BRIMONIDINE/TIMOLOL VIATRIS 2 mg/ml+5 mg/ml Collyre sol Fl/5ml

Eye drops in solution.

Clear, yellowish-green solution.

Brimonidine tartrate (equivalent to 1,3 mg of brimonidine) ...................................................................2,0 mg

Timolol (equivalent to 6,8 mg of timolol maleate) ....................................................................................5,0 mg

For 1 ml of solution.

Excipient with known effect: each millilitre contains 0,05 mg of benzalkonium chloride and 10,58 mg of phosphates.

For the full list of excipients, see section Composition.

Excipients:

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

To prevent contamination, avoid any contact of the tip with any other surface.

Dosage

Dosage recommended in adults (including in elderly patients)

The recommended dose is one drop of BRIMONIDINE/TIMOLOL VIATRIS in the affected eye or eyes twice daily, instillations should be administered approximately 12 hours apart. If several topical ophthalmic medicinal products are used concomitantly, each must be administered at an interval of at least 5 minutes.

Paediatric population

BRIMONIDINE/TIMOLOL VIATRIS is contraindicated in newborns and infants (less than 2 years) (see sections Contraindications, Warnings and precautions, Adverse effects and Overdose).

The safety and efficacy of BRIMONIDINE/TIMOLOL VIATRIS have not been established in children and adolescents (2 to 17 years). Its use is therefore not recommended in these patients (see sections Warnings and precautions and 4.8).

Method of administration

As with all eye drops, to reduce possible systemic absorption, it is recommended to press the lacrimal sac at the inner canthus (occlusion point) or to close the eyelids for two minutes. This should be done immediately after the instillation of each drop. This method may help reduce systemic adverse effects and increase local efficacy.

Use in patients with renal or hepatic impairment

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

• 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, or severe chronic obstructive pulmonary disease.

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

• Use in newborns 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, must be treated with caution and closely monitored because of the high incidence and severity of somnolence. The safety and efficacy of brimonidine / timolol in children and adolescents (2 to 17 years) have not been established (see sections Dosage and administration and 4.8).

During clinical trials, a few patients experienced allergic-type ocular reactions with brimonidine / timolol (allergic conjunctivitis and allergic blepharitis). Allergic conjunctivitis was observed in 5,2 % of patients. Its onset generally occurred between the 3e and 9e months and led to treatment discontinuation in 3,1 % of cases. Allergic blepharitis was reported infrequently (<1 %).

In the event of an allergic reaction, treatment with BRIMONIDINE /TIMOLOL VIATRIS must be discontinued.

Delayed ocular hypersensitivity reactions have been reported with a 0,2 % brimonidine tartrate ophthalmic solution, some associated with an increase in intraocular pressure (IOP).

As with other topically applied ophthalmic agents, systemic absorption of brimonidine / timolol is possible. No increase in systemic absorption of each of the active substances has been observed.

Since timolol is a beta-blocker, cardiovascular and pulmonary adverse reactions similar to those reported with systemic beta-blockers are likely to occur. The frequency of systemic adverse effects after topical ophthalmic administration is lower than after systemic administration. To reduce systemic absorption, see section Dosage and administration.

Cardiac disorders :

Cardiac reactions have been reported, including rare cases of death related to heart failure after administration of timolol maleate. In patients with cardiac disease (for example, coronary artery disease, Prinzmetal's angina or heart failure) or arterial hypotension, the administration of a beta-blocker treatment must be carefully weighed and treatment with other active substances considered. In patients with cardiovascular diseases, signs of worsening of these diseases and of adverse effects should be sought.

Because of their negative effect on conduction velocity, beta-blockers should only be administered with caution to patients with first-degree heart block.

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

Vascular disorders

Patients with severe peripheral circulatory disorders (i.e. the severe form of Raynaud's disease or Raynaud's syndrome) must be treated with caution.

Respiratory disorders

In asthmatic patients, respiratory manifestations, including death due to bronchospasm, have been reported after administration of certain ophthalmic beta-blockers. BRIMONIDINE /TIMOLOL VIATRIS must be administered with caution in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and only if the potential benefit appears to outweigh the potential risk.

Hypoglycaemia/Diabetes

Beta-adrenergic inhibitors must be administered with caution in patients prone to spontaneous hypoglycaemia or 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.

BRIMONIDINE /TIMOLOL VIATRIS must be used with caution in patients with acidosis or 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-blockers may be enhanced when timolol is administered to patients already receiving an oral beta-blocker. The response of these patients should be carefully monitored. Concomitant use of two beta-adrenergic blocking agents is not recommended (see section Interactions).

Anaphylactic reactions

During treatment with beta-blockers, patients with a history of atopy or severe anaphylactic reaction to various allergens may be more reactive to repeated administration of such allergens and may not respond to the doses of adrenaline usually used in the treatment of anaphylactic reactions.

Choroidal detachment

Choroidal detachments have been observed following filtering surgery during administration of treatment suppressing aqueous humour secretion (timolol and acetazolamide).

Surgical anesthesia

Ophthalmic beta-blocker preparations may block the effects of systemic beta-agonist agents, for example adrenaline. The anaesthetist must be informed that the patient has used timolol.

The preservative contained in BRIMONIDINE / TIMOLOL VIATRIS, benzalkonium chloride, may cause eye irritation. Wearers of contact lenses must remove them before instillation and wait at least 15 minutes before reinserting them. Benzalkonium chloride may discolour soft contact lenses. Do not use in the presence of soft lenses.

BRIMONIDINE /TIMOLOL VIATRIS has not been studied in patients with angle-closure glaucoma.

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

Additive effects resulting in hypotension and/or marked bradycardia may theoretically occur when an ophthalmic beta-blocker solution is administered in combination with oral calcium channel inhibitors, beta-blockers, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics or guanethidine.

Hypotension has been reported in very rare cases (<1 in 10 000) following instillation of brimonidine. Caution is therefore recommended when BRIMONIDINE /TIMOLOL VIATRIS is administered in combination with systemic antihypertensives.

Mydriasis has occasionally been reported when ophthalmic beta-blockers and adrenaline (epinephrine) have been used concomitantly.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents.

Beta-blockers may furthermore 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 the systemic beta-blocking effect (for example, decreased heart rate, depression) has been reported when CYP2D6 inhibitor treatments (for example, quinidine, fluoxetine, and paroxetine) are combined with 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 Brimonidine / Timolol Viatris.

Monitoring should be carried out when BRIMONIDINE /TIMOLOL VIATRIS is used 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 brimonidine / timolol Viatris. 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) that may interact with or interfere with the activity of alpha-adrenergic agonists, i.e. adrenergic receptor agonists or antagonists (for example, isoprenaline or prazosin).

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

Administration of brimonidine is contraindicated in patients receiving treatment with monoamine oxidase inhibitors (MAOIs) and in patients taking antidepressants affecting noradrenergic transmission (e.g. tricyclic antidepressants and mianserin) (see section Contraindications). Patients who have received MAOI treatment must observe an interval of 14 days before starting treatment with Brimonidine / Timolol Viatris.

Pregnancy

There are no relevant data on the use of the brimonidine / timolol combination in pregnant women. BRIMONIDINE /TIMOLOL VIATRIS should not be used during pregnancy unless absolutely 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 after 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. Consequently, if BRIMONIDINE /TIMOLOL VIATRIS 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 the product is excreted in the milk of lactating rats.

Timolol

Beta-blockers are excreted in human milk. However, at therapeutic doses of timolol in eye drops, the amount passing into human milk is unlikely to be sufficient to produce clinical symptoms in the infant. To reduce systemic absorption, refer to section Dosage and administration.

BRIMONIDINE /TIMOLOL VIATRIS must not be used in breastfeeding women.

BRIMONIDINE /TIMOLOL VIATRIS may have a slight influence on the ability to drive and use machines. BRIMONIDINE /TIMOLOL VIATRIS is likely to cause transient blurred vision, visual disturbances, fatigue and/or drowsiness that may impair the ability to drive vehicles and use machines. The patient should wait for these symptoms to disappear before driving or using machines.

Based on clinical data obtained over a period of 12 months, the most frequently reported drug-related adverse effects 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 treatment discontinuation in only 3,4% and 0,5% of patients, respectively.

The following drug-related adverse effects were reported during clinical trials conducted with brimonidine / timolol and are classified by system organ class and using the following frequencies:

Very common: ≥ 1/10

Common: ≥ 1/100 to < 1/10

Uncommon: ≥ 1/1 000 to < 1/100

Rare: ≥ 1/10 000 to < 1/1 000

Very rare: < 1/10 000

Frequency not known: cannot be estimated from the available data

Eye disorders

Very common: conjunctival hyperaemia, burning sensations.

Common: stinging sensations in the eye, allergic conjunctivitis, corneal erosion, superficial punctate keratitis, ocular pruritus, conjunctival follicular reaction, visual disturbances, blepharitis, epiphora, dry eye, ocular discharge, ocular pain, eye irritation, sensation of foreign body in the eye.

Uncommon: decreased visual acuity, conjunctival oedema, follicular conjunctivitis, allergic blepharitis, conjunctivitis, vitreous floaters, asthenopia, photophobia, papillary hypertrophy, eyelid pain, conjunctival blanching, corneal oedema, corneal infiltrates, vitreous detachment.

Psychiatric disorders

Common: depression.

Nervous system disorders

Common: somnolence, headache.

Uncommon: dizziness, syncope.

Cardiac disorders

Uncommon: congestive heart failure, palpitations.

Vascular disorders

Common: hypertension.

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 oedema, eyelid pruritus, eyelid erythema.

Uncommon: allergic contact eczema.

General disorders and administration site conditions

Common: asthenia.

The following adverse reactions have been reported since the marketing of brimonidine / timolol.

Eye disorders:

Frequency not known: blurred vision.

Cardiac disorders:

Frequency not known: arrhythmia, bradycardia, tachycardia.

Vascular disorders:

Frequency not known: hypotension.

Skin and subcutaneous tissue disorders:

Frequency not known: facial erythema.

Other adverse reactions have been reported with one of the components of the preparation and may also be observed with BRIMONIDINE/TIMOLOL VIATRIS:

Brimonidine

Eye disorders : iritis, iridocyclitis (anterior uveitis), miosis.

Disorders Psychiatric: insomnia.

Respiratory, thoracic and mediastinal disorders: Upper respiratory symptoms, dyspnoea.

Gastrointestinal disorders: Gastrointestinal symptoms.

General disorders and administration site conditions: General allergic reactions.

Disorders of the skin and subcutaneous tissue : skin reaction including erythema, facial oedema, pruritus, rash and vasodilation.

In cases where brimonidine was used as part of the medical treatment of 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 received brimonidine (see section Contraindications).

Numerous cases 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 topically administered ophthalmic medicinal products, BRIMONIDINE /TIMOLOL VIATRIS (brimonidine tartrate / timolol) is absorbed into the systemic circulation. Absorption of timolol may lead to side effects similar to those seen with systemic beta-blockers.

The incidence of systemic side effects after ophthalmic administration is lower compared with systemic administration. To reduce systemic absorption, see section Dosage and administration.

Other side effects observed with ophthalmic beta-blockers and which may potentially occur with BRIMONIDINE /TIMOLOL VIATRIS are listed below:

Disorders Immune system disorders: systemic allergic reactions including angioedema, urticaria, localised or generalised rash, pruritus, anaphylactic reaction.

Metabolism and nutrition disorders: hypoglycaemia.

Disorders psychiatric : insomnia, nightmares, memory loss, hallucinations.

Nervous system disorders: cerebrovascular accident, cerebral ischaemia, worsening of signs and symptoms of myasthenia gravis, paraesthesia.

Eye disorders: keratitis, choroidal detachment following filtration surgery (see section Warnings and precautions), decreased corneal sensitivity, corneal erosion, ptosis, diplopia.

Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure.

Vascular disorders: Raynaud's phenomenon, cold extremities.

Respiratory, thoracic and mediastinal disorders: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), dyspnoea, cough.

Gastrointestinal disorders: dyspepsia, abdominal pain, vomiting.

Skin and subcutaneous tissue disorders: alopecia, psoriasiform eruption or worsening of psoriasis, skin rash.

Musculoskeletal and systemic disorders: myalgia.

Reproductive system and breast disorders: sexual dysfunction, decreased libido.

General disorders and administration site conditions: fatigue.

Side effects reported with eye drops containing phosphates:

Cases of corneal calcification have very rarely been reported in association with the use of eye drops containing phosphates in some 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.

The rare cases of overdose with brimonidine / timolol in humans did not result in any side effects. Treatment of an overdose includes symptomatic and supportive treatment. The respiratory passages should be monitored.

Brimonidine

Ophthalmic overdose (Adults) :

In such cases, the reported events have generally been listed among the undesirable effects.

Systemic overdose resulting from accidental ingestion (Adults) :

Very little information is available regarding accidental ingestion of brimonidine in adults. The only adverse effect reported to date is hypotension. This hypotensive episode was followed by reactive hypertension.

Reported cases of oral overdose with other alpha-2 stimulants have been associated with the following symptoms: hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and convulsion.

Paediatric population

Several reports of serious adverse effects following accidental ingestion of brimonidine by children have been published or reported. Subjects presented with symptoms of central nervous system depression, typically temporary coma or reduced 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 are: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A clinical study indicated that timolol is not easily removed by dialysis.

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

Mechanism of action

BRIMONIDINE/TIMOLOL VIATRIS 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 alone as monotherapy. BRIMONIDINE/TIMOLOL VIATRIS has a rapid onset of action.

Brimonidine tartrate is an alpha2-adrenergic receptor agonist that is 1 000 times more selective for alpha2-type adrenergic receptors than for alpha1-type. This selectivity results in the absence of mydriasis and 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 receptor inhibitor that has no significant intrinsic sympathomimetic activity, no direct depressant action on the myocardium and no local anaesthetic (membrane-stabilising) effect. Timolol lowers IOP by reducing aqueous humour production. Its mechanism of action is not clearly elucidated, but it is likely to involve inhibition of the increase in cyclic AMP synthesis induced by endogenous beta-adrenergic stimulation.

Clinical efficacy and safety

In three controlled, double-blind clinical studies, brimonidine/timolol (twice daily) produced a clinically significant additional reduction in mean diurnal IOP compared with that 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 by monotherapy for at least 3 weeks, additional reductions in mean diurnal IOP reaching 4,5, 3,3 and 3,5 mmHg respectively were observed during 3 months of treatment with brimonidine/timolol (twice daily), timolol (twice daily) and brimonidine (twice daily). In this study, a statistically significant additional reduction in trough IOP could be demonstrated for brimonidine but not for timolol. However, a positive trend was observed at all other time points. In the pooled data from 2 other studies, statistical superiority versus timolol was demonstrated at all time points.

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

The IOP reduction produced by BRIMONIDINE/TIMOLOL VIATRIS was shown to be maintained during double-blind studies lasting up to 12 months.

BRIMONIDINE/TIMOLOL VIATRIS :

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

Brimonidine :

In humans, plasma concentrations of brimonidine measured after ocular administration of a 0,2% solution eye drop are low. Brimonidine is minimally metabolised in the human eye and its plasma protein binding in humans 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; the unchanged form of brimonidine is not detected in the urine. Studies conducted in vitro 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 undesirable 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 passes into the general circulation, where it is significantly metabolised by the liver. The plasma half-life of timolol is on the order of 7 hours. Timolol is partially metabolised in the liver and excreted by the kidneys with its metabolites. The binding rate of timolol to plasma proteins is low.

The ocular and systemic safety profile of each active ingredient is well established. Non-clinical data from pharmacological safety, repeated-dose toxicology, genotoxicity and carcinogenicity studies revealed no particular risk for humans. Additional repeated-dose ocular toxicity studies also indicated that brimonidine / timolol presents no particular risk for humans.

Brimonidine

Brimonidine tartrate did not produce any 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 used for treatment in humans.

Timolol

In animal studies, beta-blockers have been shown to reduce umbilical blood flow, reduce fetal growth, delay ossification and increase fetal and postnatal mortality, but without teratogenicity. With timolol, at high maternal doses, embryotoxicity (resorption) was observed in rabbits and fetotoxicity (delayed ossification) in rats. No fetal malformation was demonstrated in teratogenicity studies in mice, rats and rabbits, at oral doses of timolol up to 4 200 times the daily dose of brimonidine / timolol in humans.

2 years

After first opening: use within 28 days

To be stored at a temperature not exceeding 25 °C.

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

 

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400930140970 (Fl/5ml).

Price:

5,54 euros (Fl/5ml).

Social security reimbursement at 65% under the indications:

• Indication(s) appearing in the marketing authorisation at the date of publication of this decree

Collection.