Document: spc-doc_PL 00289-1034 change

• spc-doc_PL 00289-1034
• spc-doc_PL 04569-0853
• spc-doc_PL 06831-0203

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SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Brimonidine tartrate 2 mg/ml eye drops, solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient with known effect:

Contains benzalkonium chloride 0.05 mg/ml.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Eye drops, solution

Clear, greenish-yellow solution.

4    CLINICAL PARTICULARS

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 agents 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 adolescents and adults (including older people)

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

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

Special populations

Patients with renal and hepatic impairment

Brimonidine 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 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 have not been established in children.

4.3    Contraindications

-    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).

4.4    Special warnings and precautions for use

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 ocularallergic type reaction with brimonidine (see section 4.8 for details). If allergic reactions are observed, treatment with brimonidine should be discontinued.

Delayed ocular hypersensitivity reactions have been reported with brimonidine tartarate, with some reported to be associated with an increase in intraocular pressure (IOP).

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

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

The preservative in this product, 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.

4.5 Interaction with other medicinal products and other forms of interaction

The product is contraindicated in patients receiving MAO inhibitor therapy and patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and mianserin (see section 4.3).

Although specific drug interactions studies have not been conducted with brimonidine, 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 administration are available. Caution, however, is advised in patients taking products which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine.

After the application of brimonidine, clinically insignificant decreases in blood pressure were noted in some patients. Caution is advised when using agents such as antihypertensives and/or cardiac glycosides concomitantly with brimonidine.

Caution is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with a-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. Brimonidine should be used during pregnancy only 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 should not be used by women nursing infants.

4.7 Effects on ability to drive and use machines

Brimonidine has minor influence on the ability to drive and use machines. It may cause fatigue and/or drowsiness, which may impair the ability to drive or operate machinery. Brimonidine 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 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.

Adverse reactions reported as more than an isolated case are listed below, by system organ class and frequency. Frequencies are defined as 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)._

System organ class	Very common	Common	Uncommon	Rare	Very rare
	conjunctivitis; Ocular allergic reaction; Follicular conjunctivitis.
Respiratory, thoracic and mediastinal disorders		Upper respiratory symptoms	Nasal dryness	Dyspnoea
Gastrointestina l disorders	Oral dryness	Gastrointestinal symptoms
Vascular disorders					Hypertension , hypotension
General disorders and administration site conditions	Fatigue	Asthenia
Immune system disorders			Systemic allergic reactions
Psychiatric disorders			Depression		Insomnia

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

Eye disorders

Not known: iridocyclitis (anterior uveitis), eyelid pruritus Skin and subcutaneous tissue disorders

Not known: skin reaction including erythema, face oedema, pruritus, rash and vasodilatation

Paediatric population

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 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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. Two cases of adverse effects following inadvertent ingestion of 9-10 drops of brimonidine by adult subjects have been received. The subjects experienced a hypotensive episode, followed in one instance by rebound hypertension approximately 8 hours after ingestion. Both subjects were reported to have made a full recovery within 24 hours. No adverse effects were noted in a third subject who also ingested an unknown amount of brimonidine orally. Treatment of an oral overdose includes supportive and symptomatic therapy; patient’s airway 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 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.

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Sympathomimetics in glaucoma therapy, ATC code: S01E A 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.

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

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

5.2 Pharmacokinetic properties 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-i2h) 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 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 substance 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 Older people:

The C_max, AUC, and apparent half-life of brimonidine are similar in the older people (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 older people, systemic exposure to brimonidine was very low.

5.3 Preclinical safety data

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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Polyvinyl alcohol

Sodium citrate Citric acid monohydrate Sodium chloride

Benzalkonium chloride solution 50%

Water for injection

Hydrochloric acid or sodium hydroxide to adjust pH

6.2 Incompatibilities

Not applicable

6.3 Shelf life

Before first opening: 2 years. After first opening: 28 days.

6.4. Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze.

6.5 Nature and contents of container

White low density polyethylene (LDPE) bottles with white LDPE droppers with a 35 microlitre tip with tamper-evident purple HDPE screw caps.

Pack sizes: 5 ml bottle in packs of 1, 3 or 6 Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

TEVA UK Limited, Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG, United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/1034

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/12/2008

10    DATE OF REVISION OF THE TEXT

11/04/2015