4.1. Therapeutic indications

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).

4.2. Posology and method of administration

Posology

Recommended dosage in adults (including the elderly)

The recommended dose is one drop of Alphagan in the affected eye(s) twice daily, approximately 12 hours apart. No dosage adjustment is required for the use in elderly patients.

Use in renal and hepatic impairment

Alphagan 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).

Alphagan 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 Alphagan have not been established in children aged 2 to 12 years.

Method of administration

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. This may result in a decrease of systemic side effects and an increase in local activity. To avoid contamination of the eye or eye drops do not allow the dropper tip to come into contact with any surface.

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

4.3. Contraindications

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

- Neonates and infants (less than 2 years of age) (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).

4.4. Special warnings and precautions for use

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.

Eye disorders

Some (12.7%) patients in clinical trials experienced an ocular allergic type reaction with Alphagan (see section 4.8 for details). If allergic reactions are observed, treatment with Alphagan should be discontinued.

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

Vascular disorders

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

Hepatic and renal insufficiency

Alphagan has not been studied in patients with hepatic or renal impairment; caution should be used in treating such patients.

Benzalkonium chloride

The preservative in Alphagan, benzalkonium chloride, may cause eye irritation, symptoms of dry eyes, and may affect the tear film and corneal surface. Patients should remove contact lenses prior to application and wait at least 15 minutes before reinsertion. Benzalkonium chloride is known to discolour soft contact lenses. Patients should avoid contact with soft contact lenses.

Alphagan 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

Alphagan 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 Alphagan, 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 Alphagan 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 Alphagan, 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 Alphagan.

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).

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. Alphagan should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the foetus. To reduce the systemic absorption, see section 4.2

Breast-feeding

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

4.7. Effects on ability to drive and use machines

Alphagan may cause fatigue and/or drowsiness, which may impair the ability to drive or operate machinery. Alphagan 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.

4.8. Undesirable effects

The most commonly reported ADRs are oral dryness, ocular hyperaemia and burning/stinging, all occurring in 25.9-31.2% 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.

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).

Table 1: Tabulated list of adverse reactions

System Organ Class

Frequency

Adverse reaction

Immune system disorders

Uncommon

Allergic reactions

Psychiatric disorders

Uncommon

Depression

Very rare

Insomnia

Nervous system disorders

Very common

Headache

Common

Dizziness

Abnormal taste

Eye disorders

Very common

Ocular hyperaemia

Burning and stinging

Blurred vision

Foreign body sensation

Conjunctival folliculosis

Pruritus

Ocular allergic reaction (includes allergic blepharitis, allergic blepharoconjunctivitis, allergic conjunctivitis and follicular conjunctivitis)

Common

Eyelid hyperaemia

Eyelid oedema

Blepharitis

Conjunctival oedema

Conjunctival discharge

Eye pain

Tearing

Photophobia

Eyelid erythema

Corneal erosion and staining

Eye dryness

Conjunctival blanching

Abnormal vision

Conjunctivitis

Eye irritation

Conjunctival papillae

Very rare

Iritis

Miosis

Cardiac disorders

Uncommon

Palpitations/arrhythmias (including bradycardia and tachycardia)

Vascular disorders

Very rare

Hypertension

Hypotension

Respiratory, thoracic and mediastinal disorders

Common

Upper respiratory symptoms

Uncommon

Nasal dryness

Rare

Dyspnoea

Gastrointestinal disorders

Very common

Oral dryness

Common

Gastrointestinal symptoms

General disorders and administration site conditions

Very common

Fatigue/drowsiness

Common

Asthenia

The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Table 2: Adverse reactions identified during post-marketing use

System organ class

Adverse reaction

Eye disorders

Iritis

Iridocyclitis (anterior uveitis)

Miosis

Conjunctivitis

Eyelid pruritus

Skin and subcutaneous tissue disorders

Hypersensitivity

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

Cardiac disorders

Palpitations/arrhythmias (including bradycardia or tachycardia)

Psychiatric disorders

Depression

Vascular disorders

Hypotension

Syncope

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 Alphagan 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 or search for MHRA Yellow Card in the 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 Alphagan 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.