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

Eye drops in solution.

Clear, colourless solution with a pH between 5,5 and 6,5 and an osmolality between 270 and 330 mOsmol/kg.

• The active substances are:

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

Timolol..................................................................................................................................................5,00 mg

As timolol maleate....................................................................................................6,80 mg

For 1 mL of eye drops in solution

Excipients with known effect : each mL of solution contains 0,2 mg of benzalkonium chloride and 6,3 mg of phosphate.

Excipients:

Reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or 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).

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).

In case of concomitant use of several topical ophthalmic products, 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.

Paediatric population

In children and adolescents, efficacy and tolerability have not been established.

LATANOPROST/TIMOLOL ARROW is contraindicated in patients with:

 

• conditions associated with bronchial hyperreactivity, in particular bronchial asthma or a history of bronchial asthma, and severe chronic obstructive pulmonary disease;

• sinus bradycardia, sinus disease, sinoatrial block, second- or third-degree atrioventricular block not controlled by a pacemaker, confirmed heart failure, cardiogenic shock;

• hypersensitivity to the active substances or to any of the excipients of the medicinal product listed in section Composition.

Systemic effects

As with any topically applied ophthalmic agent, LATANOPROST/TIMOLOL ARROW may be absorbed systemically. Due to the presence of timolol, a beta-adrenergic component, cardiovascular, pulmonary 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 with cardiovascular diseases (coronary artery disease, Prinzmetal's angina and heart failure) and hypotension, treatment with beta-blockers should be carefully evaluated and treatment with other medicinal products should be considered. In patients with cardiovascular diseases, monitoring should be performed to look for signs of worsening of these conditions or adverse reactions.

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

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

Vascular disorders

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

Respiratory disorders

In asthmatic patients, respiratory manifestations, including death due to bronchospasm, have been reported following administration of some ophthalmic beta-blockers. LATANOPROST/TIMOLOL ARROW should 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-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 dry eye. 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 potentiated when latanoprost/timolol is administered to patients already receiving a systemic beta-blocker. The response of these patients should be closely monitored. The concomitant use of two beta-adrenergic blocking agents is not recommended (see section Interactions).

Anaphylactic reactions

Patients treated with beta-blockers who have a history of atopy or of severe anaphylactic reaction to various allergens may be more reactive to repeated challenge with such allergens and may not respond to the usual doses of adrenaline used to treat anaphylactic reactions.

Concomitant treatment

Interactions of timolol with other medicinal products have been described (see section Interactions).

Other prostaglandin analogues

The concomitant use of two or more prostaglandins, prostaglandin analogues or prostaglandin derivatives is not recommended (see section Interactions).

Choroidal detachment

Cases of choroidal detachment have been reported with administration of aqueous humour-suppressing therapy (e.g., timolol, acetazolamide) following filtration surgery.

Surgical anesthesia

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

Ocular effects

Latanoprost may gradually change eye colour by increasing the amount of brown pigment in the iris. As with latanoprost eye drops, an increase in iris pigmentation was observed in 16 to 20% of patients treated for up to one year with latanoprost/timolol (based on photographs); particularly in patients with multicoloured irises: green-brown, yellow-brown or blue/grey-brown. It is due to an increase in the melanin content of melanocytes in the iris stroma. Generally, in affected eyes, the brown pigmentation surrounding the pupil spreads concentrically towards the periphery, and the iris may become partially or wholly browner. Clinical studies with latanoprost show that after two years of treatment, these colour changes were only rarely observed in patients with uniformly coloured eyes that were 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 the nevi nor the ephelides of the iris were affected by the treatment.

No accumulation of pigments in the trabecular meshwork or at other points of the anterior chamber has been observed. However, patients should be examined regularly and, depending on the patient's clinical context, treatment may be discontinued in the event 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.

Changes in eyelids and eyelashes

A darker coloration of the periocular skin, which may be reversible, has been reported in association with the use of latanoprost.

Latanoprost may gradually alter the eyelashes and vellus hair of the treated eye; these changes include an increase in length, thickness, pigmentation and number of eyelashes or hairs, and inadequate orientation of the eyelashes. Eyelash changes are reversible upon discontinuation of treatment.

Glaucoma

There is currently no documented experience regarding the efficacy of latanoprost in inflammatory, neovascular, chronic angle-closure or congenital glaucoma, in open-angle glaucoma in pseudophakic patients, 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 LATANOPROST/TIMOLOL ARROW be used with caution in these situations.

Herpetic keratitis

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

Macular oedema

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

LATANOPROST/TIMOLOL ARROW contains phosphates and benzalkonium chloride

This medicine contains 6,3 mg of phosphates and 0,2 mg of benzalkonium chloride per millilitre.

In patients with severe lesions of the clear layer at the front of the eye (the cornea), phosphates may, in very rare cases, cause cloudy spots on the cornea due to calcium accumulation during treatment.

Benzalkonium chloride is known to cause eye irritation and symptoms of dry eye, and may affect the tear film and the surface of the cornea. Therefore, it should be used with caution in patients with dry eye and those at risk of corneal damage.

Use of contact lenses

Benzalkonium chloride may be absorbed by soft contact lenses and change their colour. Contact lenses should be removed before instillation of LATANOPROST/TIMOLOL ARROW and may be reinserted 15 minutes after.

No specific drug interaction studies have been conducted with latanoprost/timolol.

Paradoxical elevations of 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.

The effect on intraocular pressure or the known effects of systemic beta-blockers may be potentiated when latanoprost/timolol 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) were used concomitantly.

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

The reactive hypertensive surge occurring upon 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).

A 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.

Fertility

Neither latanoprost nor timolol has been shown to have an impact on male or female fertility in animal studies.

Pregnancy

Latanoprost

There are no data on the use of latanoprost in pregnant women. In animals, studies have shown toxicity on reproductive functions (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 a beta-blocker effect (for example, bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the newborn when beta-blockers were administered up to delivery. If LATANOPROST/TIMOLOL ARROW is administered up to delivery, the newborn should be monitored carefully during the first days of life.

Therefore, LATANOPROST/TIMOLOL ARROW must 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 will be sufficient to produce clinical symptoms of beta-blockers in the infant. To reduce systemic absorption, refer to section Dosage and administration.

Latanoprost and its metabolites may pass into breast milk. Therefore, LATANOPROST/TIMOLOL ARROW must not be used in breastfeeding women.

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 ocular system. During the extension phase of the latanoprost/timolol pivotal studies, 16 to 20 % of patients developed an increase in iris pigmentation, which may be permanent. In an open-label clinical trial studying the tolerability of latanoprost over 5 years, 33 % of patients developed an increase in 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 lead to adverse reactions similar to those seen with systemic beta-blockers. The incidence of systemic adverse reactions after topical ophthalmic administration is lower compared with systemic administration. Expected adverse reactions include those seen with the class of ophthalmic beta-blockers.

Treatment-related adverse reactions observed in clinical trials with latanoprost and timolol are listed below.

Adverse reactions are classified according to their frequency of occurrence, as follows:

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)

Nervous system disorders:

Uncommon:  headache.

Eye disorders:

Very common: increased iris pigmentation.

Frequent :  ocular irritation (notably tingling, burning sensation, itching and foreign body sensation), ocular pain.

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

Skin and subcutaneous tissue disorders:

Uncommon:  skin rash, pruritus.

Other adverse effects related to the use of either of the two components of the medicinal product have been reported in clinical studies, spontaneous notifications or from the literature.

For latanoprost :

Infections and infestations:

Herpetic keratitis.

Nervous system disorders:

Dizziness.

Eye disorders:

Changes in eyelashes and vellus hair (increase in length, thickness, pigmentation and number of eyelashes); punctate epithelial erosions; periorbital oedema; iritis/uveitis; macular oedema, including cystoid macular oedema (in aphakic or pseudophakic patients with posterior capsule rupture of the lens or in patients with known risk factors for macular oedema); dry eye; keratitis; corneal oedema and corneal erosion; misdirected eyelashes sometimes causing ocular irritation; iris cyst; photophobia; periorbital and eyelid changes following deepening of the eyelid sulcus; eyelid oedema; localised skin reaction at the eyelids; pseudopemphigoid of the ocular conjunctiva (potentially attributable to the preservative, benzalkonium chloride); darkening of eyelid skin.

Cardiac disorders:

Angina, unstable angina, 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:

Arthralgia, myalgia.

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:

Depression, memory loss, insomnia, nightmares, hallucinations

Nervous system disorders:

Dizziness, paraesthesia, headache, cerebral ischaemia, cerebrovascular accident, increased signs and symptoms of myasthenia gravis, syncope.

Eye disorders:

Signs and symptoms of ocular irritation (for example, burning, stinging, itching, tearing, redness), blepharitis, keratitis, reduced corneal sensitivity, dry eye, visual disturbances including refractive changes (due to withdrawal of miotic treatment in some cases), corneal erosion, diplopia, ptosis, blurred vision and choroidal detachment following filtration surgery (see section Warnings and precautions).

Ear and labyrinth disorders:

Tinnitus.

Cardiac disorders:

Palpitations, arrhythmia, bradycardia, cardiac arrest, heart failure, atrioventricular block, congestive heart failure, chest pain, oedema.

Vascular disorders:

Hypotension, Raynaud's syndrome, cold extremities.

Respiratory, thoracic and mediastinal disorders:

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

Gastrointestinal disorders:

Dysgeusia, nausea, diarrhoea, dyspepsia, 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 organs and breast:

Sexual dysfunction, decreased libido.

General disorders and administration site conditions:

Asthenia/fatigue.

Cases of corneal calcification have been very rarely reported with the use of phosphate-containing eye drops in patients with significant corneal damage.

Reporting of suspected adverse reactions

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

There is no clinical experience of overdose with latanoprost/timolol in humans.

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

In case of latanoprost overdose, apart from ocular irritation and conjunctival hyperaemia, no other ocular or systemic adverse effects have been reported.

In case 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 hepatic metabolism. 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 and moderate and disappeared without treatment within 4 hours after the end of the infusion.

Pharmacotherapeutic class: ophthalmological drugs - beta-blocking agents - timolol, combinations, ATC code: S01ED51.

Mechanism of action

LATANOPROST/TIMOLOL ARROW 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 an additional reduction in 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 aqueous humour outflow. The main mechanism of action is increased outflow via the uveoscleral pathway. In addition, an increase in outflow facility (decrease in outflow resistance 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 lens surgery, no damage to retinal blood vessels was detected by fluorescein angiography. Short-term treatment with latanoprost did not induce fluorescein leakage in the posterior segment of the eye of 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 proven 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 of six months' duration, 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), additional reductions in mean diurnal intraocular pressure of 3,1; 2,0 and 0,6 mmHg were observed after 6 months of treatment with latanoprost and timolol (twice daily), respectively. The intraocular pressure-lowering effect of latanoprost/timolol 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 must be kept in mind that in case of insufficient efficacy with the fixed combination, study results show that the use of the non-fixed combination of timolol twice daily and latanoprost 1 times daily may still be effective.

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

Latanoprost

Latanoprost is an isopropyl ester prodrug, inactive in itself, which becomes biologically active after hydrolysis by corneal esterases into latanoprost acid. The prodrug is well absorbed by the cornea and all of the substance penetrating into the aqueous humour is hydrolysed during 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 about 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 about 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 has been observed, despite a concentration of latanoprost acid in the aqueous humour 1-4 hours after administration of latanoprost/timolol that is 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 carried out 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, abortions and a decrease in foetal weight in rabbits at intravenous doses greater than or equal to 5 micrograms/kg/day (approximately 100 times the clinical 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 have shown that precipitation occurs when eye drops containing thiomersal are mixed with latanoprost/timolol. In case of concomitant use of these medicinal products and latanoprost/timolol, the eye drops should be administered at least 5 minutes apart.

3 years.

After first opening of the bottle: the medicinal product must be used within 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 first opening of the bottle, see section Shelf life.

No special precautions.

List I

Marketing authorisation (AMM)

CIP 3400922316208 (Bottle/2,5 ml). CIP 3400922316376 (3 Bottles/2,5 ml).

Price:

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

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