LATANOPROST/TIMOLOL EG 50 µg/5 mg per ml Eye drops solution 3Bottle/2,5ml

Eye drops in solution.

Clear, colourless solution, free from any visible particles, with a pH between 5,5 and 6,5 and an osmolality between 270 and 330 mOsmol/kg.

Timolol maleate....................................................................................................................................... 6,8 mg

Equivalent to 5 mg of timolol

Latanoprost................................................................................................................................50 micrograms

For 1 ml of solution

Excipient with known effect: benzalkonium chloride 200 micrograms/ml.

Excipients:

Reduction of intraocular pressure (IOP) in patients with open-angle glaucoma and ocular hypertension who show an insufficient response to topically administered beta-blockers or prostaglandin analogues.

Posology in adults (including the elderly)

The recommended dose is one drop in the affected eye(s) once daily.

If a dose is missed, treatment should continue as normal with the next instillation. The dose should not exceed one drop per day in the affected eye(s).

Paediatric population

The safety and efficacy in children and adolescents have not been established.

Method of administration

Contact lenses must be removed before instillation of the eye drops and may be reinserted 15 minutes after (see section Warnings and precautions).

When several topical ophthalmic products are used concomitantly, the instillations of the different products must be separated by at least five minutes.

Nasolacrimal occlusion or closure of the eyelids for 2 minutes reduces systemic absorption. This results in a reduction of systemic adverse effects and an increase in local activity.

The latanoprost/timolol combination is contraindicated in patients with:

• Conditions associated with bronchial hyperreactivity, including asthma or a history of asthma, and severe chronic obstructive pulmonary disease.

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

• Hypersensitivity to one of the active substances or to one of the excipients of the medicinal product.

Systemic effects

As with any topically applied ophthalmic agent, the latanoprost/timolol combination is absorbed systemically. Due to the presence of timolol, a beta-adrenergic component, cardiovascular and pulmonary adverse reactions and other adverse reactions similar to those seen with systemically administered beta-adrenergic blocking agents may 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

In patients suffering from cardiovascular diseases (coronary artery disease, Prinzmetal's angina, heart failure) and hypotension, treatment with beta-blockers must be carefully evaluated and treatment with other active substances must be considered. In these patients, monitoring must be carried out in order to look for signs of worsening of these conditions or adverse effects.

Due to their negative dromotropic effect, beta-blockers should only be prescribed with caution to patients with first-degree heart block.

After administration of timolol, cardiac effects and, rarely, deaths in association with heart failure have been reported.

Vascular disorders

Patients suffering from severe disorders of peripheral circulation (i.e. the severe form of the disease or Raynaud's syndrome) should be treated with caution.

Respiratory disorders

In asthmatic patients, respiratory manifestations that may go as far as death due to bronchospasm have been reported following administration of certain ophthalmic beta-blockers. The latanoprost/timolol combination must be administered with caution in patients suffering from moderate to severe chronic obstructive pulmonary disease (COPD) and only if the potential benefit appears greater than the potential risk.

Hypoglycaemia/Diabetes

Beta-blockers should be administered with caution in patients prone to spontaneous hypoglycaemia or in patients with unstable diabetes, as beta-blockers may mask the signs 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-blockers may be increased when timolol is administered to patients already receiving a systemic beta-blocker. The response of these patients must be closely monitored. The concomitant use of two locally administered beta-adrenergic blocking agents is not recommended (see section Interactions).

Anaphylactic reactions

Patients treated with beta-blockers who have a history of atopy or severe anaphylactic reaction to various allergens may be more reactive to repeated administrations 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 after glaucoma filtration surgery during administration of treatments that reduce aqueous humour secretion (e.g., timolol, acetazolamide).

Surgical anesthesia

Beta-blockers used in ophthalmology may block the effects of systemic beta-agonists such as adrenaline. The anesthetist should be informed when the patient is receiving timolol.

Concomitant treatment

Interactions of timolol with other medicinal products may occur (see section Interactions).

The concomitant use of two locally administered beta-blockers or two prostaglandins is not recommended (see section Interactions).

Ocular effects

Latanoprost may gradually change eye colour by increasing the amount of brown pigment in the iris. This pigmentation was also observed (with photographic control) in 16 to 20 % of patients treated for one year with the latanoprost + timolol combination; in particular in patients with multi-coloured irises: green-brown, yellow-brown or blue/grey-brown. It is due to an increase in the melanin content of the melanocytes of the iris stroma. Generally, in the affected eyes, the brown pigmentation surrounding the pupil spreads concentrically towards the periphery, and the iris may become partially or totally browner. Clinical studies show that after two years of treatment, these colour changes have only rarely been observed in patients with uniformly coloured eyes, blue, grey, green or brown.

Changes in iris colour develop slowly and may go unnoticed for months or even years. This effect has not been associated with any symptoms or pathological changes.

After treatment discontinuation, no further progression of brown iris pigmentation was observed, but the colour change may be permanent.

Neither iris naevi nor ephelides were affected by treatment.

No accumulation of pigment in the trabecular meshwork or at other points in the anterior chamber was observed. However, patients should be examined regularly and, depending on the clinical context of the patient, treatment may be discontinued in case of increased iris pigmentation.

Before starting treatment, patients should be informed of the risk of eye colour change. Unilateral treatment may result in permanent heterochromia.

There is currently no documented experience regarding the efficacy of latanoprost in inflammatory, neovascular, chronic angle-closure or congenital glaucoma, in aphakic open-angle glaucoma, or in pigmentary glaucoma.

Latanoprost has little or no effect on the pupil. However, there is currently no documented experience in acute angle-closure glaucoma attacks. Therefore, in the absence of additional data, it is recommended that the latanoprost/timolol combination be used with caution in these situations.

Latanoprost should be used with caution in patients with a history of herpetic keratitis and its use should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.

Cases of macular edema, including cystoid macular edema, have been reported during treatment with latanoprost. These occurred mainly in aphakic or pseudophakic patients with a posterior capsule rupture, or in patients with known risk factors for macular edema. Therefore, the latanoprost/timolol combination should be used with caution in these patients.

Use of contact lenses

The latanoprost/timolol combination contains benzalkonium chloride, commonly used as a preservative in ophthalmic products. Benzalkonium chloride has been reported to cause superficial punctate keratopathy and/or toxic ulcerative keratopathy as well as eye irritation, and is known to discolour soft contact lenses.

Close monitoring is required during frequent or prolonged use in patients with dry eye or corneal disorders. Benzalkonium chloride may be absorbed by contact lenses. Contact lenses should therefore be removed before application of the latanoprost/timolol combination but may be reinserted after 15 minutes (see section Dosage and administration).

No specific drug interaction studies have been carried out with the latanoprost/timolol combination.

Paradoxical increases in intraocular pressure have been reported following concomitant ophthalmic administration of two prostaglandin analogues. Therefore, the use of two or more prostaglandins, prostaglandin analogues, or prostaglandin derivatives is not recommended.

An additive effect, resulting in hypotension and/or bradycardia, may be observed when ophthalmic beta-blocker solution is administered concomitantly with calcium channel inhibitors, beta-adrenergic blocking agents, antiarrhythmics (notably amiodarone), digitalis glycosides, parasympathomimetics, and systemically administered guanethidine.

Potentiation of systemic beta-blocker effects (e.g., decreased heart rate, depression) has been reported when CYP2D6 inhibitor treatments (e.g., quinidine, fluoxetine, and paroxetine) are combined with timolol.

The effect on intraocular pressure or the known effects of systemic beta-blockers may be potentiated when the latanoprost/timolol combination is administered to patients already receiving an oral beta-blocker, and the use of two or more topical beta-blocking agents is not recommended.

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

The rebound hypertensive surge occurring on abrupt withdrawal of clonidine may be increased when beta-blockers are administered.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. They may mask the signs and symptoms of hypoglycaemia (see section Warnings and precautions).

Pregnancy

Latanoprost :

There are no data on the use of latanoprost in pregnant women.

In animals, studies have shown toxicity to reproductive function (see section Preclinical safety). The potential risk in humans is not known.

Timolol :

There are no adequate data on the use of timolol in pregnant women. Timolol should not be used during pregnancy unless clearly necessary. To reduce systemic absorption, see section Dosage and administration.

Epidemiological studies have not revealed a malformative effect but demonstrate a risk of intrauterine growth retardation when beta-blockers are administered orally. 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 up to delivery. If the latanoprost/timolol combination is administered up to delivery, the newborn should be closely monitored during the first days of life.

Therefore, the latanoprost/timolol combination should not be used during pregnancy (see section Preclinical safety).

Breast-feeding

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

Latanoprost and its metabolites may pass into breast milk.

Therefore, the latanoprost/timolol combination should not be used in women who are breastfeeding.

Fertility

In animals, studies have not shown effects of latanoprost or timolol on male or female fertility.

Transient visual disturbances may follow instillation of eye drops. Until these resolve, patients should not drive or use machines.

For latanoprost, the majority of adverse reactions relate to the eye. During the extension phase of the pivotal studies of the latanoprost/timolol combination, 16 to 20 % of patients developed increased iris pigmentation, which may be permanent. In an open-label clinical trial studying the tolerability of latanoprost over 5 years, 33 % of patients developed increased iris pigmentation (see section Warnings and precautions). Other ocular adverse reactions are generally transient and occur at the time of dose administration. For timolol, the most serious adverse reactions are of a systemic nature, including bradycardia, arrhythmia, congestive heart failure, bronchospasm and allergic reactions.

As with other topically applied ophthalmic medicinal products, timolol is absorbed into the systemic circulation. This may result in adverse reactions similar to those seen with systemic beta-blockers. The incidence of systemic adverse reactions after ophthalmic administration is lower compared with systemic administration. Expected adverse reactions include those observed with the class of ophthalmic beta-blockers.

Treatment-related adverse effects observed in clinical trials with the latanoprost/timolol combination are listed below.

Undesirable effects are classified according to their frequency of occurrence, as follows:

very common	(≥ 1/10)
frequent	(≥ 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)

Nervous system disorders :

Uncommon: headache.

Eye disorders :

Very common: increased pigmentation of the iris.

Common: eye irritation (including stinging, burning sensation and itching), eye pain.

Uncommon: ocular hyperaemia, conjunctivitis, blurred vision, increased lacrimal secretion, blepharitis, corneal disorder.

Skin and subcutaneous tissue disorders :

Uncommon: skin rash, pruritus.

Other undesirable effects related to the use of either component of the latanoprost/timolol combination have been reported in clinical studies, from spontaneous reports or from the literature.

For latanoprost:

Infections and infestations :

Herpetic keratitis.

Nervous system disorders :

Dizziness.

Eye disorders :

Changes in eyelashes and vellus hair of the eyelid (increased length, thickness, pigmentation and number), superficial punctate keratitis, periorbital oedema, iritis/uveitis, macular oedema (in aphakic or pseudophakic patients with posterior capsule rupture or in patients with known risk factors for macular oedema), dry eye, keratitis, corneal oedema and corneal ulceration, misdirected eyelashes sometimes causing eye irritation, iris cyst, photophobia, changes in the periorbital and eyelid area leading to deepening of the eyelid sulcus.

Cardiac disorders :

Worsening of angina pectoris in patients with pre-existing angina pathology, palpitations.

Respiratory, thoracic and mediastinal disorders :

Asthma, aggravation of asthma, dyspnoea.

Gastrointestinal disorders :

Uncommon: nausea, vomiting.

Skin and subcutaneous tissue disorders:

Darkening of the eyelids.

Musculoskeletal and systemic disorders :

Joint pain, muscle pain.

General disorders and administration site conditions :

Chest pain.

For timolol:

Immune system disorders :

Systemic allergic reactions including angioedema, urticaria, localised or generalised rash, pruritus, anaphylactic reaction.

Metabolism and nutrition disorders :

Hypoglycaemia.

Psychiatric disorders :

Insomnia, depression, nightmares, memory loss, hallucinations.

Nervous system disorders :

Syncope, cerebrovascular accident, cerebral ischaemia, increase in signs and symptoms of myasthenia gravis, dizziness, paraesthesia, headaches.

Eye disorders :

Signs and symptoms of eye irritation (for example: burning, stinging, itching, tearing, redness), blepharitis, keratitis, visual disturbances and choroidal detachment after filtering surgery (see section Warnings and precautions), decreased corneal sensitivity, dry eye, corneal erosion, ptosis, diplopia.

Ear and labyrinth disorders :

Tinnitus.

Cardiac disorders :

Bradycardia, chest pain, palpitations, oedema, arrhythmia, congestive heart failure, atrioventricular block, cardiac arrest, heart failure.

Vascular disorders :

Hypotension, Raynaud's syndrome, cold extremities (feet and hands).

Respiratory, thoracic and mediastinal disorders :

Bronchospasm (mainly in patients with pre-existing bronchospastic disease), dyspnoea, cough.

Gastrointestinal disorders :

Dysgeusia, nausea, dyspepsia, diarrhoea, dry mouth, abdominal pain, vomiting.

Skin and subcutaneous tissue disorders :

Alopecia, psoriasiform rash or exacerbation of psoriasis, skin rash.

Musculoskeletal and systemic disorders :

Myalgia.

Disorders of the reproductive system and breast :

Sexual dysfunction, decreased libido.

General disorders and administration site conditions :

Asthenia/fatigue.

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

There is no clinical experience of overdose with the latanoprost/timolol combination.

The symptoms of a systemic overdose of timolol are: bradycardia, hypotension, bronchospasm and cardiac arrest. If such symptoms occur, treatment should be symptomatic and supportive. Studies have shown that timolol is not easily dialysable.

Apart from ocular irritation and conjunctival hyperaemia, no other ocular or systemic adverse effects have been reported in cases of latanoprost overdose.

In the event of accidental ingestion of latanoprost, the following information may be useful: gastric lavage if necessary and symptomatic treatment.

Latanoprost is extensively metabolised during first pass through the liver. An intravenous infusion of 3 micrograms/kg in healthy volunteers caused no symptoms; however, a dose of 5,5-10 micrograms/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating. These effects were mild to moderate and disappeared without treatment within 4 hours after the end of the infusion.

Pharmacotherapeutic class: ophthalmic beta-blockers – timolol in combination, ATC code: S01ED51.

Mechanism of action

LATANOPROST/TIMOLOL EG 50 micrograms/5 mg per ml, eye drops in solution combines two components: latanoprost and timolol maleate. These two components reduce elevated intraocular pressure (IOP) through different mechanisms of action. The combined effect results in a further reduction of intraocular pressure compared with that obtained when each component is administered alone.

Latanoprost, a prostaglandin F analogue2alpha, is a selective FP prostanoid receptor agonist that lowers intraocular pressure by increasing the outflow of aqueous humour. The main mechanism of action is increased outflow via the uveoscleral pathway. In addition, an increase in outflow facility (decreased resistance to outflow via the trabecular pathway) has been noted in humans. Latanoprost has no significant effect on aqueous humour production, on the blood-aqueous barrier or on intraocular blood flow.

After chronic treatment with latanoprost in monkeys previously subjected to extracapsular cataract surgery, no damage to retinal blood vessels was demonstrated by fluorescein angiography. Short-term treatment with latanoprost did not induce fluorescein leakage into the posterior segment of the eye in pseudophakic patients.

Timolol is a non-selective beta-1 and beta-2 adrenergic receptor blocking agent, with no significant intrinsic sympathomimetic activity, no direct cardiac depressant effect and no membrane-stabilising effect. Timolol lowers intraocular pressure by reducing aqueous humour formation in the ciliary epithelium. The precise mechanism of action is not clearly established, but inhibition of the increase in cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is probable. It has not been shown that timolol significantly affects the permeability of the blood-aqueous barrier to plasma proteins. In rabbits, timolol had no effect on local ocular blood flow after chronic treatment.

Pharmacodynamic effects

Clinical effects

In dose-finding studies, the latanoprost/timolol combination produced a significantly greater reduction in mean diurnal intraocular pressure compared with latanoprost and timolol administered once daily as monotherapy. In two controlled, double-blind clinical studies lasting six months, the effect of the latanoprost/timolol combination on intraocular pressure was compared with that of latanoprost and timolol monotherapy, in patients with an intraocular pressure of at least 25 mmHg. After a period of 2 to 4 weeks of timolol treatment (resulting in a mean reduction in intraocular pressure of 5 mmHg compared with baseline), further reductions in mean diurnal intraocular pressure of 3,1; 2,0 and 0,6 mmHg were respectively observed after 6 months of treatment with the latanoprost/timolol combination (twice daily). The effect was maintained during the open-label extension phase of these studies up to 6 months.

Existing data suggest that evening administration may be more effective in lowering IOP than morning administration. However, when deciding between morning or evening administration, the patient's lifestyle and their ability to adhere to treatment should be given sufficient consideration.

It should be kept in mind that, in cases of insufficient efficacy with the fixed combination, study results show that the concomitant use of timolol twice daily and latanoprost 1 times daily may still be effective.

The effect of the latanoprost/timolol combination begins within one hour of administration, and a maximum effect is observed after 6 to 8 hours. With repeated administration, the reduction in intraocular pressure is maintained for up to 24 hours after instillation.

Latanoprost

Latanoprost is an inactive isopropyl ester prodrug which becomes biologically active after hydrolysis by corneal esterases to latanoprost acid. The prodrug is well absorbed through the cornea, and all of the substance entering the aqueous humour is hydrolysed during its passage through the cornea. Clinical studies in humans show that the maximum concentration in the aqueous humour, approximately 15-30 ng/ml, is reached about 2 hours after topical administration of latanoprost alone.

After topical administration in monkeys, latanoprost is distributed mainly to the anterior segment, the conjunctiva and the eyelids.

Latanoprost acid has a plasma clearance of 0,40 l/h/kg and a low volume of distribution of 0,16 l/kg, resulting in a short plasma half-life of 17 minutes. After ocular administration, the systemic bioavailability of latanoprost acid is 45 %. Latanoprost acid has a plasma protein binding of 87 %.

Latanoprost acid is practically not metabolised in the eye. Metabolism is mainly hepatic. Animal studies have shown little or no activity of the main metabolites, the 1, 2-dinor and the 1, 2, 3, 4-tetranor, which are mainly eliminated in the urine.

Timolol

The maximum concentration of timolol in the aqueous humour is reached approximately 1 hour after topical administration of the eye drops. Part of the dose is absorbed systemically and the maximum plasma concentration of 1 ng/ml is reached 10-20 minutes after daily topical administration of one drop in each eye (300 micrograms/day). The plasma half-life of timolol is approximately 6 hours. It is extensively metabolised in the liver. The metabolites are excreted in the urine together with unchanged timolol.

Latanoprost/Timolol

No pharmacokinetic interaction between latanoprost and timolol was observed, despite a concentration of latanoprost acid in the aqueous humour 1-4 hours after administration of the latanoprost/timolol combination that was twice that observed with monotherapy.

The ocular and systemic safety profile of each component is well established. No ocular or systemic adverse effects were observed in rabbits treated topically with the fixed combination or with simultaneous administration of latanoprost and timolol eye drops. Pharmacology, genotoxicity and carcinogenicity studies conducted with each of the components revealed no toxic effect in humans. Latanoprost does not reduce corneal healing in rabbits, whereas this process is inhibited in rabbits and monkeys treated more than once daily with timolol.

For latanoprost, no effect on fertility in male and female rats was observed. No teratogenic potential was detected in rats and rabbits. No embryotoxic effect was observed in rats after intravenous administration of doses up to 250 micrograms/kg/day. However, latanoprost induces embryo-foetal toxicity, characterised by an increased incidence of late resorptions and abortions, as well as a decrease in foetal weight in rabbits at intravenous doses greater than or equal to 5 micrograms/kg/day (approximately 100 times the therapeutic dose). Timolol has no effect on fertility in male or female rats. No teratogenic potential was observed in mice, rats and rabbits.

Studies in vitro showed precipitation when a collyrium containing thiomersal was mixed with the latanoprost/timolol combination. If such medicinal products are used concomitantly with the latanoprost/timolol combination, the drops must be administered with an interval of at least five minutes.

3 years.

After first opening of the bottle: the medicinal product must be stored for a maximum of 28 days at a temperature not exceeding 25°C.

Store in a refrigerator (between 2°C and 8°C).

For storage conditions after opening of the bottle, see section Shelf life.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400922316727 (Fl/2,5ml). CIP 3400922316895 (3Fl/2,5ml).

Price:

7,32 euros (Fl/2,5ml). 19,57 euros (3Fl/2,5ml).

Social security reimbursement at 65% based on the TFR: 7.32 euros (Bottle/2,5 ml), 19.57 euros (3 Bottles/2,5 ml).
Collection.