4.1. Therapeutic indications

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

4.2. Posology and method of administration

Posology

Recommended dosage for adults (including the elderly)

Recommended therapy is one eye drop in the affected eye(s) once daily.

If one dose is missed, treatment should continue with the next dose as planned. The dose should not exceed one drop in the affected eye(s) daily.

Paediatric population

The safety and efficacy in children and adolescents has not yet been established.

Method of Administration

Precautions to be taken before handling or administering the medicinal product.

Contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes (see section 4.4).

If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.

When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity.

4.3. Contraindications

Latanoprost / Timolol 50 micrograms / ml + 5 mg / ml Eye Drops, Solution is contraindicated in patients with:

• Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.

• Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree atrioventricular block not controlled with a pace-maker, overt cardiac failure, cardiogenic shock.

• Hypersensitivity to the active substances (latanoprost or timolol) or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Systemic effects

Like other topically applied ophthalmic agents, latanoprost and timolol are absorbed systemically. Due to the beta-adrenergic component timolol, the same types of cardiovascular, pulmonary and other adverse reactions as seen with systemic beta-adrenergic blocking agents may occur. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.

Cardiac disorders

In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina, and cardiac failure) and hypotension therapy with beta-blockers should be critically assessed and the therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions.

Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.

Cardiac reactions, and rarely, death in association with cardiac failures have been reported following administration of timolol.

Vascular disorders

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

Respiratory disorders

Respiratory reactions including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta- blockers.

Latanoprost / Timolol 50 micrograms / ml + 5 mg / ml Eye Drops, Solution 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.

Hypoglycaemia/diabetes

Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.

Hyperthyroidism

Beta-blockers may also mask the signs of hyperthyroidism.

Corneal diseases

Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.

Other beta-blocking agents

The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol is given to the patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended (see section 4.5).

Anaphylactic reactions

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens and unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.

Choroidal detachment

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.

Surgical anaesthesia

Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.

Concomitant therapy

Timolol may interact with other drugs, see section 4.5.

The use of two local beta-blockers or two local prostaglandins is not recommended.

Iris pigmentation changes

Latanoprost may gradually change the eye colour by increasing the amount of brown pigment in the iris. Similar to experience with latanoprost eye drops, increased iris pigmentation was seen in 16-20% of all patients treated with Latanoprost / Timolol 50 micrograms / ml + 5 mg / ml Eye Drops, Solution for up to one year (based on photographs). This effect has predominantly been seen in patients with mixed coloured irides, i.e. green-brown, yellow-brown or blue/grey-brown, and is due to increased melanin content in the stromal melanocytes of the iris. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become more brownish. In patients with homogeneously blue, grey, green or brown eyes, the change has only rarely been seen during two years of treatment in clinical trials with latanoprost.

The change in iris colour occurs slowly and may not be noticeable for several months to years and it has not been associated with any symptom or pathological changes.

No further increase in brown pigment has been observed after discontinuation of treatment, but the resultant colour change may be permanent.

Neither naevi nor freckles of the iris have been affected by treatment.

Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not been observed but patients should be examined regularly and, depending on the clinical situation, treatment may be stopped if increased iris pigmentation ensues.

Before treatment is instituted patients should be informed of the possibility of a change in eye colour. Unilateral treatment can result in permanent heterochromia.

Eyelid and eyelash changes

Eyelid skin darkening, which may be reversible, has been reported in association with the use of latanoprost.

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

Glaucoma

There is no documented experience with latanoprost in inflammatory, neovascular, or chronic angle closure glaucoma, in open angle glaucoma of pseudophakic patients and in pigmentary glaucoma. Latanoprost has no or little effect on the pupil but there is no documented experience in acute attacks of closed angle glaucoma. It is recommended, therefore, that Latanoprost / Timolol 50 micrograms / ml + 5 mg / ml Eye Drops, Solution should be used with caution in these conditions until more experience is obtained.

Herpectic keratitis

Latanoprost should be used with caution in patients with a history of herpetic keratitis, and 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

Macular oedema, including cystoid macular oedema, has been reported during treatment with latanoprost. These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular oedema. Latanoprost / Timolol should be used with caution in these patients.

Use of contact lenses

Latanoprost / Timolol 50 micrograms / ml + 5 mg / ml Eye Drops, Solution contains 0.2mg/ml (0.006mg per drop) of the preservative benzalkonium chloride which may be deposited in soft contact lenses. Hence Latanoprost / Timolol should not be used while wearing these lenses. The lenses should be removed before instillation of the drops and not reinserted earlier than 15 minutes after use (see section 4.2).

Benzalkonium chloride has been reported to cause eye irritation, symptoms of dry eyes and may affect the tear film and corneal surface. Should be used with caution in dry eye patients and in patients where the cornea may be compromised. Patients should be monitored in case of prolonged use.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed with Latanoprost / Timolol.

There have been reports of paradoxical elevations in intraocular pressure following the 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-blockade may be potentiated when Latanoprost / Timolol 50 micrograms / ml + 5 mg / ml Eye Drops, Solution is given to patients already receiving an oral beta-adrenergic blocking agent, and the use of two or more topical beta-adrenergic blocking agents is not recommended.

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

There is a potential for additive effects resulting in hypotension and/or marked bradycardia when ophthalmic beta- blockers solutions are administered concomitantly with oral calcium channel blockers, guanethidine or beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides or parasympathomimetics.

Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers.

Beta-blockers may increase the hypoglycaemic effect of anti-diabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

Latanoprost

There are no adequate data from the use of latanoprost in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Timolol

There are no adequate data for the use of timolol in pregnant women. Timolol should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2.

Epidemiological studies have not revealed malformative effects, but show a risk for intra uterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. If Latanoprost / Timolol 50 micrograms / ml + 5 mg / ml Eye Drops, Solution is administered until delivery, the neonate should be carefully monitored during the first days of life.

Consequently Latanoprost / Timolol 50 micrograms / ml + 5 mg / ml Eye Drops, Solution should not be used during pregnancy (see section 5.3).

Breastfeeding

Beta- blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce the systemic absorption, see section 4.2.

Latanoprost and its metabolites may pass into breast milk. Latanoprost / Timolol 50 micrograms / ml + 5 mg / ml Eye Drops, Solution should not be used in women who are breast-feeding.

Fertility

There are no human data on the effects of Latanoprost / Timolol 50 micrograms / ml + 5 mg / ml Eye Drops, Solution on fertility.

4.7. Effects on ability to drive and use machines

Instillation of eye drops may cause transient blurring of vision. Until this has resolved, patients should not drive or use machines.

4.8. Undesirable effects

For latanoprost, the majority of adverse events relate to the ocular system. In data from the extension phase of Latanoprost / Timolol pivotal trials, 16 - 20% of patients developed increased iris pigmentation, which may be permanent. In an open 5 year latanoprost safety study, 33% of patients developed iris pigmentation (see section 4.4). Other ocular adverse events are generally transient and occur on dose administration. For timolol, the most serious adverse events are systemic in nature, including bradycardia, arrhythmia, congestive heart failure, bronchospam and allergic reactions.

Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers.

Treatment related adverse events seen in clinical trials with Latanoprost / Timolol 50 micrograms / ml + 5 mg / ml Eye Drops, Solution are listed below.

Adverse events are categorised by frequency 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) and very rare (<1/10,000)

Nervous System Disorders:

Uncommon: Headache.

Eye Disorders:

Very common: Increased iris pigmentation.

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

Uncommon: Eye hyperaemia, conjunctivitis, vision blurred, lacrimation increased, blepharitis, corneal disorders.

Skin and Subcutaneous Tissue Disorders:

Uncommon: Skin rash, pruritus.

Additional adverse events have been reported specific to the use of the individual components of Latanoprost / Timolol 50 micrograms / ml + 5 mg / ml Eye Drops, Solution in either in clinical studies, spontaneous reports or in the available literature.

For latanoprost, these are:

Infection and Infestations:

Herpetic Keratitis.

Nervous system disorders:

Dizziness.

Eye Disorders:

Eyelash and vellus hair changes of the eyelid (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 lid changes resulting in deepening of eyelid sulcus, eyelid oedema, localized skin reaction on the eyelids, pseudopemphigoid of the ocular conjunctiva+, darkening of the palpebral skin.

Cardiac Disorders:

Angina, Angina unstable, palpitations.

Respiratory, Thoracic and Mediastinal Disorders:

Asthma, asthma aggravation, dyspnea.

Musculoskeletal, Connective Tissue and Bone Disorders:

Myalgia, arthralgia.

General disorders and Administration Site Conditions:

Chest pain

Gastro intestinal disorders:

Uncommon: Nausea, Vomiting

+ May be potentially related to the preservative benzalkonium chloride

For timolol, these are:

Immune System Disorders:

Systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylactic reaction.

Metabolism and nutrition disorders:

Hypoglycaemia.

Psychiatric Disorders:

Depression, memory loss, insomnia, nightmares, hallucinations.

Nervous System Disorders:

Dizziness, paraesthesia, cerebral ischemia, cerebrovascular accident, increase in signs and symptoms of myasthenia gravis, syncope, and headache

Eye Disorders:

Signs and symptoms of ocular irritation (e.g. burning, stinging, itching, tearing, redness), blepharitis, keratitis, blurred vision and choroidal detachment following filtration surgery (see section 4.4), decreased corneal sensitivity, dry eyes, corneal erosion, ptosis, diplopia.

Ear and Labyrinth Disorders:

Tinnitus

Cardiac Disorders:

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

Vascular Disorders:

Hypotension, Raynaud's phenomenon, cold hands and feet.

Respiratory, Thoracic and Mediastinal Disorders:

Bronchospasm (predominantly 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 connective tissue disorders:

Myalgia.

Reproductive system and breast disorders:

Sexual dysfunction, decreased libido.

General Disorders and Administration Site Conditions:

Asthenia, fatigue

Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow card scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No data are available in humans with regard to overdose with Latanoprost / Timolol50 micrograms / ml + 5 mg / ml Eye Drops, Solution.

Symptoms

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

Apart from ocular irritation and conjunctival hyperaemia, no other ocular or systemic side effects are known if latanoprost is overdosed.

Treatment

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

If accidentally ingested orally the following information may be useful:

Studies have shown that timolol does not dialyse readily Gastric lavage if needed. Latanoprost is extensively metabolised during the first pass through the liver. Intravenous infusion of 3 micrograms/kg in healthy volunteers induced no symptoms, but a dose of 5.5-10 micrograms/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating. These events were mild to moderate in severity and resolved without treatment, within 4 hours after terminating the infusion.