Combigan

Each mL contains 2.0 mg brimonidine tartrate (equivalent to 1.3 mg of brimonidine) and 5.0 mg timolol (equivalent to 6.8 mg of timolol maleate).
Excipients/Inactive Ingredients: Benzalkonium chloride, monobasic sodium phosphate, dibasic sodium phosphate, hydrochloric acid or sodium hydroxide to adjust pH, and purified water.

Pharmacotherapeutic group: Ophthalmological beta-blocking agents: Timolol, combinations. ATC code: S01ED51.
Pharmacology: Pharmacodynamics: Mechanism of action: COMBIGAN 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.
Combigan 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 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 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 effects: In these well-controlled, double-masked clinical studies, COMBIGAN (twice daily) produced significantly greater decreases in mean diurnal IOP compared with timolol (twice daily) and brimonidine (twice daily or three times a day) when administered as monotherapy.
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 of 4.5, 3.3 and 3.5 mmHg were observed during 3 months of treatment for COMBIGAN (twice daily), timolol (twice daily) and brimonidine (twice daily), respectively.
In addition, the IOP-lowering effect of COMBIGAN was consistently non-inferior to that achieved by adjunctive therapy of brimonidine and timolol (all twice daily).
The IOP-lowering effect of COMBIGAN has been shown to be maintained in double-masked studies of up to 12 months.
Pharmacokinetics: Plasma brimonidine and timolol concentrations were determined in a crossover study comparing the monotherapy treatments to COMBIGAN treatment in healthy subjects. There were no statistically significant differences in brimonidine or timolol AUC between COMBIGAN and the respective monotherapy treatments. Mean plasma C_max values for brimonidine and timolol following dosing with COMBIGAN 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 5 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. After instillation of brimonidine tartrate 0.2% eye drops to the rabbit, peak drug concentration was 0.647 μg/mL in the aqueous humour within 1 hour post-dose. Brimonidine concentrations declined subsequently in a biphasic manner with an initial half-life of 1 hour, followed by a slower terminal elimination phase from 6 to 24 hours post-dose.
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.

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

Recommended Dose: COMBIGAN is administered topically to the eye.
The recommended dose is one drop of COMBIGAN in the affected eye(s) twice daily, approximately 12 hours apart.
Mode of Administration: As with any eye drops, to reduce possible systemic absorption, it is recommended that the lacrimal sac be compressed at the medical canthus (punctual occlusion) for at least 1 minute. This should be performed immediately following the instillation of each drop.
If more than 1 topical ophthalmic drug is to be used, the different drugs should be instilled at least 5 minutes apart.

There is limited data available of overdosage in humans with the use of COMBIGAN. Bradycardia has been reported 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.
Brimonidine: Symptoms of brimonidine overdose such as hypotension, bradycardia, hypothermia, apnoea, coma, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in a few neonates, infants, and children receiving brimonidine tartrate ophthalmic solution as part of medical treatment of congenital glaucoma or by accidental oral ingestion (see Use in Children under Precautions).
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: There have been reports of inadvertent overdosage with timolol ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as bradycardia, hypotension, bronchospasm, headache, dizziness, shortness of breath and cardiac arrest. An in vitro haemodialysis study, using 14C timolol added to human plasma or whole blood showed that timolol was readily dialysed from these fluids; however, a study of patients with renal failure showed that timolol did not dialyse readily.
If overdose occurs, treatment should be symptomatic and supportive.

COMBIGAN is contraindicated in patients with the following conditions: Reactive airway disease including bronchial asthma, a history of bronchial asthma or severe chronic obstructive pulmonary disease.
Sinus bradycardia, sick sinus syndrome, sino-atrial nodal block, second and third degree atrioventricular block not controlled with a pacemaker, overt cardiac failure, cardiogenic shock.
Use in neonates and infants (children under the age of 2 years).
Patients receiving monoamine oxidase (MAO) inhibitor therapy.
Hypersensitivity to any component of this medication.

As with other topically applied ophthalmic agents, the active substances (brimonidine tartrate and timolol) in COMBIGAN may be absorbed systemically. No enhancement of the systemic absorption of the individual active substance 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.
Respiratory and cardiac reaction have been reported including, rarely, death due to bronchospasm or associated with cardiac failure.
COMBIGAN has not been studied in children under the age of 18 years. However, in a 3-month phase 3 study in children (ages 2-7 years) with glaucoma inadequately controlled by beta-blockers, the use of brimonidine tartrate ophthalmic solution 0.2% led to a high incidence and severity of somnolence in children 2 years of age and above, especially those weighing ≤20 kg (see Use in Children as follows).
Delayed ocular hypersensitivity reactions have been reported with brimonidine tartrate ophthalmic solution 0.2%, with some reported to be associated with an increase in IOP.
Caution should be exercised in treating patients with severe or unstable and uncontrolled cardiovascular disease (e.g., coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension. Cardiac failure should be adequately controlled before beginning therapy. Patients with a history of severe cardiac disease should be watched for sign of cardiac failure and have their pulse rates checked. Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block. Cardiac and respiratory reactions, including death due to bronchospasm in patients with asthma, and, rarely, death in association with cardiac failures have been reported following administration of timolol maleate.
Beta-blockers may also mask the signs of hyperthyroidism and cause worsening of Prinzmetal angina, severe peripheral and central circulatory disorders and hypotension.
Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.
COMBIGAN should be used with caution in patients with depression, cerebral or coronary insufficiency, with severe peripheral circulatory disturbance/disorders (i.e Raynaud's phenomenon), orthostatic hypotension.
Patients with chronic obstructive pulmonary disease of mild or moderate severity should, in general, not receive products containing beta-blockers, including COMBIGAN; however, if COMBIGAN is deemed necessary in such patients, it should be administered with caution.
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. Such patients may be unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.
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.
Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol).
Caution should be exercised when used concomitantly with systemic beta-adrenergic blocking agents because of the potential for additive effects on systemic beta-blockade.
The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended.
Ophthalmic beta-blockers may impair compensatory tachycardia and increase risk of hypotension when used in conjunction with anesthetics. The anesthetist must be informed if the patient is using COMBIGAN.
The preservative in COMBIGAN, 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 COMBIGAN before reinsertion. Benzalkonium chloride is known to be absorbed by and discolour 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.
COMBIGAN 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 machines: As with other similar medications, COMBIGAN may cause fatigue and/or drowsiness in some patients. Patients who engage in activities such as driving and operating machinery should be cautioned of the potential for a decrease in mental alertness. COMBIGAN may also cause blurred vision or visual disturbance. The patient should wait until these symptoms have cleared before driving or using machinery.
Use in Children: COMBIGAN should not be used in neonates.
The safety and effectiveness of COMBIGAN in children and adolescents have not been established and therefore, its use is not recommended in children or adolescents.
There are no adequate and well-controlled studies with COMBIGAN in children (less than 18 years old). In a 3-month, Phase 3 study in children (ages 2-7 years) with glaucoma inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with brimonidine tartrate ophthalmic solution 0.2% as adjunctive treatment to topical beta-blockers. This was severe in 8% of the children and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, the least being in the 7 year old age group (25%), but was more affected by weight, occurring more frequently in children weighing ≤20 kg (63%) compared to those weighing >20 kg (25%).
During post-marketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in neonates, infants, and children receiving brimonidine either for congenital glaucoma or by accidental ingestion (see Contraindications).
Use in the Elderly: No overall differences in safety and effectiveness have been observed between elderly and other adult patients.

Pregnancy: There are no adequate data for the use of COMBIGAN in pregnant women. Because animal reproduction studies are not always predictive of human response, COMBIGAN should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Brimonidine tartrate: In animal studies, brimonidine tartrate did not cause any teratogenic effects. Brimonidine tartrate has been shown to cause 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: Teratogenicity studies in mice, rats and rabbits, at oral doses up to 4200 times the human daily dose of COMBIGAN, shown no evidence of foetal malformation.
However, epidermiological studies suggest that a risk of intra uterine growth retardation may exist following exposure to systemic beta-blockers. In addition, some signs and symptoms of beta-blockade (e.g. bradycardia) have been observed in both the foetus and the neonate.
Consequently, COMBIGAN should not be used during pregnancy unless clearly necessary.
Lactation: Timolol has been detected in human milk following oral and ophthalmic drug administration. It is not known if brimonidine is excreted in human milk but is excreted in the milk of the lactating rat. Because of the potential for serious adverse reactions from timolol or brimonidine tartrate in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Therefore, COMBIGAN should not be used by women breast-feeding infants.

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 cases were mild and led to discontinuation rates of only 3.4% and 0.5%, respectively. The following adverse drug reactions were reported during clinical trials with COMBIGAN.
Eye disorders: Very Common (>1/10): conjunctival hyperaemia, burning sensation in the eye.
Common (>1/100, <1/10): stinging sensation in the eye, eye pruritus, allergic conjunctivitis, conjunctival folliculosis, visual disturbance, blepharitis, epiphora, corneal erosion, superficial punctuate keratitis, eye dryness, eye discharge, eye pain, eye irritation, foreign body sensation.
Uncommon (>1/1000, <1/100): visual acuity worsened, conjunctival oedema, follicular conjunctivitis, conjunctivitis, vitreous floater, asthenopia, photophobia, papillary hypertrophy, eyelid pain, conjunctival blanching, corneal oedema, corneal infiltrates, vitreous detachment.
Psychiatric disorders: Common (>1/100, <1/10): depression.
Nervous system disorders: Common (>1/100, <1/10): somnolence, headache.
Uncommon (>1/1000, <1/100): dizziness, syncope.
Cardiac disorders: Uncommon (>1/1000, <1/100): congestive heart failure, palpitations, bradycardia.
Vascular disorders: Common (>1/100, <1/10): hypertension.
Respiratory, thoracic and mediastinal disorders: Uncommon (>1/1000, <1/100): rhinitis, nasal dryness.
Gastrointestinal disorders: Common (>1/100, <1/10): oral dryness.
Uncommon (>1/1000, <1/100): taste perversion, diarrhea.
Skin and subcutaneous tissue disorders: Common (>1/100, <1/10): eyelid oedema, eyelid pruritus, eyelid erythema.
Uncommon (>1/1000, <1/100): allergic contact dermatitis.
General disorders and administration site conditions: Common (>1/100, <1/10): asthenic conditions.
Investigations: Common (>1/100, <1/10): LFTs abnormal.
Additional Adverse Reactions: Additional adverse events that have been reported in clinical experience with the individual components are listed as follows.
Brimonidine: Eye disorders: iridocyclitis (anterior uveitis), iritis, miosis.
Immune system disorders: hypersensitivity, skin reaction (including erythema, face oedema, pruritus, rash), vasodilation.
Psychiatric disorders: insomnia.
Cardiac disorders: arrhythmias (including bradycardia and tachycardia).
Vascular disorders: hypotension.
Respiratory, thoracic and mediastinal disorders: upper respiratory symptoms, dyspnoea.
Gastrointestinal disorders: gastrointestinal symptoms.
General disorders and administration site conditions: systemic allergic reactions.
Timolol: Eye disorders: decreased corneal sensitivity, diplopia, keratitis, pseudopemphigoid, ptosis, choroidal detachment (following filtration surgery), cystoid macular edema, refractive changes (due to withdrawal of miotic therapy in some cases).
Psychiatric disorders: insomnia, nightmares, behavioral changes and psychic disturbances 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.
Ear and labyrinth disorders: tinnitus.
Cardiac disorders: heart block, cardiac arrest, arrhythmia, atrioventricular block, cardiac failure, chest pain, oedema, pulmonary oedema, worsening of angina pectoris.
Vascular disorders: hypotension, 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, nasal congestion, respiratory failure, upper respiratory infection.
Gastrointestinal disorders: abdominal pain, anorexia, vomiting, nausea, diarrhoea, dyspepsia.
Skin and subcutaneous tissue disorders: alopecia, skin rash, psoriasiform rash or exacerbation of psoriasis.
Musculoskeletal, connective tissue and bone disorders: myalgia.
Immune system disorders: systemic allergic reactions including anaphylaxis, angioedema, generalized and localized rash, pruritus, urticarial, systemic lupus erythematosus.
Metabolism and nutrition disorders: hypoglycemia (in diabetic patients).
Reproductive system and breast disorders: decreased libido, Peyronie's disease, retroperitoneal fibrosis, sexual dysfunction.
General disorders and administration site conditions: oedema, chest pain.
Postmarketing Experience: The following adverse reactions have been identified during postmarketing use of COMBIGAN in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.
Eye disorders: Blurred vision, Reduced visual acuity.
Nervous system disorders: Dizziness.
Cardiac disorders: Bradycardia.
Vascular disorders: Hypotension.
Gastrointestinal disorders: Nausea.
Skin and subcutaneous tissue disorders: Facial erythema.
Carcinogenesis, mutagenesis, impairment of fertility: The ocular and systemic safety profile of the individual components is well established. Preclinical data reveal no special hazard for humans based on conventional studies of the individual components of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. Additional repeated dose toxicity studies on COMBIGAN also showed no special hazard for humans.

No interaction studies have been performed with COMBIGAN. Although specific drug interactions studies have not been conducted with COMBIGAN, 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 eye drops with timolol are administered concomitantly with oral calcium-channel blockers, guanethidine, beta-blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides or parasympathomimetics. After the application of brimonidine, very rare (<1 in 10,000) cases of hypotension have been reported. Caution is therefore advised when using COMBIGAN 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 sign 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 quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P450 enzyme, CYP2D6.
Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with COMBIGAN in humans can lead to resulting interference with the IOP lowering effect. No data on the level of circulating catecholamines after COMBIGAN 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. Concomitant administration of MAO inhibitors is contraindicated (see Contraindications). Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with COMBIGAN.
Caution is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact which 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 COMBIGAN, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered.
Patients who are receiving a systemic (e.g., oral or intravenous) beta-adrenergic blocking agent and COMBIGAN should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure.

Store below 25°C. Keep the bottle in the outer carton. Discard unused contents 4 weeks after opening.

Antiglaucoma Preparations

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

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