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

Eye drops in solution.

The solution is clear and colourless.

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

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

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

For 1 mL.

Excipients with a notable effect :

• Benzalkonium chloride 0,2 mg/mL,

• Disodium phosphate (E339ii),

• Sodium phosphate monobasic monohydrate (E339i) 6,39 mg/mL (containing a total of 6,3 mg/mL of phosphate).

Excipients:

LATANOPROST/TIMOLOL VIATRIS is indicated in adults (including elderly patients) for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers or prostaglandin analogues.

Dosage

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 of LATANOPROST/TIMOLOL VIATRIS have not been established in children and adolescents.

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.

LATANOPROST/TIMOLOL VIATRIS is contraindicated in patients presenting 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 listed in section Composition.

Systemic effects

As with any topically applied ophthalmic agent, LATANOPROST/TIMOLOL VIATRIS may be absorbed systemically. Due to the presence of timolol, a beta-adrenergic component, cardiovascular and pulmonary adverse reactions and other adverse reactions identical to those seen with systemically administered beta-adrenergic blocking agents may occur.

The frequency 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 must be carefully evaluated and treatment with other medicinal products should be considered. In these patients, monitoring should be carried out to detect 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.

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, including death due to bronchospasm, have been reported following administration of certain ophthalmic beta-blockers. LATANOPROST/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-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 potentiated when timolol is administered to patients already receiving an oral 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 administration of such allergens and may not respond to the doses of adrenaline usually used to treat anaphylactic reactions.

Choroidal detachment

Choroidal detachments have been observed after filtering surgery for glaucoma with the 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 have been described (see section Interactions).

Other prostaglandin analogues

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

Changes in iris pigmentation

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 combination LATANOPROST/TIMOLOL VIATRIS ; in particular in patients with multicoloured 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 completely browner. Clinical studies show that after two years of treatment, these colour changes were only rarely observed in patients with uniformly coloured eyes, blue, grey, green or brown. The change in iris colour progresses slowly and may go unnoticed for months or even years. This effect has not been associated with any symptoms or pathological change.

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.

Changes in eyelids and eyelashes

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

Latanoprost may gradually change the eyelashes and vellus hair of the treated eye; these changes include increased length, thickness, pigmentation and number of eyelashes or hairs, and misdirected growth of the eyelashes. Eyelash changes are reversible upon discontinuation of treatment.

Glaucoma

There is currently no documented experience on the efficacy of latanoprost in inflammatory or neovascular glaucoma, in chronic angle-closure glaucoma, in open-angle glaucoma of 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 the combination LATANOPROST/TIMOLOL VIATRIS 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 active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.

Macular oedema

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

Preservative

The combination LATANOPROST/TIMOLOL VIATRIS 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 and may cause eye irritation. Close monitoring is necessary during frequent or prolonged use of LATANOPROST/TIMOLOL VIATRIS in patients with dry eye or corneal disorders.

Contact lenses

Benzalkonium chloride may be absorbed and is known to discolour soft contact lenses. Contact lenses must be removed before instillation of the combination LATANOPROST/TIMOLOL VIATRIS and may be reinserted 15 minutes after. (see section Dosage and administration).

No specific drug interaction studies have been carried out with the combination LATANOPROST/TIMOLOL VIATRIS.

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 blockers, beta-adrenergic blocking agents, antiarrhythmics (notably amiodarone), digitalis glycosides, parasympathomimetics, or systemically administered guanethidine.

Potentiation of systemic beta-blocking effects (for example: decreased heart rate, depression) has been reported when CYP2D6 inhibitor treatments (for example: 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 LATANOPROST/TIMOLOL VIATRIS 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 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-blocking effect (for example: bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the newborn when beta-blockers have been administered until delivery. If LATANOPROST/TIMOLOL VIATRIS is administered until delivery, the newborn should be closely monitored during the first days of life.

Therefore, LATANOPROST/TIMOLOL VIATRIS should not be used during pregnancy (see section Preclinical safety).

Breast-feeding

Beta-blockers are excreted in human milk. However, at therapeutic doses of timolol in eye drops, the amount passing into breast milk is unlikely to 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, LATANOPROST/TIMOLOL VIATRIS should not be used in breast-feeding women.

Fertility

It has not been shown that latanoprost or timolol could have an impact on male or female fertility in animal studies.

LATANOPROST/TIMOLOL VIATRIS has a minor influence on the ability to drive and use machines. As with other ophthalmic preparations, instillation of eye drops may be followed by transient visual disturbances. Until these are resolved, patients must not drive or use machines.

For latanoprost, the majority of adverse effects relate to the ocular system. During the extension phase of the pivotal studies of the latanoprost/timolol Viatris combination, 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 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.

Adverse effects are classified according to their frequency of occurrence, as follows: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000) and very rare (<1/10000).

Table 1: Adverse effects observed during trials with latanoprost/timolol

System organ class	Very common (≥ 1/10)	Common ≥ 1/100 to < 1/10	Uncommon ≥ 1/1 000 to < 1/100
Nervous system disorders			Headache
Eye disorders	Iris hyperpigmentation	Eye pain, eye irritation (including tingling, burning sensation, itching, foreign body sensation)	Corneal damage, conjunctivitis, blepharitis, ocular hyperaemia, blurred vision, increased lacrimation
Skin and subcutaneous tissue disorders			Skin rash, pruritus

Other adverse effects related to the use of either component of the LATANOPROST/TIMOLO VIATRIS combination have been reported in clinical studies, spontaneous notifications, or from the literature.

For latanoprost:

Table 2: Adverse effects of latanoprost
System organ class	Adverse effects
Infections and infestations	Herpetic keratitis
Nervous system disorders	Dizziness
Eye disorders	Changes to eyelashes and periorbital vellus hair (increased length, thickness, pigmentation and number of eyelashes); punctate keratitis, periorbital oedema, iritis; uveitis; macular oedema, including cystoid macular oedema; dry eye; keratitis; corneal oedema; corneal erosion; trichiasis; 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+ ; darker pigmentation of the eyelid skin
Cardiac disorders	Angina; unstable angina; palpitations
Respiratory, thoracic and mediastinal disorders	Asthma; worsening of asthma; dyspnoea
Gastrointestinal disorders*	Nausea*; vomiting*
Musculoskeletal and connective tissue disorders	Myalgia; arthralgia
General disorders and administration site conditions	Chest pain
* Identified after marketing with an estimated frequency of uncommon + Potentially attributable to the preservative, benzalkonium chloride

For timolol:

Table 3: Adverse effects of timolol maleate (ocular instillation)
System organ class	Adverse effects
Immune system disorders	Systemic allergic reactions including anaphylactic reaction, angioedema, urticaria, localised or generalised rash, pruritus
Metabolism and nutrition disorders	Hypoglycaemia
Psychiatric disorders	Memory loss, insomnia, depression, nightmares, hallucinations
Nervous system disorders	Cerebrovascular accident, cerebral ischaemia, dizziness, increase in signs and symptoms of myasthenia gravis, paraesthesia, headache, syncope
Eye disorders	Choroidal detachment after filtering surgery (see section Warnings and precautions), corneal erosion, keratitis, diplopia, decreased corneal sensitivity, signs and symptoms of eye irritation (for example: burning, stinging, itching, tearing and redness), dry eye, ptosis, blepharitis, blurred vision
Ear and labyrinth disorders	Tinnitus
Cardiac disorders	Cardiac arrest, heart failure, atrioventricular block, congestive heart failure, chest pain, arrhythmia, bradycardia, oedema, palpitations
Vascular disorders	Cold extremities, hypotension, Raynaud's phenomenon
Respiratory, thoracic and mediastinal disorders	Bronchospasm (mainly in patients with pre-existing bronchospastic disease), cough, dyspnoea
Gastrointestinal disorders	Abdominal pain, vomiting, diarrhoea, dry mouth, dysgeusia, dyspepsia, nausea
Skin and subcutaneous tissue disorders	Skin rash, psoriasiform rash, exacerbation of psoriasis, alopecia
Musculoskeletal and connective tissue disorders	Myalgia
Disorders of the reproductive system 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 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 VIATRIS combination.

Symptoms

The symptoms of systemic timolol overdose are: bradycardia, hypotension, bronchospasm and cardiac arrest.

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

Treatment

If symptoms of overdose occur, treatment should be symptomatic and supportive.

In case of accidental ingestion, the following information may be useful:

Studies have shown that timolol is not easily dialysed. Gastric lavage if necessary.

Latanoprost is extensively metabolised during first hepatic passage. An intravenous infusion of 3 micrograms/kg in healthy volunteers caused no symptoms, whereas 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-blocker – timolol, in combination, ATC code: S01ED51

Mechanism of action

The LATANOPROST/TIMOLOL VIATRIS combination 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 in intraocular pressure compared with that obtained when each component is administered alone.

Latanoprost, a prostaglandin F analogue2α, 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 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 efficacy and safetys

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 mm Hg.

After a period of 2 to 4 weeks of timolol treatment (resulting in a mean reduction in intraocular pressure of 5 mm Hg from baseline), further mean diurnal intraocular pressure reductions of 3,1, 2,0 and 0,6 mm Hg were observed after 6 months of treatment with latanoprost/timolol, latanoprost and timolol (twice daily), respectively. 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 borne in mind that if efficacy with the fixed combination is insufficient, study results show that 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 up to 24 hours after instillation.

Latanoprost

Absorption

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 passage through the cornea.

Distribution

Clinical studies in humans show that the maximum concentration in 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 small 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%.

Biotransformation and elimination

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

Absorption and distribution

The maximum concentration of timolol in aqueous humour is reached about 1 hour after topical administration of the eye drops. A portion 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).

Biotransformation

The plasma half-life of timolol is approximately 6 hours. It is extensively metabolised in the liver.

Élimination

Metabolites are excreted in the urine together with unchanged timolol.

Latanoprost/timolol combination

Pharmacokinetic/pharmacodynamic relationships

No pharmacokinetic interaction between latanoprost and timolol was observed, despite a concentration of latanoprost acid in aqueous humour 1-4 hours after administration of latanoprost/timolol 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 effects in humans. Latanoprost does not impair corneal wound 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 was observed in male or female rats. 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-fetal toxicity, characterised by an increased incidence of late resorptions, abortions and a decrease in fetal weight in rabbits at intravenous doses greater than or equal to 5 micrograms/kg/day (approximately 100 times the therapeutic dose). Timolol does not cause any effect on fertility in male or female rats. No teratogenic potential was observed in mice, rats and rabbits.

Studies in vitro showed precipitation when an eye drop solution containing thiomersal was mixed with latanoprost.

If such medicinal products are used concurrently with LATANOPROST/TIMOLOL VIATRIS, the drops must be administered at an interval of at least five minutes.

Before first opening: 3 years.

After first opening of the bottle: 4 weeks.

Before first opening: store in a refrigerator (between 2ºC and 8ºC).

After first opening: store at a temperature not exceeding 25 °C.

Use within 4 weeks (see section Shelf life).

Store the vial in the outer carton in order to protect from light.

The safety cap must be removed before use.

List I

Marketing authorisation (AMM)

CIP 3400927480850 (Fl/2,5ml). CIP 3400927480911 (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 (Fl/2,5ml), 19.57 euros (3Fl/2,5ml) in the indications:

• Indication(s) listed in the marketing authorisation at the date of publication of this decree (Fl/2,5ml, 3Fl/2,5ml)

Collection.