4.1. Therapeutic indications

Travoprost/Timolol Mylan is indicated in adults for the decrease of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers or prostaglandin analogues (see section 5.1).

4.2. Posology and method of administration

Posology

Use in adults, including the elderly

The dose is one drop of Travoprost/Timolol Mylan in the conjunctival sac of the affected eye(s) once daily, in the morning or evening. It should be administered at the same time each day.

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

Special populations

Hepatic and renal impairment

No studies have been conducted with travoprost/timolol 40 micrograms/ml + 5 mg/ml eye drops, solution or with timolol 5 mg/ml eye drops in patients with hepatic or renal impairment.

Travoprost has been studied in patients with mild to severe hepatic impairment and in patients with mild to severe renal impairment (creatinine clearance as low as 14 ml/min). No dose adjustment was necessary in these patients.

Patients with hepatic or renal impairment are unlikely to require dose adjustment with Travoprost/Timolol Mylan (see section 5.2).

Paediatric population

The safety and efficacy of travoprost/timolol 40 micrograms/ml + 5 mg/ml eye drops, solution in children and adolescents below the age of 18 years have not been established. No data are available.

Method of administration

For ocular use.

The patient should remove the protective sachet immediately prior to initial use. To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle.

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 (see section 4.4).

If more than one topical ophthalmic medicinal product is being used, the medicinal products must be administered at least 5 minutes apart (see section 4.5).

When substituting another ophthalmic antiglaucoma medicinal product with Travoprost/Timolol Mylan, the other medicinal product should be discontinued and Travoprost/Timolol Mylan should be started the following day.

Patients must be instructed to remove soft contact lenses prior to application of Travoprost/Timolol Mylan and wait 15 minutes after instillation of the dose before reinsertion (see section 4.4).

4.3. Contraindications

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

- Hypersensitivity to other beta-blockers.

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

- Sinus bradycardia, sick sinus syndrome, including sino-atrial block, second- or third- degree atrioventricular block not controlled with pacemaker. Overt cardiac failure, cardiogenic shock.

- Severe allergic rhinitis and corneal dystrophies.

4.4. Special warnings and precautions for use

Systemic effects

Like other topically applied ophthalmic agents, travoprost and timolol are absorbed systemically. Due to the beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions seen with systemic beta-adrenergic blocking medicinal products may occur. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. For information on how to reduce 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 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 their negative effect on conduction time, beta-blockers should only be given with caution to patients with first-degree heart block.

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.

Travoprost/Timolol Mylan 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 in patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.

Muscle weakness

Beta-adrenergic blocking medicinal products have been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis and generalised weakness).

Corneal diseases

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

Choroidal detachment

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

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 patients already receiving a systemic beta-blocking medicinal product. 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).

Surgical anaesthesia

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

Hyperthyroidism

Beta-blockers may mask the signs of hyperthyroidism.

Skin contact

Prostaglandins and prostaglandin analogues are biologically active substances that may be absorbed through the skin. Women who are pregnant or attempting to become pregnant should exercise appropriate precautions to avoid direct exposure to the contents of the bottle. In the unlikely event of coming in contact with a substantial portion of the contents of the bottle, thoroughly cleanse the exposed area immediately.

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 dose of adrenaline used to treat anaphylactic reactions.

Concomitant therapy

Timolol may interact with other medicinal products (see section 4.5).

The use of two local prostaglandins is not recommended.

Ocular effects

Travoprost may gradually change the eye colour by increasing the number of melanosomes (pigment granules) in melanocytes. Before treatment is instituted, patients must be informed of the possibility of a permanent change in eye colour. Unilateral treatment can result in permanent heterochromia. The long-term effects on the melanocytes and any consequences thereof are currently unknown. The change in iris colour occurs slowly and may not be noticeable for months to years. The change in eye colour has predominantly been seen in patients with mixed coloured irides, i.e. blue-brown, grey-brown, yellow-brown and green-brown; however, it has also been observed in patients with brown eyes. 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. After discontinuation of therapy, no further increase in brown iris pigment has been observed.

In controlled clinical trials, periorbital and/or eyelid skin darkening in association with the use of travoprost has been reported.

Periorbital and lid changes, including deepening of the eyelid sulcus, have been observed with prostaglandin analogues.

Travoprost may gradually change eyelashes in the treated eye(s); these changes were observed in about half of the patients in clinical trials and include: increased length, thickness, pigmentation, and/or number of lashes. The mechanism of eyelash changes and their long term consequences are currently unknown.

Travoprost has been shown to cause slight enlargement of the palpebral fissure in studies in the monkey. However, this effect was not observed during the clinical trials and is considered to be species specific.

There is no experience of travoprost/timolol 40 micrograms/ml + 5 mg/ml eye drops, solution in inflammatory ocular conditions, nor in neovascular, angle-closure, narrow-angle or congenital glaucoma and only limited experience in thyroid eye disease, in open-angle glaucoma of pseudophakic patients and in pigmentary or pseudoexfoliative glaucoma.

Macular oedema has been reported during treatment with prostaglandin F2α analogues. Caution is recommended when using Travoprost/Timolol Mylan in aphakic patients, pseudophakic patients with a torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema.

In patients with known predisposing risk factors for iritis/uveitis, and in patients with active intraocular inflammation, Travoprost/Timolol Mylan can be used with caution.

Travoprost/Timolol Mylan contains benzalkonium chloride and macrogolglycerol hydroxystearate 40

Benzalkonium chloride may be absorbed by soft contact lenses and may change the colour of the contact lenses. You should remove contact lenses before using this medicine.

Benzalkonium chloride has been reported to cause eye irritation, symptoms of dry eyes and may affect the tear film and corneal surface. It 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.

Macrogolglycerol hydroxystearate 40 may cause skin reactions.

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

No specific drug interaction studies have been performed with travoprost or timolol.

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

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

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.

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

Beta-blockers may increase the hypoglycaemic effect of antidiabetic medicinal products.

Beta-blockers can mask the signs and symptoms of hypoglycaemia (see section 4.4).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/contraception

Travoprost/Timolol Mylan must not be used in women of child-bearing age/potential unless adequate contraceptive measures are in place (see section 5.3).

Pregnancy

Travoprost has harmful pharmacological effects on pregnancy and/or the foetus/newborn child.

There are no or limited amount of data from the use of travoprost/timolol 40 micrograms/ml + 5 mg/ml eye drops, solution or the individual components in pregnant women. Timolol should not be used during pregnancy unless clearly necessary.

Epidemiological studies have not revealed malformative effects but show a risk for intrauterine 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 Travoprost/Timolol Mylan is administered until delivery, the neonate should be carefully monitored during the first days of life.

Travoprost/Timolol Mylan should not be used during pregnancy unless clearly necessary. For information on how to reduce systemic absorption, see section 4.2.

Breast-feeding

It is unknown whether travoprost from eye drops is excreted in human breast milk. Animal studies have shown excretion of travoprost and metabolites in breast milk. Timolol is excreted in breast milk and has the potential to cause serious adverse reactions in the breast-fed infant. 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. For information on how to reduce the systemic absorption, see section 4.2.

The use of Travoprost/Timolol Mylan by breast-feeding women is not recommended.

Fertility

There are no data on the effects of travoprost/timolol 40 micrograms/ml + 5 mg/ml eye drops, solution on human fertility. Animal studies showed no effect of travoprost on fertility at doses up to 75 times the maximum recommended human ocular dose, whereas no relevant effect of timolol was noted at this dose level.

4.7. Effects on ability to drive and use machines

Travoprost/Timolol Mylan has minor influence on the ability to drive and use machines.

As with any eye drops, temporary blurred vision or other visual disturbances may occur. If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machines. Travoprost/Timolol Mylan may also cause hallucinations, dizziness, nervousness and/or fatigue (see section 4.8) which may affect the ability to drive and use machines. Patients should be advised not to drive and use machines if these symptoms occur.

4.8. Undesirable effects

Summary of the safety profile

In clinical studies involving 2,170 patients treated with travoprost/timolol 40 micrograms/ml + 5 mg/ml eye drops,solution the most frequently reported treatment-related adverse reaction was ocular hyperaemia (12.0%).

Tabulated summary of adverse reactions

The adverse reactions listed in the table below were observed in clinical studies or with post-marketing experience. They are ranked according to system organ class and classified according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in decreasing order of seriousness.

System Organ Class

Frequency

Adverse reactions

Immune system disorders

Uncommon

hypersensitivity

Psychiatric disorders

Rare

nervousness

Not known

hallucinations* depression

Nervous system disorders

Uncommon

dizziness, headache

Not known

cerebrovascular accident, syncope, paraesthesia

Eye disorders

Very common

ocular hyperaemia

Common

punctate keratitis, eye pain, visual disturbance, vision blurred, dry eye, eye pruritus, ocular discomfort, eye irritation

Uncommon

keratitis, iritis, conjunctivitis, anterior chamber inflammation, blepharitis, photophobia, visual acuity reduced, asthenopia, eye swelling, lacrimation increased, erythema of eyelid, growth of eyelashes, eye allergy, conjunctival oedema, eyelid oedema

Rare

corneal erosion, meibomianitis, conjunctival haemorrhage, eyelid margin crusting, trichiasis, distichiasis

Not known

macular oedema, eyelid ptosis, lid sulcus deepened, iris hyperpigmentation, corneal disorder

Cardiac disorders

Uncommon

bradycardia

Rare

arrhythmia, heart rate irregular

Not known

cardiac failure, tachycardia, chest pain

palpitations

Vascular disorders

Uncommon

hypertension, hypotension

Not known

oedema peripheral

Respiratory, thoracic and mediastinal disorders

Uncommon

dyspnoea, postnasal drip

Rare

dysphonia, bronchospasm, cough, throat irritation, oropharyngeal pain, nasal discomfort

Not known

asthma

Gastrointestinal disorders

Not known

dysgeusia

Hepatobiliary disorders

Rare

alanine aminotransferase increased, aspartate aminotransferase increased

Skin and subcutaneous tissue disorders

Uncommon

dermatitis contact, hypertrichosis, skin hyperpigmentation (periocular)

Rare

urticaria, skin discolouration, alopecia

Not known

rash

Musculoskeletal and connective tissue disorders

Rare

pain in extremity

Renal and urinary disorders

Rare

chromaturia

General disorders and administration site conditions

Rare

thirst, fatigue

* adverse reactions observed with timolol.

Additional adverse reactions that have been seen with one of the active substances and may potentially occur with Travoprost/Timolol Mylan:

Travoprost

System Organ Class

MedDRA Preferred Term

Immune system disorders

seasonal allergy

Psychiatric disorders

anxiety, insomnia

Eye disorders

uveitis, conjunctival follicles, eye discharge, periorbital oedema, eyelids pruritus, ectropion, cataract, iridocyclitis, ophthalmic herpes simplex, eye inflammation, photopsia, eczema eyelids, halo vision, hypoaesthesia eye, anterior chamber pigmentation, mydriasis, eyelash hyperpigmentation, eyelash thickening, visual field defect

Ear and labyrinth disorders

vertigo, tinnitus

Vascular disorders

blood pressure diastolic decreased, blood pressure systolic increased

Respiratory, thoracic and mediastinal disorders

asthma aggravated, rhinitis allergic, epistaxis, respiratory disorder, nasal congestion, nasal dryness

Gastrointestinal disorders

peptic ulcer reactivated, gastrointestinal disorder, diarrhoea, constipation, dry mouth, abdominal pain, nausea, vomiting

Skin and subcutaneous tissue disorders

skin exfoliation, hair texture abnormal, dermatitis allergic, hair colour changes, madarosis, pruritus, hair growth abnormal, erythema

Musculoskeletal and connective tissue disorders

musculoskeletal pain, arthralgia

Renal and urinary disorders

dysuria, urinary incontinence

General disorders and administration site conditions

asthenia

Investigations

prostatic specific antigen increased

Timolol

Like other topically applied ophthalmic medicinal products, timolol is absorbed into the systemic circulation. This may cause undesirable effects similar to those seen with systemic beta-blocking agents. Additional listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. For information on how to reduce systemic absorption, see section 4.2.

System Organ Class

MedDRA Preferred Term

Immune system disorders

systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritus, anaphylaxis

Metabolism and nutrition disorders

hypoglycaemia

Psychiatric disorders

insomnia, nightmares, memory loss, hallucinations

Nervous system disorders

cerebral ischaemia, increases in signs and symptoms of myasthenia gravis

Eye disorders

signs and symptoms of ocular irritation (e.g. burning, stinging, itching, tearing, redness), choroidal detachment following filtration surgery (see section 4.4), decreased corneal sensitivity, diplopia

Cardiac disorders

oedema, congestive heart failure, atrioventricular block, cardiac arrest

Vascular disorders

Raynaud's phenomenon, cold hands and feet.

Gastrointestinal disorders

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

Skin and subcutaneous tissue disorders

psoriasiform rash or exacerbation of psoriasis

Musculoskeletal and connective tissue disorders

myalgia

Reproductive system and breast disorders

sexual dysfunction, decreased libido

General disorders and administration site conditions

asthenia

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the 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

A topical overdose with Travoprost/Timolol Mylan is not likely to occur or to be associated with toxicity.

In case of accidental ingestion, symptoms of overdose from systemic beta blockade may include bradycardia, hypotension, bronchospasm and heart failure.

If overdose with Travoprost/Timolol Mylan occurs, treatment should be symptomatic and supportive. Timolol does not dialyse readily.