Brimonidine Tartrate 2mg/Ml Eye Drops Solution
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Brimonidine Tartrate 2mg/ml Eye Drops Solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml solution contains 2.0 mg brimonidine tartrate, equivalent to 1.3 mg of brimonidine. 1 drop of solution = approximately 35 pl = 70 pg brimonidine tartrate
Excipients: contains Benzalkonium chloride 0.05 mg/ml
For full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Eye drops, solution
Clear, greenish-yellow to light 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 medications when the target IOP is not achieved with a single agent (see Section 5.1).
4.2 Posology and method of administration
Ocular use.
Recommended dosage in adults (including 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.
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 medicinal product is to be used, the different medicinal product should be instilled 5-15 minutes apart.
Use in renal and hepatic impairment
Brimonidine tartrate has not been studied in patients with hepatic or renal impairment - see section 4.4.
Use in paediatric subjects
Brimonidine tartrate should not be used in neonates and is not recommended for use in children below 12 years (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.
No clinical studies have been performed in adolescents (12-17).
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients of the formulation.
Brimonidine tartrate 2 mg/ml is contraindicated:
• for use in neonates
• in 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 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 2 mg/ml, with some reported to be associated with an increase in IOP.
Brimonidine tartrate should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension or thromboangiitis obliterans.
Brimonidine tartrate has not been studied in patients with hepatic or renal impairment; caution should be used in treating such patients.
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 noradrenergic transmission (e.g. tricyclic antidepressants and mianserin). Although specific medicinal product 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 medicinal product 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
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.
It is not known if brimonidine is excreted in human milk. The compound is excreted in the milk of the lactating rat. Brimonidine tartrate should not be used by women nursing infants.
4.7 Effects on 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 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 (> 1/1,000 to < 1/100)
Palpitations/arythmias (including bradycardia and tachycardia)
Nervous System Disorders
Very Common: (> 1/10)
Headache
Drowsiness
Common: (> 1/100 to < 1/10) Abnormal taste
Dizziness
Very Rare: (< 1/10,000)
Syncope
Eye disorders
Very Common: (> 1/10)
- ocular irritation including allergic reactions (hyperaemia, burning and stinging, pruritis, foreign body sensation, conjunctival follicles).
- blurred vision.
- allergic blepharitis, allergic blepharoconjunctivitis, allergic conjunctivitis, ocular allergic reaction, and follicular conjunctivitis
Common: (> 1/100 to < 1/10 )
- 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: (< 1/10,000)
Iritis (anterior uveitis)
Miosis
Respiratory, thoracic and mediastinal disorders
Common: (> 1/100 to < 1/10)
Upper respiratory symptoms
Uncommon (> 1/1,000 to < 1/100)
Nasal dryness
Rare (> 1/10,000 to < 1/1,000)
Dyspnoea
Gastrointestinal disorders
Very Common: (> 1/10)
Oral dryness
Common: (> 1/100 to < 1/10) Gastrointestinal symptoms
Vascular disorders Very Rare: (<1/10,000) Hypertension
Hypotension
General disorders and administration site conditions
Very Common: (> 1/10) Fatigue
Common: (> 1/100 to < 1/10) Asthenia
Immune System Disorders
Uncommon (> 1/1,000 to < 1/100) Systemic allergic reactions
Psychiatric Disorders
Uncommon (> 1/1,000 to < 1/100) Depression
Very Rare: (< 1/10,000)
Insomnia
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:
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 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 Yellow Card Scheme: www.mhra.gov.uk/yellowcard
4.9 Overdose
Adults
Ophthalmic overdose:
the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion:
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 by paediatric subjects have been published. 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
Pharmacotherapheutic 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 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.
Brimonidine eye dropshave a rapid onset of action, with peak ocular hypotensive effect seen at two hours post-dosing. In two 1 year studies, brimonidine eye drops solution 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 trials show that brimonidine eye drops solution is effective in combination with topical beta-blockers. Shorter term studies also suggest that brimonidine 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 nghr/ml, as compared to 0.23 nghr/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 medicinal product 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.
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 Polyvinyl alcohol Sodium chloride Sodium citrate, dihydrate Citric acid, monohydrate Purified water
Hydrochloric acid 10% (for pH-adjustment) or Sodium hydroxide 1N (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
No special storage conditions are required.
6.5 Nature and contents of container
White low density polyethylene dropper bottles with a 35 microlitre tip. The cap is a conventional polystyrene white screw cap.
Pack sizes:
A bottle containing 5 ml of eye drops solution.
Three bottles, each containing 5 ml of eye drops solution.
Six bottles, each containing 5 ml of eye drops solution.
Not all pack sizes may be marketed
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Medicom Healthcare Limited
235 Hunts Pond Road
Titchfield Common
Fareham
Hants
PO14 4PJ
8 MARKETING AUTHORISATION NUMBER(S)
PL 18956/0016
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
22/12/2013
10
DATE OF REVISION OF THE TEXT
01/09/2015