic circulation was approximately 3 hours in humans after topical dosing.

The plasma protein binding of brimonidine after topical dosing in humans is approximately 29%.

Brimonidine binds reversibly to melanin in ocular tissues, in vitro and in vivo. Following 2 weeks of ocular instillation, the concentrations of brimonidine in iris, ciliary body and choroid-retina were 3- to 17-fold higher than those after a single dose. Accumulation does not occur in the absence of melanin.

The significance of melanin binding in humans is unclear. However, no significant ocular adverse reaction was found during biomicroscopic examination of eyes in patients treated with brimonidine eye drops for up to one year, nor was significant ocular toxicity found during a one year ocular safety study in monkeys given approximately four times the recommended dose of brimonidine tartrate.

Following oral administration to man, brimonidine is well absorbed and rapidly eliminated. The major part of the dose (around 75% of the dose) was excreted as metabolites in urine within five days; no unchanged drug was detected in urine. In vitro studies, using animal and human liver, indicate that the metabolism is mediated largely by aldehyde oxidase and cytochrome P450. Hence, the systemic elimination seems to be primarily hepatic metabolism.

Kinetics profile:

No great deviation from dose proportionality for plasma Cmax and AUC was observed following a single topical dose of 0.08%, 0.2% and 0.5%.

b) Characteristics in patients

Characteristics in elderly patients:

The Cmax, AUC, and apparent half-life of brimonidine are similar in the elderly (subjects 65 years or older) after a single dose compared with young adults, indicating that its systemic absorption and elimination are not affected by age.

Based on data from a 3 month clinical study, which included elderly patients, systemic exposure to brimonidine was very low.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Benzalkonium Chloride

Poly(vinyl alcohol)

Sodium chloride

Sodium citrate

Citric acid monohydrate

Water for Injection

Hydrochloric acid (for pH-adjustment) or

Sodium hydroxide (for pH-adjustment)

Not applicable.

Before first opening: 2 years

After first opening: Use within 28 days.

Do not store above 25°C.

Brimonidine Tartrate 2 mg/ml Eye drops, solution is packed in 5 ml LDPE bottle with white opaque LDPE open nozzle and white color HDPE TSTR Tear off cap.

Pack size: 5ml in 5ml low density polyethylene bottle.

No special requirements.

Brown & Burk UK Ltd

5 Marryat Close

Hounslow West

Middlesex

TW4 5DQ

United Kingdom

PL 25298/0251

28/01/2021

28/01/2021