Document: spc-doc_PL 04569-0853 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 mg of brimonidine tartrate,    equivalent to    1.3 mg

brimonidine.

Excipient with known effect: Benzalkonium chloride 0.05 mg/ml For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Eye drops, solution

Clear, slightly greenish-yellow solution, with a pH between 5.5-6.5 and osmolality of 275-315 mOsm/kg.

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 medications when the target IOP is not achieved with a single agent (see section 5.1).

4.2 Posology and method of administration

Posology

Adults (including the elderly)

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

Patients with renal and hepatic impairment

Brimonidine tartrate 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 is not recommended for use in children below 12 years and is contraindicated in neonates and infants (less than 2 years of age) (see section 4.3, section 4.4 and section 4.9). It is known that severe adverse reactions can occur in neonates. The safety and efficacy of brimonidine tartrate have not been established in children.

Method of administration For ocular use.

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.

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

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).

Cardiovascular disease

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

Allergic reactions

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

Delayed ocular hypersensitivity reactions have been reported with brimonidine tartrate, with some reported to be associated with an increase in IOP.

Other special patient populations

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

Patients with renal/hepatic impairment

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

Excipients

The preservative in Brimonidine tartrate, 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

Brimonidine tartrate 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, 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 tartrate 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 tartrate, 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.

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

Breast-feeding

It is unknown whether brimonidine tartrate metabolites are excreted in human milk. The compound is excreted in the milk of the lactating rat. Brimonidine tartrate should not be used during breast-feeding.

4.7 Effects on ability to drive and use machines

Brimonidine has minor or moderate influence on the ability to drive and use machines

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

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following frequencies 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).

Immune system disorders

Psychiatric disorders

Uncommon:

Cardiac disorders	- miosis
Uncommon: Vascular disorders	- palpitations/arrythmias (including bradycardia and tachycardia)
Very rare:	-    hypertension -    hypotension

Respiratory, thoracic and mediastinal disorders

Common:	- upper respiratory symptoms
Uncommon:	- nasal dryness
Rare: Gastrointestinal disorders	- dyspnoea
Very common:	- oral dryness
Common:	- gastrointestinal symptoms

General disorders and administration site conditions

Very common:	- fatigue
Common:	- asthenia

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

Not known:

- iridocyclitis (anterior uveitis) - eyelid pruritus

Skin and subcutaneous tissue disorders

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

Paediatric population

In cases where brimonidine tartrate has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine tartrate 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 tartrate (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 tartrate 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 tartrate 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 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 tartrate 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

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: sympathomimetics in glaucoma therapy, ATC code: S01EA05.

Mechanism of action

Brimonidine tartrate 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.

Clinical efficacy and safety

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

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

5.2 Pharmacokinetic properties

Absorption

After ocular administration of a 0.2% solution twice daily for 10 days, plasma concentrations were low (mean C_max was 0.06 ng/ml).

There was a slight accumulation in the blood after multiple (2 times daily for 10 days) instillations.

Following oral administration to man, brimonidine tartrate is well absorbed.

Distribution

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

Brimonidine tartrate binds reversibly to melanin in ocular tissues, in vitro and in vivo. Following 2 weeks of ocular instillation, the concentrations of brimonidine tartrate 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 tartrate 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.

Biotransformation

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.

Elimination

Following oral administration to man, brimonidine tartrate is rapidly eliminated. The mean apparent half-life in the systemic circulation was approximately 3 hours in humans after topical dosing.

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.

Characteristics in elderly patients:

The C_max, AUC, and apparent half-life of brimonidine tartrate 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 tartrate was very low.

Linearitv/non-linearitv

The area under the plasma concentration-time curve over 12 hours at steady state (AUC_0-i2_h) was 0.31 nghr/ml, as compared to 0.23 nghr/ml after the first dose. No great deviation from dose proportionality for plasma C_max and AUC was observed following a single topical dose of 0.08%, 0.2% and 0.5%.

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

Benzalkonium chloride Poly(vinyl) alcohol Sodium chloride Sodium citrate Citric acid, monohydrate Purified water

Hydrochloric acid, dilute (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

6.2 Incompatibilities

Not applicable.

6.3    Shelf life

Before first opening: 3 years

After first opening: use within 28 days.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

5 ml or 10 ml solution in low density polyethylene (LDPE) dropper bottles with a low density polyethylene (LDPE) dropper tip (approximately 35 microliter) and a high density polyethylene (HDPE) dropper tip cap.

Pack sizes:    1 x 5 ml, 3 x 5 ml, 6 x 5 ml,

1 x 10ml, 3 x 10ml, 6 x 10 ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/0853

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19/09/2013

10    DATE OF REVISION OF THE TEXT

14/10/2015