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).

Recommended dosage in adults (including the elderly)

The recommended dose is one drop of Brimo 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

Brimo has not been studied in patients with hepatic or renal impairment (see section 4.4).

Use in paediatric subjects

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

Brimo 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 Brimo have not been established in
children.

Hypersensitivity to the active substance or to any of the excipients. 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).

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).

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

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

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

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

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

The preservative in Brimo, 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.

Brimo 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 Brimo, 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 Brimo 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 Brimo, 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 Brimo.

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).

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. Brimo should be used during pregnancy only if the potential benefit
to the mother outweighs the potential risk to the foetus.

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

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

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.

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 Brimo 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

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 Brimo 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).

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 Brimo by paediatric subjects
have been published or reported to Allergan. 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 = S01EA 05.

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.

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.

Brimo has a rapid onset of action, with peak ocular hypotensive effect seen at two hours post-dosing.
In two 1 year studies, Brimo 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 Brimo may lower IOP by reducing aqueous humour formation
and enhancing uveoscleral outflow.

Clinical trials show that Brimo is effective in combination with topical beta-blockers. Shorter term
studies also suggest that Brimo 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 (AUC0-12h) 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 Brimo 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
Purified water
Hydrochloric acid (for pH-adjustment) or
Sodium hydroxide (for pH-adjustment)

Not applicable.

24 Months

Do not store above 30°C. Discard after 30 days or opening

10 ml LDPE opaque bottle

No special requirements