Combigan 2 mg/ml + 5 mg/ml eye drops, solution

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

Contains benzalkonium chloride 0.05 mg/mL.

For a full list of excipients, see section 6.1

Eye drops, solution.

Clear, greenish-yellow solution.

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

To avoid contamination of the eye or eye drops do not allow the dropper tip to come into contact with any surface.

Recommended dosage in adults (including the elderly)

The recommended dose is one drop of Combigan 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.

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.

Use in renal and hepatic impairment

Combigan has not been studied in patients with hepatic or renal impairment. Therefore, caution should be used in treating such patients.

Use in children and adolescents

Combigan is contraindicated in neonates and infants (less than 2 years of age) (see section 4.3 Contraindications, section 4.4 Special warnings and precautions for use, section 4.8 Undesirable effects and section 4.9 Overdose).

The safety and effectiveness of Combigan 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).

• Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.

• Sinus bradycardia, 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)

• Hypersensitivity to the active substances or to 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 Combigan 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, Combigan may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed.

Some patients have experienced ocular allergic type reactions (allergic conjunctivitis and allergic blepharitis) with Combigan 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 Combigan should be discontinued.

Due to the beta-adrenergic component, timolol, the same types of cardiovascular and pulmonary adverse reactions as seen with systemic beta-blockers may occur.

Caution should be exercised in treating patients with severe or unstable and uncontrolled cardiovascular disease. Cardiac failure should be adequately controlled before beginning therapy. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked. 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.

In patients with severe renal impairment on dialysis, treatment with timolol has been associated with pronounced hypotension.

Timolol may impair compensatory tachycardia and increase risk of hypotension when used in conjunction with anaesthetics. The anaesthetist must be informed if the patient is using Combigan.

Beta-blockers may also mask the signs of hyperthyroidism and cause worsening of Prinzmetal angina, severe peripheral and central circulatory disorders and hypotension. Combigan must be used with caution in patients with metabolic acidosis and untreated phaeochromocytoma.

Beta-adrenergic blocking agents 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, palpitations and sweating.

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

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 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.

Choroidal detachment after filtration procedures has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide).

The preservative in Combigan, 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.

Combigan has not been studied in patients with closed-angle glaucoma.

No interaction studies have been performed. 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, or beta-blocking agents, anti-arrhythmics, 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 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 (see 4.4 Special warnings and precautions for use)

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers.

Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine 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 (see section 4.4), and therefore the anaesthetist must be informed if the patient is using Combigan.

Caution must be exercised if Combigan 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 Combigan 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 Combigan, 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 (see section 4.3). Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with Combigan.

Pregnancy

There are no adequate data for the use of Combigan 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 Preclinical safety data). The potential risk for humans is unknown.

Timolol

Studies in animals have shown reproductive toxicity at doses significantly higher than would be used in clinical practice (see 5.3). However, epidemiological studies have not revealed malformative effects but have shown a risk for intra uterine growth retardation when betablockers are administered by the oral route. In addition, signs and symptoms of betablockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. Therefore, if Combigan is administered in pregnancy up to the time of delivery, the neonate should be carefully monitored during the first days of life.

Combigan should not be used during pregnancy unless clearly necessary.

Lactation

Timolol is excreted in human milk. It is not known if brimonidine is excreted in human milk but it is excreted in the milk of the lactating rat. Combigan should not be used by women breast-feeding infants.

Combigan has minor influence on the ability to drive and use machines. Combigan 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.

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.

The following adverse drug reactions were reported during clinical trials with Combigan:

Eye disorders

Very Common (>1/10): conjunctival hyperaemia, burning sensation

Common (>1/100, <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, <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

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

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

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

The following adverse drug reactions have been reported since Combigan has been marketed:

Cardiac disorders

Not known: arrhythmia, bradycardia, tachycardia

Vascular disorders

Not known: hypotension

Additional adverse events that have been seen with one of the components and may potentially occur also with Combigan:

Brimonidine

Eye disorders: iritis, miosis

Psychiatric disorders: insomnia

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

Eye disorders: decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases)

Psychiatric disorders: insomnia, nightmares, decreased libido

Nervous system disorders: memory loss, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia

Ear and labyrinth disorders: tinnitus

Cardiac disorders: heart block, cardiac arrest

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

Skin and subcutaneous tissue disorders: alopecia, psoriasiform rash or exacerbation of psoriasis

Musculoskeletal, connective tissue and bone disorders: systemic lupus erythematosus

Renal and urinary disorders: Peyronie's disease

General disorders and administration site conditions: oedema, chest pain

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 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 cardiac arrest. A study of patients showed that timolol did not dialyse readily.

If overdose occurs treatment should be symptomatic and supportive.

Pharmacotherapeutic group: Ophthalmological – antiglaucoma preparations and miotics - beta-blocking agents – timolol, combinations

ATC code: S01ED51

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 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 effects

In three controlled, doublemasked clinical studies, Combigan (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.

In a study in patients whose IOP was insufficiently controlled following a minimal 3week runin 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 Combigan (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 IOPlowering effect of Combigan was consistently non-inferior to that achieved by adjunctive therapy of brimonidine and timolol (all twice daily).

The IOPlowering effect of Combigan has been shown to be maintained in double-masked studies of up to 12 months.

Combigan

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 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.

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 ocular repeated dose toxicity studies on Combigan 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 foetal growth, delayed ossification and increased foetal and postnatal death, but no teratogenicity. With timolol, embryotoxicity (resorption) in rabbit and foetotoxicity (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 Combigan, showed no evidence of foetal malformation.

Benzalkonium chloride

Sodium phosphate, monobasic monohydrate

Sodium phosphate, dibasic heptahydrate

Hydrochloric acid or sodium hydroxide to adjust pH

Purified water

Not applicable.

21 months.

After first opening: Use within 28 days.

Keep the bottle in the outer carton in order to protect from light.

White low density polyethylene bottles with polystyrene screw caps. Each bottle has a fill volume of 5 ml.

The following pack sizes are available: cartons containing 1 or 3 bottles of 5 ml. Not all pack sizes may be marketed.

No special requirements.

Allergan Pharmaceuticals Ireland

Castlebar Road

Westport

Co. Mayo

Ireland

PL 05179/0006

12^th April 2005

18^th November 2008