Brimolol

Brimonidine tartrate, timolol maleate.

A clear greenish-yellow solution.
Active ingredient(s): Each ml contains: Brimonidine Tartrate 2 mg/ml, Timolol Maleate (equivalent to Timolol 5 mg/ml) 6.8 mg/ml.
Excipients/Inactive Ingredients: Preservative: Benzalkonium Chloride 0.005% w/v.

Pharmacotherapeutic group: Ophthalmological, antiglaucoma preparations and miotics - beta-blocking agents - timolol, combinations. ATC code: S01ED51.
Pharmacology: Pharmacodynamics: YSP BRIMOLOL EYE DROP 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. YSP BRIMOLOL EYE DROP has a rapid onset of action.
Brimonidine tartrate is an alpha-2 adrenergic receptor aqonist that is 1000-fold more selective for the alpha-2 adrenoreceptor 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 suppressing aqueous humour inflow and enhancing uveoscleral outflow. Timolol is a beta-1 and beta-2 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.
Pharmacokinetics: YSP BRIMOLOL EYE DROP: There were no statistically siqnificant differences in brimonidine or timolol AUC between YSP BRIMOLOL EYE DROP and the respective monotherapy treatments. Mean plasma Cmax values for brimonidine and timolol following dosing with YSP BRIMOLOL EYE DROP were 0.0327 and 0.406 ng/mL respectively.
Brimonidine: After ocular administration of 0.2% eve 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.
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. 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 human 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 by 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.

Reduction of intraocular pressure (IOP) in patients with chronic open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers.

Use in children and adolescents: YSP BRIMOLOL EYE DROP is CONTRAINDICATED in neonates and infants (less than 2 years of age). The safety and effectiveness of YSP BRIMOLOL EYE DROP 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.
Recommended dosage in adults (including the elderly): The recommended dose is one drop of YSP BRIMOLOL EYE DROP in the affected eye(s) twice daily, approximately 12 hours apart. If more than one topical product is to be used, the different products should be instilled at least 5 minutes apart. As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctual occlusion) for one minute. This should be performed immediately following the instillation of each drop. To avoid contamination of the eye or drops do not allow the dropper tip to come in contact with any surface.
For ophthalmic administration.

Bradycardia has been in association with use of a higher than recommended dose. If overdosage occurs, treatment should be symptomatic and supportive; a patent airway should be maintained.
Inadvertent overdosage with timolol ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, hypotension, bronchospasm and cardiac arrest. Patients with renal do not dialyse timolol readily.
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 a loss of consciousness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea, coma, lethargy, pallor, respiratory depression and somnolence 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 to Allergan. The subjects experienced symptoms of CNS depression, 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 cardia arrest. Timolol does not dialyse readily.
If overdose occurs treatment should be symptomatic and supportive.

Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.
Sinus bradycardia, sick sinus syndrome, sino-atrial nodal 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 Dosage & Administration.
Patients receiving monoamine oxidase (MAO) inhibitor therapy.
Patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and mianserin).
Hypersensitivity to the active substances or any of the excipients.

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 YSP BRIMOLOL EYE DROP in children and adolescents (2 to 7 years of age) have not been established. Delayed ocular hypersensitivity reactions have been reported with brimonidine tartrate ophthalmic solution 0.2% is associated with an increase in IOP.
If allergic reactions are observed, treatment with YSP BRIMOLOL EYE DROP should be discontinued.
Like other topically applied ophthalmic agents, YSP BRIMOLOL EYE DROP may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed. Due to the beta-adrenergic component, timolol, the same types of cardiovascular and pulmonary adverse reactions as seen with systemic beta-blockers may occur. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see Dosage & Administration.
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 with the 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 its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
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.
Respiratory disorders: Respiratory reactions, including death due to bronchospasm in patients with asthma, have been reported following administration of some ophthalmic beta-blockers. YSP BRIMOLOL EYE DROP 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 beta-agonist effects e.g. of adrenaline. The anaesthetist must be informed if the patient is using YSP BRIMOLOL EYE DROP.
In patients with severe renal impairment on dialysis, treatment with timolol has been associated with pronounced hypotension.
Other beta-blocking agents: The effect on intraocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol is given to the patient 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 Interactions).
Hyperthyroidism: Beta-blockers may also mask the signs of hyperthyroidism.
YSP BRIMOLOL EYE DROP 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.
Hypoglycemia/diabetes: Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to uncontrolled diabetic patients (especially those 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, palpitation and sweating.
Vascular disorders: Patients with severe peripheral circulatory disturbance/disorders (i.e. Raynaud's phenomenon) should be treated with caution.
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 unresponsive to the usual dose of adrenaline used to treat anaphylactic reaction.
Choroidal detachment: Choroidal detachment after filtration procedures has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide).
The preservative in YSP BRIMOLOL EYE DROP, benzalkonium chloride, may cause eye irritation. Patients wearing soft (hydrophilic) contact lenses should be instructed to remove contact lenses prior to application and wait at least 15 minutes after instilling YSP BRIMOLOL EYE DROP before reinsertion. Benzalkonium chloride is known to discolour soft contact lenses. Avoid contact with soft contact lenses.
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures to avoid eye injury and contamination of eye drops.
YSP BRIMOLOL EYE DROP has not been studied in patients with closed-angle glaucoma.
YSP BRIMOLOL EYE DROP has not been studied in patients with hepatic or renal impairment. Therefore, caution should be used in treating such patients.
Effects on Ability to Drive and Use Machine: YSP BRIMOLOL EYE DROP has minor influence on the ability to drive and use machines.
YSP BRIMOLOL EYE DROP may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. Patients who engage in activities such as driving and operating machinery should be cautioned of the potential for a decrease in mental alertness. The patient should wait until these symptoms have cleared before driving or using machinery.

Pregnancy: YSP BRIMOLOL EYE DROP should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.
Brimonidine tartrate: No adequate clinical data on exposed pregnancies are available.
Timolol: There is risk for intrauterine 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 betablockers have been administered until delivery. If the YSP BRIMOLOL EYE DROP is administered until delivery, the neonate should be carefully monitored during the first days of life. YSP BRIMOLOL EYE DROP should not be used during pregnancy unless clearly necessary.
Lactation: Timolol is excreted in human milk. YSP BRIMOLOL EYE DROP should not be used by women breastfeeding infants.

The most common ADRs were conjunctival hyperaemia and burning sensation in the eye. The majority of cases was mild. Adverse drug reactions reported: (See table.)

Click on icon to see table/diagram/image

Additional Adverse Reactions: Additional adverse events that have been seen with one of the components and may potentially occur also with YSP BRIMOLOL EYE DROP: Brimonidine: Eye disorders: blurring, ocular allergic reaction, corneal staining, conjunctival discharge, conjunctival papillae, iritis, iridiocyclitis (anterior uveitis), miosis.
Immune system disorders: hypersensitivity, skin reaction (including erythema, face oedema, pruritus, rash), vasodilation.
Psychiatric disorders: insomnia.
Cardiac disorders: arrhythmias, tachycardia.
Respiratory, thoracic and mediastinal disorders: upper respiratory symptoms.
Gastrointestinal disorders: gastrointestinal symptoms.
General disorders and administration site conditions: fatigue/drowsiness and 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. A high incidence of somnolence has been reported in children 2 years of age and above, especially those in 2-7 age range and/or weighing <20 kg.
Timolol: Eye disorders: decreased corneal sensitivity, blepharoptosis, diplopia, keratitis, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), cystoid macular oedema, pseudopemphigoid.
Psychiatric disorders: insomnia, nightmares, decreased libido, behavioral changes and psychic distrubances including anxiety, confusion, disorientation, hallucinations, memory loss, nervousness.
Nervous system disorders: increase in signs and symptoms of myasthenia gravis, paresthesia, cerebral ischaemia, cerebral vascular accident, insomnia, nightmares. behavioural changes and psychic disturbances including confusion, hallucinations, anxiety, disorientation, nervousness, memory loss, fatigue and paraesthesia.
Ear and labyrinth disorders: tinnitus.
Cardiac disorders: heart block, cardiac arrest, arrhythmia, bradycardia, atrioventricular block, cardiac failure, chest pain, oedema, pulmonary oedema, worsening of angina pectoris.
Vascular disorders: syncope.
Respiratory, thoracic and mediastinal disorders: bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough, respiratory failure, exacerbation of asthma, nasal congestion, upper respiratory infection.
Gastrointestinal disorders: dyspepsia, abdominal pain, anorexia, vomiting.
Skin and subcutaneous tissue disorders: alopecia, psoriasiform rash or exacerbation of psoriasis, skin rash.
Musculoskeletal, connective tissue and bone disorders: myalgia.
Renal and urinary disorders: Peyronie's disease, retroperitoneal fibrosis.
Immune system disorders: Signs and symptoms of systemic allergic reactions including angioedema, generalized and localized rash, pruritus, urticaria; Systemic lupus erythematosus.
Endocrine disorders: Masked symptoms of hypoglycaemia in diabetes patients.
Other: Decreased libido, sexual dysfunction.

There is possibility of an addictive 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 beta-blocker eye drops are administered concomitantly with oral calcium channel blockers, guanethidine, beta-blocking agents, anti-arrhythmics (including amiodarone), digitalis glycosides parasympathomimetics and other anti-hypertensives. Caution is advised when using YSP BRIMOLOL EYE DROP with systemic antihypertensives. Although timolol has little or no effect on the size of the pupil, mydriasis has occasionally been reported when timolol has been used with mydriatic agents such as adrenaline. Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia.
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, selective serotonin reuptake inhibitors (SSRIs)] and timolol, possibly because quinidine inhibits the metabolism of timolol via the P450 enzyme, CYP2D6.
Concomitant use of a beta-blocker with anaesthetic drugs may attenuate compensatory tachycardia and increase the risk of hypotension and therefore the anaesthetist must be informed if the patient is using YSP BRIMOLOL EYE DROP. Caution must be exercised if YSP BRIMOLOL EYE DROP is used concomitantly with iodine contrast products or intravenously administered lidocaine. Cimetidine, hydralazine and alcohol may increase the plasma concentrations of timolol.
The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers. No data on the level of circulating catecholamines after YSP BRIMOLOL EYE DROP administration are available. Caution however is advised in patients taking tricyclic antidepressants 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 YSP BRIMOLOL EYE DROP, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered. Concomitant administration of MAO inhibitors is contraindicated. Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with YSP BRIMOLOL EYE DROP.
Patients who are receiving a systemic (e.g., oral or intravenous) beta-adrenergic blocking agent and YSP BRIMOLOL EYE DROP should be observed for potential additive effects of beta-blockade both systemic and on intraocular pressure.

Instructions for Use: If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart. As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctual occlusion) for one minute. This should be performed immediately following the instillation of each drop. To avoid contamination of the eye or drops do not allow the dropper tip to come into contact with any surface.

Store below 30°C. On prescription only. Keep the bottle in the outer carton. Discard unused contents 4 weeks after opening.
Shelf Life: 2 years.

Antiglaucoma Preparations

S01ED51 - timolol, combinations ; Belongs to the class of beta blocking agents. Used in the treatment of glaucoma.

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