BIMATOPROST/TIMOLOL ZENTIVA 0,3 mg/5 mg par ml Collyre sol Fl/3ml

Eye drops in solution.

Solution practically clear, practically free of particles.

Colourless to slightly yellow solution.

The pH of the solution is 6,5 to 7,8, the osmolality is 260 to 320 mOsmol/kg.

Bimatoprost...................................................................................................................................................0,3 mg

Timolol...............................................................................................................................................................5 mg

As timolol maleate.............................................................................................................6,8 mg

Per mL of solution

Excipients with known effect :

Each mL of solution contains 0,05 mg of benzalkonium chloride.

Each mL of solution contains 0,95 mg of phosphates.

For the full list of excipients, see section Composition.

Excipients:

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

Dosage

Recommended posology in adults (including elderly subjects)

The recommended dose is one drop of BIMATOPROST/TIMOLOL ZENTIVA in the affected eye or eyes once a day, either in the morning or in the evening. It should be administered each day at the same time.

Literature data on bimatoprost/timolol suggest that evening administration may be more effective than morning administration in lowering IOP. However, the choice of administering bimatoprost/timolol in the morning or in the evening should be based on the best potential for compliance (see section Pharmacodynamics).

If a dose is missed, the next dose should be administered as scheduled. The posology must not exceed one drop per day in the affected eye or eyes.

Renal or hepatic impairment

Bimatoprost/timolol has not been studied in patients with hepatic impairment or renal impairment. Therefore, it should be used with caution in these patients.

Paediatric population

The safety and efficacy of bimatoprost/timolol in children aged 0 to 18 years have not been established. No data are available.

Method of administration

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

Performing nasolacrimal occlusion or closing the eyelids for 2 minutes reduces systemic absorption. This practice aims to minimise systemic side effects and promote the local action of the eye drops.

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

• Bronchial hyperreactivity, including bronchial asthma or history of bronchial asthma, and severe chronic obstructive pulmonary disease.

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

As with other topical ophthalmic medicinal products, the active substances (timolol/bimatoprost) contained in BIMATOPROST/TIMOLOL ZENTIVA can pass into the systemic circulation. No increase in the systemic absorption of each active substance has been observed. Due to the presence of a beta-adrenergic component, timolol, cardiovascular, pulmonary and other adverse reactions, similar to those reported with systemic beta-blockers, may occur. Systemic adverse reactions after topical ophthalmic administration are lower than after systemic administration. To reduce systemic absorption, see section Dosage and administration.

Cardiac disorders

Patients with cardiovascular disease (for example, coronary artery disease, Prinzmetal's angina or heart failure) and treated with beta-blockers for hypotension should be thoroughly evaluated, and treatment with 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.

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.

BIMATOPROST/TIMOLOL ZENTIVA 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.

Endocrine disorders

Beta-adrenergic inhibitors should 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.

Beta-blockers may also mask the signs of hyperthyroidism.

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 the usual doses of adrenaline used to treat anaphylactic reactions.

Choroidal detachment

Choroidal detachment has been reported after administration of aqueous humour-suppressing therapy (for example, timolol, acetazolamide) following filtration 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.

Hepatic

In patients who, before treatment, had a history of moderate liver disease or abnormal levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin, no adverse effect on liver function has been reported during 24 months of treatment with bimatoprost. Ocular timolol is not associated with any known adverse effect on liver function.

Ocular

Before starting treatment, patients should be informed of the possibility of eyelash growth, darkening of the eyelid skin or periocular skin, and increased brown pigmentation of the iris, as observed in studies in patients treated with bimatoprost and bimatoprost/timolol. The increase in iris pigmentation is likely to be permanent. It may result in differences in appearance between the eyes if only one eye is treated. The change in iris pigmentation may be permanent after discontinuation of bimatoprost/timolol treatment. After 12 months of treatment with bimatoprost/timolol, the incidence of change in iris pigmentation was 0,2 %. After 12 months of treatment with an eye drop containing bimatoprost alone, the incidence was 1,5 % and did not increase during the 3 years of treatment. The pigmentation change is due to increased melanin content in melanocytes rather than an increase in the number of melanocytes. The long-term effects of increased iris pigmentation are not known. Iris colour changes observed with ophthalmic administration of bimatoprost may go unnoticed for several months or years. Neither iris naevi nor iris freckles appear to be affected by treatment. In some patients, periorbital tissue pigmentation has been reported to be reversible.

Cases of macular edema, including cases of cystoid macular edema, have been reported with bimatoprost/timolol. Therefore, BIMATOPROST/TIMOLOL ZENTIVA should be used with caution in aphakic patients, in pseudophakic patients with posterior capsule rupture, and in patients with known risk factors for macular edema (for example, intraocular surgery, retinal vein occlusions, inflammatory eye disease, and diabetic retinopathy).

BIMATOPROST/TIMOLOL ZENTIVA should be used with caution in patients with active intraocular inflammation (for example, uveitis) as the inflammation may be exacerbated.

Skin

Eyelash growth may be increased in areas where the solution of BIMATOPROST/TIMOLOL ZENTIVA repeatedly contacts the skin surface. It is therefore important to apply BIMATOPROST/TIMOLOL ZENTIVA according to the instructions and to avoid run-off onto the cheek or other skin areas.

Excipients

Benzalkonium chloride

This medicine contains 0,15 mg of benzalkonium chloride in 3 mL of solution, which is equivalent to 0,05 mg/mL.

Benzalkonium chloride is known to cause eye irritation, symptoms of dry eye syndrome, and may affect the tear film and corneal surface. Should be used with caution in patients with dry eye and those at risk of corneal damage. Patients should be monitored during prolonged use.

Benzalkonium chloride may be absorbed by soft contact lenses and change their colour. Remove contact lenses before application and wait at least 15 minutes before reinserting them.

Phosphates

This medicine contains 2,85 mg of phosphates in 3 mL of solution, which is equivalent to 0,95 mg/mL.

Other conditions

Bimatoprost/timolol has not been studied in patients with inflammatory eye, neovascular, inflammatory, narrow-angle, or angle-closure or congenital glaucoma.

Studies with bimatoprost 0,3 mg/mL in patients with glaucoma or ocular hypertension have shown that administration of more than one daily dose of bimatoprost into the eye may result in a smaller decrease in IOP. Patients using BIMATOPROST/TIMOLOL ZENTIVA with other prostaglandin analogues should be monitored for changes in intraocular pressure.

No specific interaction study has been performed with the bimatoprost/timolol fixed combination.

Additive effects resulting in hypotension and/or marked bradycardia may occur when an ophthalmic solution containing beta-blockers is administered in combination with oral calcium channel blockers, guanethidine, adrenergic beta-blockers, parasympathomimetics, antiarrhythmics (including amiodarone) and digitalis glucosides.

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

Mydriasis due to concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has occasionally been reported.

Pregnancy

There are no relevant data on the use of the fixed combination bimatoprost/timolol in pregnant women. BIMATOPROST/TIMOLOL ZENTIVA should not be used during pregnancy unless clearly necessary. To reduce systemic absorption, see section Dosage and administration.

Bimatoprost

There are no relevant clinical data on use in pregnant women. Animal studies have shown reproductive toxicity at high, maternotoxic doses (see section Preclinical safety).

Timolol

Epidemiological studies have not shown evidence of foetal malformation, but have shown a risk of intra-uterine growth retardation following exposure to oral beta-blockers. In addition, signs and symptoms of beta-blockade (for example, bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the newborn when beta-blockers were administered until delivery. If BIMATOPROST/TIMOLOL ZENTIVA is administered until delivery, the newborn should be closely monitored during the first days of life.

Studies performed with timolol in animals have shown reproductive toxic effects at systemic exposure levels significantly higher than those used in clinical practice (see section Preclinical safety).

Breast-feeding

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.

Bimatoprost

The passage of bimatoprost into human milk is not known, but bimatoprost is excreted in the milk of lactating rats. It is therefore recommended that BIMATOPROST/TIMOLOL ZENTIVA not be used in breast-feeding women.

Fertility

There are no data on the effects of bimatoprost/timolol on human fertility.

Bimatoprost/timolol has negligible influence on the ability to drive and use machines. As with any ophthalmic treatment, if transient blurred vision occurs after instillation, the patient should wait until vision is clear before driving or using machines.

Summary of the safety profile

The adverse effects observed in clinical studies using bimatoprost/timolol were limited to those previously reported for each of the active substances, bimatoprost and timolol, taken separately. No other adverse effects specific to bimatoprost/timolol were observed in clinical studies.

Most adverse reactions reported in clinical studies using bimatoprost/timolol were ocular and mild in intensity, and none were classified as serious. Based on clinical data obtained over 12 months, the most frequently reported adverse reaction was conjunctival hyperaemia (generally very slight to mild and considered non-inflammatory), which occurred in approximately 26% of patients and led to discontinuation of treatment in 1,5% of patients.

Tabulated list of adverse reactions

Table 1 presents the adverse reactions that have been reported with all presentations of bimatoprost/timolol (multidose bottle and single-dose container) during clinical studies (within each frequency category, adverse reactions are presented in decreasing order of seriousness) or after marketing.

The frequency of possible adverse effects presented below is defined using the following convention:

Very common	≥ 1/10
Common	≥ 1/100, < 1/10
Uncommon	≥ 1/1 000, < 1/100
Rare	≥ 1/10 000, < 1/1 000
Very rare	< 1/10 000
Frequency not known	Cannot be estimated from the available data

Table 1

System organ class	Frequency	Adverse reaction
Immune system disorders	Frequency not known	Hypersensitivity reactions including signs or symptoms of allergic dermatitis, angioedema, ocular allergy
Psychiatric disorders	Frequency not known	Insomnia2, nightmares2
Nervous system disorders	Common	Headache
	Frequency not known	Dysgeusia2, dizziness
Eye disorders	Very common	Conjunctival hyperaemia
	Common	Punctate keratitis, corneal erosion2, burning sensation2, conjunctival irritation1, ocular pruritus, stinging sensation in the eye2, foreign body sensation, dry eye, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbances2, eyelid pruritus, decreased visual acuity2, blepharitis2, eyelid oedema, ocular irritation, increased lacrimal secretion, eyelash growth.
	Uncommon	Iritis2, conjunctival oedema2, eyelid pain2, abnormal sensation in the eye1, asthenopia, trichiasis2, iris hyperpigmentation2, periorbital and eyelid changes associated with periorbital fat atrophy and skin tension resulting in deepening of the eyelid sulcus, blepharoptosis, enophthalmos, lagophthalmos and eyelid retraction1,2, alteration of eyelash colour (darkening)1
	Frequency not known	Cystoid macular oedema2, eye swelling, blurred vision2, ocular discomfort
Cardiac disorders	Frequency not known	Bradycardia
Vascular disorders	Frequency not known	Hypertension
Respiratory, thoracic and mediastinal disorders	Common	Rhinitis2
	Uncommon	Dyspnoea
	Frequency not known	Bronchospasm (especially in patients with pre-existing bronchospastic disease)2, asthma
Skin and subcutaneous tissue disorders	Common	Eyelid pigmentation2, hirsutism2, cutaneous (periocular) hyperpigmentation
	Frequency not known	Alopecia, skin discolouration (periocular)
General disorders and administration site conditions	Frequency not known	Fatigue

1 Adverse reactions observed only with bimatoprost/timolol in single-dose container.

2 Adverse reactions observed only with bimatoprost/timolol in multi-dose bottle.

As with other topical ophthalmic products, bimatoprost/timolol is absorbed into the systemic circulation. Absorption of timolol may cause adverse reactions similar to those observed 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.

Other adverse reactions that have been reported with either of the two active substances (bimatoprost or timolol), and therefore may be observed with this medicinal product, are listed below in table 2:

Table 2

System organ class	Adverse reaction
Immune system disorders	Systemic allergic reactions including anaphylaxis1
Metabolism and nutrition disorders	Hypoglycaemia1
Psychiatric disorders	Depression1, memory loss1, hallucination1
Nervous system disorders	Syncope1, cerebrovascular accident1, worsening of signs and symptoms of myasthenia gravis1, paraesthesia1, cerebral ischaemia1
Eye disorders	Decreased corneal sensitivity1, diplopia1, ptosis1, choroidal detachment after filtering surgery (see section Warnings and precautions)1, keratitis1, blepharospasm2, retinal haemorrhage2, uveitis2
Cardiac disorders	Atrioventricular block1, cardiac arrest1, arrhythmias1, heart failure1, congestive heart failure1, chest pain1, palpitations1, edema1
Vascular disorders	Hypotension1, Raynaud's phenomenon1, coldness of hands and feet1
Respiratory, thoracic and mediastinal disorders	Asthma exacerbation2, COPD exacerbation2, cough1
Gastrointestinal disorders	Nausea1,2, diarrhoea1, dyspepsia1, dry mouth1, abdominal pain1, vomiting1
Skin and subcutaneous tissue disorders	Psoriasiform rash1 or worsening of psoriasis1, skin rash1
Musculoskeletal and systemic disorders	Myalgia1
Disorders of the reproductive system and breast	Sexual dysfunction1, decreased libido1
General disorders and administration site conditions	Asthenia1,2
Investigations	Abnormal liver function tests2

1 Adverse effects observed with timolol.

2 Adverse effects observed with bimatoprost.

Adverse effects reported with eye drops containing phosphate

Very rarely, cases of corneal calcification have been reported with the use of phosphate-containing eye drops in some patients with significant corneal damage.

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 reactions via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/.

A topical overdose of BIMATOPROST/TIMOLOL ZENTIVA is unlikely to occur or to be associated with toxicity.

Bimatoprost

If BIMATOPROST/TIMOLOL ZENTIVA is accidentally ingested, the following information may be useful: in two-week oral studies in rats and mice, doses up to 100 mg/kg/day caused no toxicity. This dose, expressed in mg/m2, is at least 70 times greater than the dose corresponding to accidental ingestion of one bottle of bimatoprost/timolol by a child weighing 10 kg.

Timolol

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

In case of overdose, symptomatic and supportive treatment should be instituted.

Pharmacotherapeutic class: Ophthalmological drugs, Beta-blockers, ATC code: S01ED51.

Mechanism of action

BIMATOPROST/TIMOLOL ZENTIVA contains two active substances: bimatoprost and timolol. These two components lower elevated intraocular pressure (IOP) through complementary mechanisms of action, and their combined effect produces an additional reduction in IOP compared with that induced by either compound alone in monotherapy. Bimatoprost/timolol has a rapid onset of action.

Bimatoprost is a potent ocular hypotensive active substance. It is a synthetic prostamide, structurally related to prostaglandin F2α (PGF2α) that does not act through known prostaglandin receptors. Bimatoprost selectively mimics the effects of newly discovered biosynthetic substances called prostamides. However, the structure of prostamide receptors has not yet been identified. Bimatoprost reduces intraocular pressure in humans by increasing aqueous humour outflow through the trabecular meshwork and by improving uveoscleral outflow.

Timolol is a non-selective beta1- and beta2-adrenergic agent that has no significant intrinsic sympathomimetic activity, no direct depressant action on the myocardium and no local anaesthetic effect (membrane-stabilising activity). Timolol lowers IOP by reducing aqueous humour formation. Its exact 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 effects

The reduction in IOP produced by bimatoprost/timolol is not inferior to that observed with a treatment combining bimatoprost (once daily) and timolol (twice daily).

Literature data on bimatoprost/timolol suggest that evening administration may be more effective than morning administration in lowering IOP. However, the choice of administering bimatoprost/timolol in the morning or evening should be based on the best potential for adherence.

Paediatric population

The safety and efficacy of bimatoprost/timolol in children aged 0 to 18 years have not been established.

Bimatoprost/timolol medicinal product

Plasma concentrations of bimatoprost and timolol were measured in a crossover study comparing the effects of these two monotherapies with those of bimatoprost/timolol in healthy subjects. Systemic absorption of each active substance was minimal; it was not affected by co-administration in a single formulation.

No accumulation of either active substance was demonstrated during the two 12-month studies in which systemic absorption was measured.

Bimatoprost

Bimatoprost penetrates well into the human cornea and sclera in vitro. After ocular administration, systemic exposure to bimatoprost is very low. No accumulation is observed over time. After repeated administration for two weeks of one drop per day of bimatoprost 0,03% in both eyes, the plasma peak is reached 10 minutes after instillation. Circulating plasma concentrations fall below the limit of detection (0,025 ng/mL) after approximately 1 hour 30 after instillation. The mean values of the Cmax and of ASC0-24 h (area under the curve) were comparable to those on day 7e day and to day 14e day (approximately 0,08 ng/mL and 0,09 ng•h/mL), indicating that a steady drug concentration is reached during the first week of treatment.

Bimatoprost is moderately distributed in body tissues, and the systemic volume of distribution is 0,67 L/kg at steady state in humans. In blood, bimatoprost is found mainly in plasma in a form bound to plasma proteins (approximately 88%).

Unchanged bimatoprost is the predominant entity in systemic circulation after ocular administration. Bimatoprost undergoes oxidative metabolism (N-deethylation and glucuronidation) leading to the formation of various metabolites.

Bimatoprost is mainly eliminated by renal excretion. In healthy volunteers, up to 67% of an intravenously administered dose is eliminated in urine and 25% is excreted in faeces. The elimination half-life determined after intravenous administration is approximately 45 minutes; the total blood clearance is 1,5 L/h/kg.

Characteristics in elderly subjects

With administration at a rate of two instillations per day, the systemic exposure to bimatoprost observed in elderly patients (subjects aged 65 years or older) (AUC0-24 h : 0,0634 ng•h/mL) is clearly higher than that observed in young adults (AUC0-24 h : 0,0218 ng•h/mL). However, due to the low systemic passage by the ocular route, this systemic exposure to bimatoprost remains low and of no clinical relevance, both in elderly and young subjects. Given the absence of accumulation of bimatoprost in the blood, the safety profile would be comparable in elderly and young patients.

Timolol

The peak timolol concentration reaches 898 ng/mL in the aqueous humour one hour after ocular administration of a 0,5% solution eye drops in subjects undergoing surgical treatment of cataract. A portion of the dose enters the systemic circulation and undergoes significant hepatic metabolism. The plasma half-life of timolol is approximately 4 to 6 hours. Timolol is partially metabolised in the liver and excreted with its metabolites by the kidneys. The degree of binding of timolol to plasma proteins is low.

Bimatoprost/timolol medicinal product

Repeated-dose ocular toxicity studies of bimatoprost/timolol did not reveal any particular risk for humans. The ocular and systemic safety profile of each active substance is well established.

Bimatoprost

Non-clinical data from conventional safety pharmacology, genotoxicity and carcinogenicity studies did not reveal any particular risk for humans. In rodent studies, species-specific abortions were observed at systemic exposure levels 33 to 97 times higher than those achieved in humans after ocular instillation.

In monkeys, daily ocular administration of bimatoprost at concentrations ≥ 0,03% for one year resulted in increased iris pigmentation and reversible, dose-dependent periocular changes characterised by prominence of the upper and/or lower fornices and widening of the palpebral fissure. The process of increased iris pigmentation appears to be due to increased stimulation of melanin production in melanocytes rather than an increase in the number of melanocytes. No functional or microscopic changes related to these periocular effects were observed. The mechanism underlying these periocular effects is unknown.

Timolol

Non-clinical data from conventional safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive function studies did not reveal any particular risk for humans.

3 years

4 weeks after first opening.

This medicine does not require any particular storage precautions.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400930216996 (Fl/3ml).

Price:

6,62 euros (Fl/3ml).

Reimbursed by Social Security at 65% based on the TFR: 6.62 euros (Fl/3ml) in the indications:

• Ocular hypertension, second-line treatment (of)
• Chronic open-angle glaucoma, second-line treatment (of the)

Collection.