SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Brimonidine Tartrate/Timolol 2 mg/ml + 5 mg/ml Eye Drops, Solution
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml solution contains: - 2.0 mg brimonidine tartrate, equivalent to 1.3 mg of brimonidine, - 5.0 mg timolol as 6.8 mg timolol maleate.
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. Osmolality 260 – 320 mOsmol/kg pH 6.6 – 7.2
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Reduction of intraocular pressure (IOP) in patients with chronic open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers.
4.2 Posology and method of administration
To avoid contamination of the eye or eye drops do not allow the dropper tip to come into contact with any surface.
Posology in adults (including the elderly)
The recommended dose is one drop of brimonidine tartrate/timolol in the affected eye(s) twice daily, approximately 12 hours apart. If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart.
Method of administration
As with any eye drops, when using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity: it is recommended that the lachrymal sac be compressed at the medial canthus (punctual occlusion) for two minutes. This should be performed immediately following the instillation of each drop.
August 2012 1 Special populations
Use in renal and hepatic impairment Brimonidine tartrate/timolol has not been studied in patients with hepatic or renal impairment. Therefore, caution should be used in treating such patients.
Paediatric population Brimonidine tartrate/timolol is contraindicated in neonates and infants (less than 2 years of age) (see section 4.3, section 4.4 , section 4.8 and section 4.9).
The safety and effectiveness of brimonidine tartrate/timolol in children and adolescents (2 to 17 years of age) have not been established and therefore, its use is not recommended in children or adolescents (see also section 4.4 and section 4.8).
4.3 Contraindications
- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. - Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease. - Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree atrioventricular block not controlled with a pace-maker, overt cardiac failure, cardiogenic shock. - Use in neonates and infants (less than 2 years of age) (see section 4.8) - Patients receiving monoamine oxidase (MAO) inhibitor therapy. - 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 of somnolence. The safety and effectiveness of brimonidine tartrate/timolol in children and adolescents (2 to 17 years of age) have not been established (see section 4.2 and section 4.8).
Like other topically applied ophthalmic agents, brimonidine tartrate/timolol may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed. However, due to the beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions seen with systemic beta-adrenergic blocking agents may occur. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.
Some patients have experienced ocular allergic type reactions (allergic conjunctivitis and allergic blepharitis) with brimonidine tartrate/timolol in clinical trials. Allergic conjunctivitis was seen in 5.2% of patients. Onset was typically between 3 and 9 months resulting in an overall discontinuation rate of 3.1%. Allergic blepharitis was uncommonly reported (<1%). If allergic reactions are observed, treatment with brimonidine tartrate/timolol should be discontinued.
Cardiac disorders
In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension therapy with beta-blockers should be critically assessed and therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions.
Due to their negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
August 2012 2 As with systemic beta-blockers, if discontinuation of treatment is needed in patients with coronary heart disease, therapy should be withdrawn gradually to avoid rhythm disorders, myocardial infarct or sudden death.
Vascular disorders
Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud’s disease or Raynaud’s syndrome) should be treated with caution.
Brimonidine tartrate/timolol should be used with caution in patients with depression or cerebral insufficiency. In patients with severe renal impairment on dialysis, treatment with timolol has been associated with pronounced hypotension.
Respiratory disorders
Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration some ophthalmic beta-blockers.
Brimonidine tartrate/timolol should be used with caution in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.
Surgical anaesthesia
Beta-blocking ophthalmological preparations may block the systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.
Hypoglycaemia/diabetes
Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia. The indicatory signs of acute hypoglycaemia may be masked, in particular tachycardia, palpitations and sweating.
Beta-blockers may also mask the signs of hyperthyroidism.
Brimonidine tartrate/timolol must be used with caution in patients with metabolic acidosis and untreated phaeochromocytoma.
Corneal diseases
Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
Other beta-blocking agents
The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol is given to patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended (see section 4.5).
Anaphylactic reactions
While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens and unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.
August 2012 3 Choroidal detachment
Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.
The preservative in this medicinal product, benzalkonium chloride, may cause eye irritation. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion. Benzalkonium chloride is known to discolour soft contact lenses. Avoid contact with soft contact lenses.
Brimonidine tartrate/timolol has not been studied in patients with closed-angle glaucoma.
4.5 Interaction with other medicinal products and other forms of interaction
No specific drug interaction studies have been performed. Although specific drug interactions studies have not been conducted with brimonidine tartrate/timolol, the theoretical possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.
There is potential for additive effects resulting in hypotension, and/or marked bradycardia when ophthalmic beta-blocker solution is administered concomitantly with oral calcium channel blockers, beta-adrenergic blocking agents, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine. After the application of brimonidine, very rare (<1 in 10,000) cases of hypotension have been reported. Caution is therefore advised when using brimonidine tartrate/timolol with systemic antihypertensives.
Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.
Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see section 4.4).
The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta- blockers.
Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.
Concomitant use of a beta-blocker with anaesthetic drugs may attenuate compensatory tachycardia and increase the risk of hypotension (see section 4.4), and therefore the anaesthetist must be informed if the patient is using brimonidine tartrate/timolol.
Caution must be exercised if brimonidine tartrate/timolol is used concomitantly with iodine contrast products or intravenously administered lidocain.
Cimetidine, hydralazine and alcohol may increase the plasma concentrations of timolol.
No data on the level of circulating catecholamines after brimonidine tartrate/timolol administration are available. Caution, however, is advised in patients taking medication which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine.
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).
Although specific drug interactions studies have not been conducted with brimonidine tartrate/timolol, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered.
August 2012 4
Concomitant administration of MAO inhibitors is contraindicated (see section 4.3). Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with brimonidine tartrate/timolol.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data for the use of brimonidine tartrate/timolol in pregnant women.
Brimonidine tartrate There are no adequate data from the use of brimonidine tartrate in pregnant women. Studies in animals have shown reproductive toxicity at high maternotoxic doses (see section 5.3). The potential risk for humans is unknown.
Timolol There are no adequate data for the use of timolol in pregnant women. It should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2.
Epidemiological studies have not revealed malformative effects but show a risk for intra-uterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. Therefore, if brimonidine tartrate/timolol is administered until delivery, the neonate should be carefully monitored during the first days of life.
Brimonidine timolol/tartrate should not be used during pregnancy unless clearly necessary.
Breast-feeding Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce the systemic absorption, see section 4.2.
It is not known if brimonidine is excreted in human milk but it is excreted in the milk of the lactating rat.
Brimonidine tartrate/timolol should not be used by women breast-feeding infants.
4.7 Effects on ability to drive and use machines
Brimonidine tartrate/timolol has minor influence on the ability to drive and use machines. It may cause transient blurring of vision, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery.
4.8 Undesirable effects
Based on 12 month clinical data, the most commonly reported ADRs were conjunctival hyperaemia (approximately 15% of patients) and burning sensation in the eye (approximately 11% of patients). The majority of these cases was mild and led to discontinuation rates of only 3.4% and 0.5% respectively. Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects to those seen with systemic beta-blocking agents. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers.
August 2012 5 The following adverse drug reactions were reported during clinical trials:
Psychiatric disorders Common (≥1/100 to <1/10): depression
Nervous system disorders Common (≥1/100 to <1/10): somnolence, headache Uncommon (≥1/1000 to <1/100): dizziness, syncope
Eye disorders Very common (≥1/10): conjunctival hyperaemia, burning sensation Common (≥1/100 to <1/10): stinging sensation in the eye, allergic conjunctivitis, corneal erosion, superficial punctuate keratitis, eye pruritus, conjunctival folliculosis, visual disturbance, blepharitis, epiphora, eye dryness, eye discharge, eye pain, eye irritation, foreign body sensation Uncommon (≥1/1000 to <1/100): visual acuity worsened, conjunctival oedema, follicular conjunctivitis, allergic blepharitis, conjunctivitis, vitreous floater, asthenopia, photophobia, papillary hypertrophy, eyelid pain, conjunctival blanching, corneal oedema, corneal infiltrates, vitreous detachment
Cardiac disorders Uncommon (≥1/1000 to <1/100): congestive heart failure, palpitations
Vascular disorders Common (≥1/100 to <1/10): hypertension
Respiratory, thoracic and mediastinal disorders Uncommon (≥1/1000 to <1/100): rhinitis, nasal dryness
Gastrointestinal disorders Common (≥1/100 to <1/10): oral dryness Uncommon (≥1/1000 to <1/100): taste perversion
Skin and subcutaneous tissue disorders Common (≥1/100 to <1/10): eyelid oedema, eyelid pruritus, eyelid erythema Uncommon (≥1/1000 to <1/100): allergic contact dermatitis
General disorders and administration site conditions Common (≥1/100 to to<1/10): asthenic conditions
Investigations Common (≥1/100 to <1/10): LFTs abnormal
The following adverse drug reactions have been reported since brimonidine tartrate/timolol has been marketed:
Cardiac disorders Not known (cannot be estimated from the available data): arrhythmia, bradycardia, tachycardia
Vascular disorders Not known (cannot be estimated from the available data): hypotension
August 2012 6 Additional adverse events that have been seen with one of the components and may potentially occur also with the fixed combination:
Brimonidine
Psychiatric disorders: insomnia Eye disorders: iritis, miosis Respiratory, thoracic and mediastinal disorders: upper respiratory symptoms, dyspnoea Gastrointestinal disorders: gastrointestinal symptoms General disorders and administration site conditions: systemic allergic reactions
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, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3).
A high incidence of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing <20 kg (see section 4.4).
Timolol (further additional adverse reactions have been seen with ophthalmic beta-blockers and may potentially occur with timolol)
Immune system disorders: systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylactic reaction Metabolism and nutrition disorders: hypoglycaemia Psychiatric disorders: insomnia, nightmares, memory loss Nervous system disorders: cerebrovascular accident, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia Eye disorders: decreased corneal sensitivity, blurred vision, diplopia, ptosis, choroidal detachment (following filtration surgery – see section 4.4), refractive changes (due to withdrawal of miotic therapy in some cases) Ear and labyrinth disorders: tinnitus Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: cerebrovascular accident, claudication, Raynaud's phenomenon, cold hands and feet Respiratory, thoracic and mediastinal disorders: bronchospasm (predominantly in patients with pre- existing bronchospastic disease), dyspnoea, cough, respiratory failure Gastrointestinal disorders: nausea, diarrhoea, dyspepsia, abdominal pain, vomiting Skin and subcutaneous tissue disorders: alopecia, psoriasiform rash or exacerbation of psoriasis; skin rash Musculoskeletal and connective tissue disorders: myalgia, systemic lupus erythematosus Renal and urinary disorders: Peyronie's disease Reproductive system and breast disorders: sexual dysfunction, decreased libido
4.9 Overdose
Brimonidine
Ophthalmic overdose 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, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine.
Systemic overdose resulting from accidental ingestion Several reports of serious adverse events following inadvertent ingestion of brimonidine by paediatric subjects have been published or reported. The subjects experienced symptoms of CNS depression,
August 2012 7 typically temporary coma or low level of consciousness, hypotonia, bradycardia, hypothermia 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.
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 ingested an unknown amount of brimonidine orally.
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.
Timolol
Symptoms of systemic timolol overdose are: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily. If overdose occurs treatment should be symptomatic and supportive.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Ophthalmologicals – Antiglaucoma preparations and miotics – Beta- blocking agents – timolol, combinations ATC code: S01ED51
Mechanism of action
This fixed combination consists of two active substances: brimonidine tartrate and timolol maleate. These two components decrease elevated intraocular pressure (IOP) by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound administered alone. The fixed combinatino has a rapid onset 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.
It is thought that brimonidine tartrate lowers IOP by enhancing uveoscleral outflow and reducing aqueous humour formation.
Timolol is a beta1 and beta2 non-selective adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane- stabilising) activity. Timolol lowers IOP by reducing aqueous humour formation. The precise mechanism of action is not clearly established, but inhibition of the increased cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is probable.
Clinical efficacy and safety
In three controlled, double-masked clinical studies, fixed-combination brimonidine tartrate/timolol (twice daily) produced a clinically meaningful additive decrease in mean diurnal IOP compared with timolol (twice daily) and brimonidine (twice daily or three times a day) when administered as monotherapy.
August 2012 8 In a study in patients whose IOP was insufficiently controlled following a minimal 3-week run-in on any monotherapy, additional decreases in mean diurnal IOP of 4.5, 3.3 and 3.5 mmHg were observed during 3 months of treatment for fixed-combination brimonidine tartrate/timolol (twice daily), timolol (twice daily) and brimonidine (twice daily), respectively. In this study, at trough, a significant additional decrease in IOP could only be demonstrated on comparison with brimonidine but not with timolol, however a positive trend was seen with superiority at all other timepoints. In the pooled data of the other two trials statistical superiority versus timolol was seen throughout.
In addition, the IOP-lowering effect of fixed-combination brimonidine tartrate/timolol was consistently non-inferior to that achieved by adjunctive therapy of brimonidine and timolol (all twice daily).
The IOP-lowering effect of fixed-combination brimonidine tartrate/timolol has been shown to be maintained in double-masked studies of up to 12 months.
5.2 Pharmacokinetic properties
Fixed-combination brimonidine tartrate/timolol
Plasma brimonidine and timolol concentrations were determined in a crossover study comparing the monotherapy treatments to fixed-combination treatment with brimonidine tartrate and timolol in healthy subjects. There were no statistically significant differences in brimonidine or timolol AUC between the fixed combination and the respective monotherapy treatments. Mean plasma Cmax values for brimonidine and timolol following dosing with the fixed combination were 0.0327 and 0.406 ng/ml respectively.
Brimonidine
After ocular administration of 0.2% eye drops solution in humans, plasma brimonidine concentrations are low. Brimonidine is not extensively metabolised in the human eye and human plasma protein binding is approximately 29%. The mean apparent half-life in the systemic circulation was approximately 3 hours after topical dosing in man.
Following oral administration to man, brimonidine is well absorbed and rapidly eliminated. The major part of the dose (around 74% 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.
Brimonidine binds extensively and reversibly to melanin in ocular tissues without any untoward effects. Accumulation does not occur in the absence of melanin.
Brimonidine is not metabolised to a great extent in human eyes.
Timolol
After ocular administration of a 0.5% eye drops solution in humans undergoing cataract surgery, peak timolol concentration was 898 ng/ml in the aqueous humour at one hour post-dose. Part of the dose is absorbed systemically where it is extensively metabolised in the liver. The half-life of timolol in plasma is about 7 hours. Timolol is partially metabolised by the liver with timolol and its metabolites excreted by the kidney. Timolol is not extensively bound to plasma protein.
5.3 Preclinical safety data
The ocular and systemic safety profile of the individual components is well established. Non-clinical data reveal no special hazard for humans based on conventional studies of the individual components in safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenicity studies. Additional
August 2012 9 ocular repeated dose toxicity studies on fixed-combination brimonidine tartrate/timolol also showed no special hazard for humans.
Brimonidine
Brimonidine tartrate did not cause any teratogenic effects in animals, but caused abortion in rabbits and postnatal growth reduction in rats at systemic exposures approximately 37-times and 134-times those obtained during therapy in humans, respectively.
Timolol
In animal studies, beta-blockers have been shown to produce reduced umbilical blood flow, reduced fetal growth, delayed ossification and increased fetal and postnatal death, but no teratogenicity. With timolol, embryotoxicity (resorption) in rabbit and fetotoxicity (delayed ossification) in rats have been seen at high maternal doses. Teratogenicity studies in mice, rats and rabbits, at oral doses of timolol up to 4200 times of that in the human daily dose of fixed-combination brimonidine tartrate/timolol, showed no evidence of fetal malformation.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Benzalkonium chloride Sodium dihydrogen phosphate dihydrate Disodium phosphate dihydrate Hydrochloric acid or sodium hydroxide to adjust pH Water for injections
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Unopened bottle: 18 months.
After first opening: Use within 28 days. Chemical and physical in-use stability has been demonstrated for 28 days when stored below 30°C and kept in outer carton to protect from light. From a microbiological point of view, once opened, the product may be stored for a maximum of 28 days when stored below 30°C and kept in outer carton to protect from light. Other in-use storage times and conditions are the responsibility of the user.
6.4 Special precautions for storage
Store below 30 °C. Keep the bottle in the outer carton to protect from light. For storage conditions of the finished product after first opening, see section 6.3.
6.5 Nature and contents of container
White low density polyethylene bottles with a low density polyethylene dropper and a high density polyethylene tamper proof orange screw cap. Each bottle has a fill volume of 5 ml. The following pack sizes are available: cartons containing 1, 3, 5, 6 or 10 bottles of 5 ml. Not all pack sizes may be marketed.
August 2012 10
6.6 Special precautions for disposal and other handling
No special requirements.
7. MARKETING AUTHORISATION HOLDER
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
August 2012 11
Package leaflet: Information for the user
Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have further questions, ask your doctor, pharmacist or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.
What is in this leaflet: 1. What
1. What
Your eye contains a clear, watery liquid that feeds the inside of the eye. Liquid is constantly being drained out of the eye and new liquid is made to replace this. If the liquid cannot drain out quickly enough, the pressure inside the eye builds up and could eventually damage your sight.
2. What you need to know before you use
Do not use
- if you are allergic to brimonidine tartrate, timolol, beta-blockers or any of the other ingredients of this medicine (listed in section 6). Symptoms of an allergic reaction may include swelling of the face, lips and throat, wheeziness, feeling faint, shortness of breath. - itching or redness around the eye. - if you have now or have had in the past respiratory problems such as asthma, or severe chronic obstructive bronchitis (severe lung disease which may cause wheeziness, difficulty in breathing and/or long-standing cough). - if you have heart problems such as heart beat disorders (unless controlled by a pacemaker) or heart weakness. - if you are taking monoamine oxidase (MAO) inhibitors or certain other antidepressant drugs.
If you think any of these points apply to you, do not use
Warnings and precautions
Talk to your doctor, pharmacist or nurse before using
Tell your doctor before you have an operation that you are using
Other medicines and
It is particularly important to tell your doctor if you are taking: - pain killers - medicines to help you sleep or for anxiety - medicines to treat high blood pressure (hypertension) - medicines for heart conditions (for example an abnormal heartbeat) such as beta-blockers or digoxin - another eyedrop used to lower high pressure in the eye (glaucoma) - medicines for depression - medicines to treat severe allergic reactions - medicines that affect some of the hormones in your body, like adrenaline and dopamine - medicines that affect the muscles in your blood vessels - medicines to treat diabetes or high blood sugar - medicines to treat heartburn or stomach ulcers - quinidine (used to treat heart conditions and some types of malaria) - antidepressants known as fluoxetine and paroxetine.
If the dose of any of your current medicines is changed or if you are regularly consuming alcohol you should tell your doctor.
If you are due to have an anaesthetic, you should tell the doctor or dentist that you are taking
August 2012 2 Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Do not use
Do not use
Driving and using machines
Contact lenses - Do not use
3. How to use
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.
Use in children and adolescents
Use in adults (including the elderly) The recommended dose is one drop of
If you have other eye drops as well as
Instructions for use You must not use the bottle if the tamper-proof seal on the bottle neck is broken before you first begin to use it.
Wash your hands before opening the bottle. Tilt your head back and look at the ceiling.
1. Gently pull down the lower eyelid until there is a small pocket. 2. Turn the bottle upside down and squeeze it to release one drop into each eye that needs treatment. 3. Let go of the lower lid, and close your eye. 4. After using
August 2012 3
If a drop misses your eye, try again.
To avoid contamination, do not let the tip of the bottle touch your eye or anything else. Put the screw- cap back on to close the bottle, straight after you have used it.
If you use more
Adults If you use more
Babies and children Several cases of overdose have been reported in babies and children receiving brimonidine (one of the ingredients of
Adults and children If
If you forget to use
If you forget to use
If you stop using
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
You can usually carry on taking the drops, unless the effects are serious. If you're worried, talk to a doctor or pharmacist. Do not stop using
If you experience any of the following side effects, please contact your doctor immediately: - Heart failure (eg. chest pain) or irregular heart rate - Increased or decreased heart rate or low blood pressure
The following side effects may be seen with
Very common (may affect more than 1 in 10 people): Eye redness or burning.
Common (may affect up to 1 in 10 people): Stinging, an allergic reaction in the eye or on the skin around the eye, small breaks in the surface of the eye (with or without inflammation), high blood pressure, swelling and redness of the eyelid, irritation, or a feeling of something in the eye, dry eyes, depression, headache, itching of the eye and
August 2012 4 eyelid, blurred vision, sleepiness, dry mouth, general weakness or an increase in blood-test results that show how your liver is working.
Uncommon (may affect up to 1 in 100 people): Congestive heart failure (heart disease with shortness of breath and swelling of the feet and legs due to fluid build-up), irregular heart rate, light-headedness, fainting, dizziness, dry nose or taste disturbances, white spots under the eyelid or sensitivity to light.
Not known (frequency cannot be estimated from the available data): Increased or decreased heart rate or low blood pressure
Some of these effects may be due to an allergy to any of the ingredients.
The following side effects have been seen with brimonidine or timolol and so may possibly be seen with
If you get any side effects , talk to your doctor, pharmacist or nurse. This includes any side effects not listed in this leaflet.
5. How to store
Keep this medicine out of the sight and reach of children. Store below 30°C. Keep the bottle in the outer carton to protect it from light. After first opening of the bottle, use within 28 days. You should only use one bottle at a time. Do not use this medicine after the expiry date which is stated on the label of the bottle and the carton after EXP. The expiry date refers to the last day of that month. You must throw away the bottle four weeks after you first opened it, even if there are still some drops left. This will help to prevent infections. To help you remember, write down the date that you opened it in the space on the carton. August 2012 5 Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information
What
- The active substances are brimonidine tartrate and timolol. - One millilitre of solution contains 2 milligrams of brimonidine tartrate and timolol maleate equivalent to 5 milligrams of timolol. - The other ingredients are benzalkonium chloride (a preservative), sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate and water for injections. Small amounts of hydrochloric acid or sodium hydroxide may be added to bring the solution to the correct pH (a measure of the acidity or alkalinity of the solution).
What
Marketing Authorisation Holder and Manufacturer
This medicinal product is authorised in the Member States of the EEA under the following names:
This leaflet was last revised in
August 2012 6 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING
OUTER PACKAGING
1. NAME OF THE MEDICINAL PRODUCT
[Brimonidine Tartrate/Timolol 2 mg/ml + 5 mg/ml eye drops, solution] Brimonidine tartrate/Timolol
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each millilitre contains 2 mg brimonidine tartrate and 5 mg timolol as timolol maleate.
3. LIST OF EXCIPIENTS
Contains benzalkonium chloride, sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, hydrochloric acid or sodium hydroxide to adjust pH, water for injections
See leaflet for further information
4. PHARMACEUTICAL FORM AND CONTENTS
Eye drops, solution
5ml 1 bottle of 5 ml 3 bottles of 5 ml 5 bottles of 5 ml 6 bottles of 5 ml 10 bottles of 5 ml
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Ocular use
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP August 2012 1
Discard 28 days after first opening. Opened:
9. SPECIAL STORAGE CONDITIONS
Store below 30°C. Keep the bottle in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
12. MARKETING AUTHORISATION NUMBER
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
August 2012 2
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
BOTTLE
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION
[Brimonidine tartrate/Timolol 2 mg/ml + 5 mg/ml eye drops, solution] Brimonidine tartrate/Timolol
Ocular use
2. METHOD OF ADMINISTRATION
Read the package leaflet before use.
3. EXPIRY DATE
EXP Discard 28 days after first opening.
4. BATCH NUMBER
LOT
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
5 ml
6. OTHER
Store below 30°C. Keep the bottle in the bottle in the outer carton in order to protect from light.
August 2012 3