COMBIGAN 2 mg/ml + 5 mg/ml Eye drops, solution Bottle/5ml

Eye drops in solution (eye drops).

Clear, yellowish-green solution.

Brimonidine ..................................................................................................................................................1,3 mg

in the form of 2,0 mg of brimonidine tartrate

Timolol............................................................................................................................................................5,0 mg

in the form of 6,8 mg of timolol maleate

For 1 mL of solution

Excipients with known effect : 1 mL of solution contains 0,05 mg of benzalkonium chloride and 10,58 mg of phosphates.

Excipients:

Reduction of intraocular pressure (IOP) in patients with chronic open-angle glaucoma or ocular hypertension who have an insufficient response to topical beta-blockers.

Dosage

Recommended posology in adults (including elderly patients)

The recommended dose is one drop of COMBIGAN in the affected eye or eyes twice daily, instillations being administered approximately 12 hours apart.

Paediatric population

COMBIGAN is contraindicated in newborns and infants aged less than 2 years (see section Contraindications, section Warnings and precautions, section Adverse effectsand section Overdose).

The safety and efficacy of COMBIGAN have not been established in children and adolescents aged 2 to 17 years, therefore its use is not recommended in children and adolescents (see sections Warnings and precautions, Adverse effects and 4.9).

Use in patients with renal or hepatic impairment

COMBIGAN has not been studied in patients with renal or hepatic impairment. Consequently, it should be used with caution in these patients.

Method of administration

As with all eye drops, to reduce the possibility of systemic absorption, it is recommended to press the lacrimal sac at the inner canthus (punctal occlusion) or to close the eyelids for two minutes. This should be done immediately after the instillation of each drop. This practice aims to minimise systemic adverse effects and to promote the local action of the eye drops.             
To prevent contamination of the eye or of the solution, avoid any contact of the tip with any other surface.

If several topical ophthalmic medicinal products are used concomitantly, each must be administered at an interval of at least 5 minutes.

• Hypersensitivity to the active substances or to any of the excipients listed in section Composition.

• Bronchial hyperreactivity including bronchial asthma or a history of bronchial asthma, severe chronic obstructive bronchopulmonary disease.

• Sinus bradycardia, sinus node dysfunction syndrome, sinoatrial block, second- or third-degree atrioventricular block not controlled by a pacemaker, overt heart failure, cardiogenic shock.

• Use in neonates and infants (less than 2 years) (see section Adverse effects).

• Patients taking a monoamine oxidase inhibitor (MAOI).

• Patients taking antidepressants that affect noradrenergic transmission (tricyclic antidepressants and mianserin, for example).

Paediatric population

Children aged 2 years or older, in particular those aged 2 to 7 years and/or weighing less than or equal to 20 kg, should be treated with caution and closely monitored because of the high incidence and severity of somnolence. The safety and efficacy of COMBIGAN in children and adolescents (2 to 17 years) have not been established (see sections Dosage and administration and Adverse effects).

Eye disorders 

During clinical trials, some patients experienced allergic-type ocular reactions with COMBIGAN (allergic conjunctivitis and allergic blepharitis). Allergic conjunctivitis was observed in 5,2% of patients. Its onset was generally between the 3th and 9th month and led to discontinuation of treatment in 3,1% of cases. Allergic blepharitis was infrequently reported (<1%). In case of an allergic reaction, treatment with COMBIGAN should be discontinued.

Delayed-hypersensitivity ocular reactions have been reported with the use of a 0,2% brimonidine tartrate ophthalmic solution, some being associated with an increase in IOP.             
COMBIGAN has not been studied in patients with angle-closure glaucoma.

Systemic effects 

As with other topically applied ophthalmic agents, systemic absorption of COMBIGAN is possible. No increase in systemic absorption of each of the active substances has been observed. Due to the presence of a beta-adrenergic component, timolol, cardiovascular and pulmonary adverse reactions and other adverse reactions similar to those reported with systemic beta-blockers are likely to occur. The incidence of systemic adverse reactions after topical ophthalmic administration is lower than after systemic administration. To reduce systemic absorption, see section Dosage and administration.

Cardiac disorders 

Following administration of timolol, cardiac reactions have been reported, including, rarely, deaths associated with heart failure. In patients with cardiovascular disease (for example, coronary artery disease, Prinzmetal's angina and heart failure) associated with hypotension, treatment with beta-blockers should be carefully evaluated and the use of other active substances should be considered. Patients with cardiovascular disease should be monitored for signs of worsening of their disease and of adverse reactions.

Due to their negative effect on conduction time, beta-blockers should be administered with caution to patients with first-degree heart block.

As with systemic beta-blockers, a gradual withdrawal is required if treatment interruption is necessary in patients with coronary artery disease, to avoid the development of arrhythmias, myocardial infarction or sudden death.

Vascular disorders 

Patients with severe disorders/disturbances of peripheral circulation (i.e., severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.

Respiratory disorders 

Respiratory reactions, including deaths due to bronchospasm in patients with asthma, have been reported following the administration of certain ophthalmic beta-blockers.

COMBIGAN 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.

Hypoglycemia/diabetes

Beta-adrenergic inhibitors should be administered with caution in patients prone to spontaneous hypoglycaemia and in patients with unstable diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.

Hyperthyroidism 

Beta-blockers may also mask the signs of hyperthyroidism.

COMBIGAN should be used with caution in patients with metabolic acidosis and untreated pheochromocytoma.

Corneal diseases 

Ophthalmic beta-blockers may cause ocular dryness. Patients with corneal diseases should be treated with caution.

Other beta-blocking agents

The effect on intraocular pressure or the known effects of systemic beta-adrenergic blockade may be potentiated when timolol is administered to patients already receiving a systemic beta-blocking agent. The response of these patients should be closely monitored. The use of two topical beta-blockers is not recommended (see section Interactions).

Anaphylactic reactions

During treatment with beta-blockers, patients with a history of atopy or of severe anaphylactic reaction to various allergens may be more sensitive to repeated exposure to these allergens or refractory to adrenaline at the doses usually used to treat anaphylactic reactions.

Choroidal detachment 

Choroidal detachments have been described after administration of aqueous humour secretion-suppressing therapy (for example: timolol, acetazolamide) following filtering surgery.

Surgical anesthesia 

Ophthalmic preparations of beta-blockers may block the systemic beta-agonist effects of adrenaline, for example. The anaesthetist should be informed that the patient is receiving treatment with timolol.

Benzalkonium chloride 

The preservative contained in COMBIGAN, benzalkonium chloride, may cause eye irritation, symptoms of dry eye, and may damage the tear film and corneal surface with prolonged use. Contact lens wearers should remove their lenses before instillation and wait at least 15 minutes before reinserting them. Benzalkonium chloride is likely to discolour soft contact lenses. Avoid contact with soft contact lenses.

COMBIGAN should be used with caution in patients with dry eye and in patients whose corneal condition may be damaged. Patients should be monitored during prolonged use.

Phosphates

COMBIGAN contains phosphate, which may in rare cases cause opacities on the cornea due to calcium deposition during treatment.

No interaction study has been carried out with the brimonidine/timolol fixed combination. Although no specific drug interaction study has been conducted with COMBIGAN, the theoretical possibility of an additive effect or potentiation with central nervous system depressants (alcohol, barbiturates, opiates, sedatives or anaesthetics) should be considered.

Additive effects resulting in hypotension and/or marked bradycardia could occur when an ophthalmic solution containing beta-blockers is administered in combination with calcium channel blockers, adrenergic beta-blockers, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics or guanethidine. In addition, hypotension has been reported in very rare cases (<1 in 10 000) following instillation of brimonidine. Caution is therefore recommended when COMBIGAN is administered in combination with systemic antihypertensives.

Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has occasionally been reported. Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers may also mask the signs and symptoms of hypoglycaemia (see section Warnings and precautions).

Hypertension induced by abrupt withdrawal of clonidine may be potentiated by the intake of beta-blockers.

Potentiation of systemic beta-adrenergic blockade (e.g. decreased heart rate, depression) has been described during treatment combining CYP2D6 inhibitors (for example: quinidine, fluoxetine, paroxetine) and timolol.

Concomitant use of a beta-blocker and anaesthetics may attenuate compensatory tachycardia and increase the risk of hypotension (see section Warnings and precautions) : therefore the anaesthetist must be informed that the patient is being treated with COMBIGAN.

Caution is advised when using COMBIGAN with iodinated contrast media or during intravenous administration of lidocaine.

Cimetidine, hydralazine and alcohol may increase plasma concentrations of timolol.

No data are available on circulating catecholamine levels following administration of COMBIGAN. Nevertheless, caution is recommended in patients taking medicinal products that may alter the metabolism and uptake of circulating amines, for example chlorpromazine, methylphenidate and reserpine.

Caution is advised when initiating (or changing the dose of) concomitant systemic treatment (regardless of pharmaceutical form). capable of interacting with agonists α-adrenergic or interfering with their activity, i.e. agonists or antagonists of adrenergic receptors (for example: isoprenaline or prazosin).

Although no specific drug interaction study has been conducted with COMBIGAN, the theoretical possibility of an additive effect on IOP reduction with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered.

Brimonidine is contraindicated in patients treated with monoamine oxidase (MAO) inhibitors and in patients taking antidepressants that affect noradrenergic transmission (for example: tricyclic antidepressants and mianserin) (see section Contraindications). Patients who have received treatment with MAOIs must observe an interval of 14 days before starting treatment with COMBIGAN.

Pregnancy

There is no relevant data on the safety of use of the fixed combination brimonidine/timolol in pregnant women. COMBIGAN should not be used during pregnancy unless clearly necessary. To reduce systemic absorption, see section Dosage and administration.

 

Brimonidine tartrate

There are no relevant data on the use of brimonidine tartrate in pregnant women. Animal studies have shown reproductive toxicity at high maternotoxic doses (see section Preclinical safety). The potential risk for humans is not known.

Timolol

Animal studies have shown reproductive toxicity at doses significantly higher than those used in clinical practice (see section Preclinical safety).

Epidemiological studies have not shown signs of malformation but have shown a risk of intrauterine growth retardation following exposure to oral beta-blockers. In addition, signs and symptoms suggestive of beta-adrenergic blockade (e.g.: bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the newborn when beta-blockers were administered until delivery. If COMBIGAN is administered until delivery, the newborn should be closely monitored during the first days of life.

Breast-feeding

Brimonidine tartrate

It has not been established whether brimonidine is excreted in human milk, but it is excreted in the milk of lactating rats.

Timolol

Beta-blockers are excreted in human milk. However, at therapeutic doses of timolol eye drops, it is unlikely that sufficient quantities would be present in breast milk to cause clinical symptoms of beta-blockade in the infant. To reduce systemic absorption, see section Dosage and administration.

COMBIGAN should not be used during breast-feeding.

COMBIGAN has a minor influence on the ability to drive and use machines. COMBIGAN may cause transient blurred vision, visual disturbances, fatigue and/or drowsiness which may impair the ability to drive or use machines. Patients should wait for these symptoms to resolve before driving or using machines.

Based on clinical data obtained over a period of 12 months, the most frequently reported adverse reactions were conjunctival hyperaemia (in approximately 15% of patients) and ocular burning sensations (in approximately 11% of patients). In the majority of cases, these reactions were mild and led to discontinuation of treatment in only 3,4% and 0,5% of patients, respectively.

The following adverse reactions have been reported during clinical trials with COMBIGAN and since COMBIGAN has been marketed:

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The following terminology was used to classify the frequency of adverse reactions:

Very common (≥ 1/10) ; 
Common (≥ 1/100, < 1/10) ; 
Uncommon (≥ 1/1 000 to < 1/100);  
Rare (≥ 1/10 000 to < 1/1 000);  
Very rare (<1/10 000);  
Frequency not determinable (cannot be estimated from the available data).

Table 1: List of adverse reactions reported during clinical trials of COMBIGAN and since COMBIGAN has been marketed

System organ class	Frequency	Adverse effects
Eye disorders	Very common	Conjunctival hyperaemia Burning sensations.
	Common	Tingling sensations in the eye Allergic conjunctivitis Corneal erosion Superficial punctate keratitis Ocular pruritus Conjunctival follicular reaction Vision disorders Blepharitis Epiphora Dry eye Ocular discharge Ocular pain Eye irritation Foreign body sensation in the eye
	Uncommon	Decreased visual acuity Conjunctival oedema Follicular conjunctivitis Allergic blepharitis Conjunctivitis Floaters in the vitreous Asthenopia Photophobia Papillary hypertrophy Eyelid pain Conjunctival blanching Corneal edema Corneal infiltrates Detachment of the vitreous
	Frequency not known	Blurred vision
Psychiatric disorders	Common	Depression
Nervous system disorders	Common	Somnolence Headache
	Uncommon	Vertigo Syncope
Cardiac disorders	Uncommon	Congestive heart failure Palpitations
	Frequency not known	Arrhythmia Bradycardia Tachycardia
Vascular disorders	Common	Hypertension
	Frequency not known	Hypotension
Respiratory, thoracic and mediastinal disorders	Uncommon	Rhinitis Nasal dryness
Gastrointestinal disorders	Common	Dry mouth
	Uncommon	Dysgeusia Nausea Diarrhoea
Skin and subcutaneous tissue disorders	Common	Eyelid edema Pruritus of the eyelids Erythema of the eyelids
	Uncommon	Allergic contact dermatitis
	Frequency not known	Facial erythema
General disorders and administration site conditions	Common	Asthenia

 

 

Other adverse reactions have been reported with one of the components and may also be observed with COMBIGAN:

Table 2: List of additional adverse reactions observed with brimonidine and potentially occurring with COMBIGAN

System organ class	Adverse effects
Eye disorders	Iritis Iridocyclitis (anterior uveitis) 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
Disorders of the skin and subcutaneous tissue	Hypersensitivity Skin reactions including erythema, facial oedema, pruritus and rash Vasodilation

 

Paediatric population

In cases where brimonidine was used as medical treatment for congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in newborns and infants (less than 2 years) who had received brimonidine (see section Contraindications).

A high incidence and severity of somnolence have been reported in children aged 2 years or older, particularly those aged 2 to 7 years and/or weighing less than or equal to 20 kg (see section Warnings and precautions).

Timolol

As with other topical ophthalmic products, COMBIGAN (brimonidine tartrate/timolol) is absorbed into the systemic circulation. Absorption of timolol may cause adverse reactions similar to those seen with systemic beta-blockers.

The incidence of systemic adverse reactions after topical ophthalmic administration is lower than after systemic administration. To reduce systemic absorption, see section Dosage and administration.

Table 3: List of additional adverse reactions observed with ophthalmic beta-blockers and potentially occurring with COMBIGAN

System organ class	Adverse effects
Immune system disorders	Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritus, anaphylaxis
Metabolism and nutrition disorders	Hypoglycaemia
Psychiatric disorders	Insomnia Nightmares Memory loss Hallucinations
Nervous system disorders	Cerebrovascular accident Cerebral ischaemia Worsening of signs and symptoms of myasthenia gravis Paresthesia
Eye disorders	Keratitis Choroidal detachment after filtering surgery (see section Warnings and precautions) Conjunctivitis Cystoid macular oedema Decreased corneal sensitivity Corneal erosion Ptosis Diplopia Pseudo pemphigoid Refractive changes
Cardiac disorders	Chest pain Oedema Atrioventricular block Cardiac arrest Heart failure
Vascular disorders	Raynaud's phenomenon, cold hands and feet
Respiratory, thoracic and mediastinal disorders	Bronchospasm (especially in patients with pre-existing bronchospastic disease) Dyspnoea Cough
Gastrointestinal disorders	Dyspepsia Abdominal pain Vomiting
Skin and subcutaneous tissue disorders	Alopecia Psoriasiform rash or worsening of psoriasis Skin rash
Musculoskeletal and connective tissue disorders	Myalgia
Disorders of the reproductive system and breast	Sexual dysfunction Decreased libido
General disorders and administration site conditions	Fatigue

 

 

Adverse effects reported with eye drops containing phosphates :

A few rare cases of corneal calcification have been reported in association with the use of phosphate-containing drops in certain patients with severely damaged corneas.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/.

Rare cases of overdose with COMBIGAN have been reported in humans with no deleterious consequences. In case of overdose, symptomatic and supportive treatment, as well as airway management measures, should be instituted.

Brimonidine

Ophthalmic overdose (adults)

Among the cases received, the events reported were generally among the known adverse effects.

Systemic overdose resulting from accidental ingestion (adults)

There is little information on accidental ingestion of brimonidine in adults. The only adverse effect reported to date has been hypotension. The hypotensive episode was followed by rebound hypertension. Reported cases of oral overdose with other alpha2-adrenergic agonists have mentioned symptoms such as: hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and convulsions.

Paediatric population :

Several reports of serious adverse effects following accidental ingestion of brimonidine eye drops by children have been published or reported. Subjects presented with symptoms of central nervous system depression, typically temporary coma, or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, requiring admission to intensive care with intubation if necessary. Complete recovery was reported in all subjects, generally within 6 to 24 hours.

Timolol

Symptoms of systemic overdose with timolol include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study in patients indicated that timolol is not easily removed by dialysis.

Pharmacotherapeutic class: Ophthalmological drugs - antiglaucoma and miotics - beta-blockers - timolol in combination, ATC code: S01ED51.

Mechanism of action

COMBIGAN contains two active substances: brimonidine tartrate and timolol maleate. These two components reduce elevated intraocular pressure (IOP) through complementary mechanisms of action; this combined effect results in an additional reduction in IOP compared with that induced by either active substance as monotherapy. COMBIGAN has a rapid onset of action.

Brimonidine tartrate is an alpha2-adrenergic receptor agonist that is 1 000 times more selective for alpha2 than for alpha1receptors. This selectivity results in the absence of mydriasis and of microvascular vasoconstriction associated with human retinal xenografts.

Brimonidine tartrate is thought to lower IOP by increasing aqueous humor outflow via the uveoscleral pathway and by reducing aqueous humor production.

Timolol is a non-selective beta1- and beta2-adrenergic blocker which has no significant intrinsic sympathomimetic activity, nor direct depressant action on the myocardium, nor local anesthetic (membrane-stabilizing) effect. Timolol lowers IOP by reducing aqueous humor production. Its mechanism of action is not clearly elucidated, but it probably involves inhibition of the increase in cyclic AMP synthesis induced by endogenous beta-adrenergic stimulation.

Clinical efficacy and safety

In three double-masked, controlled clinical studies, COMBIGAN (twice daily) produced a clinically significant additional reduction in mean diurnal IOP compared with those observed with timolol (twice daily) or brimonidine (two or three times daily) as monotherapy.

In a study conducted in patients whose IOP was insufficiently controlled after a minimum period of 3 weeks on any monotherapy, additional reductions in mean diurnal IOP of 4,5; 3,3 and 3,5 mmHg were observed during the 3 months of treatment with COMBIGAN (twice daily), timolol (twice daily) and brimonidine (twice daily), respectively. In this study, a statistically significant additional reduction in IOP at the lowest point could only be demonstrated versus brimonidine, but not versus timolol; however, a positive trend with superiority was observed at all other assessment points. In pooled data from the 2 other studies, statistical superiority versus timolol was demonstrated at all time points.

Furthermore, the IOP reduction produced by COMBIGAN was consistently non-inferior to that observed with add-on therapy combining brimonidine and timolol (twice daily in all cases).

The IOP reduction produced by COMBIGAN was shown to be maintained during the double-masked studies for up to 12 months.

COMBIGAN

Plasma concentrations of brimonidine and timolol were determined during a crossover study comparing monotherapies with COMBIGAN in healthy subjects. No statistically significant difference in the areas under the curve (AUC) of brimonidine and timolol was detected between COMBIGAN and the two monotherapies. In patients treated with COMBIGAN, the Cmax Mean plasma concentrations of brimonidine and timolol were 0,0327 and 0,406 ng/mL, respectively.

Brimonidine

In humans, plasma brimonidine concentrations measured after ocular administration of a 0,2 % solution eye drop are low. Brimonidine is poorly metabolised in the human eye, and its binding rate to human plasma proteins is approximately 29 %. The mean apparent systemic half-life is close to 3 hours after ocular administration in humans.

Brimonidine is well absorbed and rapidly eliminated after oral administration in humans. The major part of the dose (approximately 74 % of the dose) is excreted in the urine as metabolites within five days; unchanged brimonidine is not detected in the urine. In vitro studies on animal and human livers indicated that metabolism largely involves aldehyde oxidase and cytochrome P450. Consequently, systemic elimination appears to be mainly due to hepatic metabolism.

Brimonidine is significantly and reversibly bound to melanin in ocular tissues, without any deleterious effects. Accumulation does not occur in the absence of melanin.

Brimonidine does not undergo significant metabolism in the human eye.

Timolol

Peak timolol concentrations reached 898 ng/mL in the aqueous humour one hour after ocular administration of a 0,5 % solution eye drop in subjects undergoing cataract surgery. Part of the dose enters the general circulation, where it is significantly metabolised by the liver. The plasma half-life of timolol is of the order of 7 hours. Timolol is partially metabolised in the liver and excreted by the kidneys together with its metabolites. The binding rate of timolol to plasma proteins is low.

The ocular and systemic safety profile of each active substance is well established. Non-clinical data from conventional studies of safety pharmacology, repeated-dose toxicology, genotoxicity and carcinogenicity did not reveal any particular risk for humans. Additional repeated-dose ocular toxicity studies also indicated that COMBIGAN presents no particular risk for humans.

Brimonidine

Brimonidine tartrate induced no teratogenic effect in animals, but caused abortions in rabbits and postnatal growth retardation in rats at systemic exposures approximately 37 and 134 times higher, respectively, than those obtained with treatment in humans.

Timolol

In animal studies, beta-blockers have been shown to reduce umbilical blood flow, reduce foetal growth, delay ossification and increase foetal and postnatal mortality, but without teratogenicity. With timolol, at high maternal doses, embryotoxicity (resorption) was observed in rabbits and foetotoxicity (delayed ossification) in rats. No foetal malformation was demonstrated in teratogenicity studies in mice, rats and rabbits, at oral timolol doses up to 4200 times the daily dose of COMBIGAN in humans.

21 months.

After first opening of the bottle: to be used within 28 days.

Store the bottle in the outer packaging, protected from light.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400937172240 (Fl/5 mL).

Price:

6,11 euros (Fl/5 mL).

Social Security reimbursement at 65%.
Collection.