Alcon Laboratories (U.K) Limited

DuoTrav 40 micrograms/ml + 5 mg/ml eye drops, solution.

Each ml of solution contains 40 micrograms of travoprost and 5 mg of timolol (as timolol maleate).

Excipient(s): Each ml of solution contains polyquaternium-1 (POLYQUAD) 10 microgram, propylene glycol 5 mg, polyoxyethylene hydrogenated castor oil 40 1 mg (see section 4.4).

For a full list of excipients, see section 6.1.

Eye drop, solution (eye drop)

Clear, colourless solution

Decrease of intraocular pressure (IOP) in adult patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers or prostaglandin analogues (see section 5.1).

Posology

Use in adults, including the elderly population

The dose is one drop of DuoTrav 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 DuoTrav 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 DuoTrav (see section 5.2).

Paediatric population

The safety and efficacy of DuoTrav 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 overwrap 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.

Nasolacrimal occlusion or gently closing the eyelid after administration is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic adverse reactions.

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 DuoTrav, the other medicinal product should be discontinued and DuoTrav should be started the following day.

Patients must be instructed to remove soft contact lenses prior to application of DuoTrav and wait 15 minutes after instillation of the dose before reinsertion.

• Hypersensitivity to the active substances, or to any of the excipients

• Bronchial asthma, a history of bronchial asthma or severe chronic obstructive pulmonary disease

• Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, or cardiogenic shock

• Severe allergic rhinitis and bronchial hyper reactivity; corneal dystrophies; hypersensitivity to other beta-blockers

Systemic effects

Like other topically applied ophthalmic medicinal products, Travoprost and Timolol are absorbed systemically. Due to the beta-adrenergic active substance, timolol, the same types of cardiovascular and pulmonary adverse reactions as seen with systemic beta adrenergic blocking medicinal products may occur. Cardiac failure should be adequately controlled before beginning therapy with timolol. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked. Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death in association with cardiac failure, have been reported following administration of timolol maleate. Beta-adrenergic blocking medicinal products should be administered with caution in patients subject to spontaneous hypoglycaemia or to diabetic patients (especially those with labile diabetes) as beta-adrenergic blocking medicinal products may mask the signs and symptoms of acute hypoglycaemia. They may also mask the signs of hyperthyroidism and cause worsening of Prinzmetal angina, severe peripheral and central circulatory disorders and hypotension.

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 adrenergic blocking medicinal products, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.

Concomitant therapy

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

The effect on intraocular pressure or the known effects of systemic beta blockade may be potentiated when DuoTrav is given to patients already receiving an oral beta blocking medicinal product.

The use of two local beta-adrenergic blocking medicinal products or 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.

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 DuoTrav 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.

Caution is recommended when using DuoTrav 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, DuoTrav can be used with caution.

Excipients

DuoTrav contains propylene glycol which may cause skin irritation.

DuoTrav contains polyoxyethylene hydrogenated castor oil 40 which may cause skin reactions.

Patients must be instructed to remove contact lenses prior to application of DuoTrav and wait 15 minutes after instillation of the dose before reinsertion.

No interaction studies have been performed.

There is a potential for additive effects results in hypotension and/or marked bradycardia when eye drops with timolol are administered concomitantly with oral calcium channel blockers, guanethidine or beta-blocking medicinal products, antiarrhythmics, digitalis glycosides or parasympathomimetics.

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

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).

Women of childbearing potential/contraception

DuoTrav must not be used in women who may become pregnant unless adequate contraceptive measures are in place (see section 5.3).

Pregnancy

Travoprost has harmful pharmacological effects on pregnancy and/or the foetus/new-born child.

Well controlled epidemiological studies with systemic use of beta-blockers did not indicate malformative effects, but some pharmacological effects such as bradycardia have been observed in foetuses or neonates. Data on a limited number of exposed pregnancies indicate no adverse effects of timolol in eye drops on pregnancy or on the health of the foetus/newborn child but bradycardia and arrhythmia have been reported in one case in the foetus of a woman treated with timolol eye drops. To date, no other relevant epidemiological data are available.

DuoTrav should not be used during pregnancy unless clearly necessary.

Breastfeeding

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. However, at therapeutic doses of timolol in eye drops the calculated dose of timolol for the infant would be too low to produce clinical beta-blockade. The use of DuoTrav by breast-feeding women is not recommended.

Fertility

There are no data on the effects of DuoTrav on human fertility. Animal studies showed no effect of travoprost or timolol on fertility at doses more than 250 times the maximum recommended human ocular dose.

As with any eye drop, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machines.

In clinical studies involving 938 patients, DuoTrav (benzalkonium chloride-preserved) was administered once daily. The most frequently reported treatment-related adverse reaction was ocular hyperaemia (15.0%). Almost all patients (96%) who experienced ocular hyperaemia did not discontinue therapy as a result of this reaction.

The following 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 <1/1000), 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.

DuoTrav (benzalkonium chloride-preserved)

In 3 clinical trials involved in the development of DuoTrav (polyquaternium-1-preserved), 372 patients/subjects were exposed for up to 12 months. The most frequently reported treatment-related undesirable effect with DuoTrav (polyquaternium-1-preserved) was hyperaemia of the eye (11.8%), which included ocular or conjunctival hyperaemia. The majority of patients (91%) who experienced hyperaemia of the eye did not discontinue therapy as a result of this reaction.

The following adverse reactions listed in the table below were observed in the clinical studies.

DuoTrav (polyquaternium-1-preserved)

Additional adverse reactions that have been seen with one of the active substances and may potentially occur with DuoTrav:

Travoprost

Eye disorders - uveitis, conjunctival disorder, conjunctival follicles, iris hyper pigmentation.

Skin and subcutaneous tissue disorders - skin exfoliation

Timolol

Metabolism and nutrition disorders - hypoglycaemia

Nervous system disorders - cerebral ischaemia, myasthenia gravis

Eye disorders - diplopia

Cardiac disorders - cardiac arrest, atrioventricular block, palpitations

Respiratory, thoracic and mediastinal disorders - respiratory failure, nasal congestion

Gastrointestinal disorders - diarrhoea, nausea

General disorders and administration site conditions - asthenia

A topical overdose with travoprost is not likely to occur or to be associated with toxicity.

The most common symptoms of a systemic timolol overdose are bradycardia, hypotension, bronchospasm and heart failure.

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

Pharmacotherapeutic group: Ophthalmologicals antiglaucoma preparations and miotics.ATC code: S01ED51.

Mechanism of action

DuoTrav contains two active substances: travoprost and timolol maleate. These two components lower intraocular pressure by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound alone.

Travoprost, a prostaglandin F_2α analogue, is a full agonist which is highly selective and has a high affinity for the prostaglandin FP receptor, and reduces the intraocular pressure by increasing the outflow of aqueous humour via trabecular meshwork and uveoscleral pathways. Reduction of IOP in man starts within approximately 2 hours after administration and maximum effect is reached after 12 hours. Significant lowering of intraocular pressure can be maintained for periods exceeding 24 hours with a single dose.

Timolol is a non-selective adrenergic blocking agent that has no intrinsic sympathomimetic, direct myocardial depressant or membrane-stabilising activity. Tonography and fluorophotometry studies in man suggest that its predominant action is related to reduced aqueous humour formation and a slight increase in outflow facility.

Secondary pharmacology

Travoprost significantly increased optic nerve head blood flow in rabbits following 7 days of topical ocular administration (1.4 micrograms, once-daily).

Pharmacodynamic effects

Clinical effects

In a twelve-month, controlled clinical study in patients with open-angle glaucoma or ocular hypertension and baseline mean IOP of 25 to 27 mmHg, the mean IOP-lowering effect of DuoTrav dosed once-daily in the morning was 8 to 10 mmHg. The non-inferiority of DuoTrav as compared to latanoprost 50 micrograms/ml + timolol 5 mg/ml in the mean IOP reduction was demonstrated across all time-points at all visits.

In a three-month, controlled clinical study in patients with open-angle glaucoma or ocular hypertension and baseline mean IOP of 27 to 30 mmHg, the mean IOP-lowering effect of DuoTrav dosed once-daily in the morning was 9 to 12 mmHg, and was up to 2 mmHg greater than that of travoprost 40 micrograms/ml dosed once-daily in the evening and 2 to 3 mmHg greater than that of timolol 5 mg/ml dosed twice daily. A statistically superior reduction in morning mean IOP (8AM-24 hours after the last dose of DuoTrav) was observed compared to travoprost at all visits throughout the study.

In two three-month, controlled clinical studies in patients with open-angle glaucoma or ocular hypertension and baseline mean IOP of 23 to 26 mmHg, the mean IOP-lowering effect of DuoTrav dosed once-daily in the morning was 7 to 9 mmHg. Mean IOP reductions were non-inferior, although numerically lower, to those achieved by concomitant therapy with travoprost 40 micrograms/ml dosed once-daily in the evening and timolol 5 mg/ml dosed once-daily in the morning.

In a 6-week, controlled clinical study in patients with open-angle glaucoma or ocular hypertension and baseline mean IOP of 24 to 26 mmHg, the mean IOP-lowering effect of DuoTrav (polyquaternium-1-preserved) dosed once-daily in the morning was 8 mmHg and equivalent to that of DuoTrav (benzalkonium chloride-preserved).

Inclusion criteria were common across the studies, with the exception of the IOP entry criteria and response to previous IOP therapy. The clinical development of DuoTrav included both patients naive and on therapy. Insufficient responsiveness to monotherapy was not an inclusion criterion.

Existing data suggest that evening dosing might have some advantages in the mean IOP reduction. Consideration should be given to patient convenience and their likely compliance when recommending morning vs. evening dosing.

Absorption

Travoprost and timolol are absorbed through the cornea. Travoprost is a prodrug that undergoes rapid ester hydrolysis in the cornea to the active free acid. Following once-daily administration of DuoTrav PQ in healthy subjects (N=22 ) for 5 days, Travoprost free acid was not quantifiable in plasma samples from the majority of subjects (94.4%) and generally was not detectable one hour after dosing. . When measurable ( 0.01 ng/ml, the assay limit of quantitation), concentrations ranged from 0.01 to 0.03 ng/ml. The mean timolol steady-state C_max was 1.34 ng/ml and T_max was approximately 0.69 hours after once-daily administration of DuoTrav.

Distribution

Travoprost free acid can be measured in the aqueous humour during the first few hours in animals and in human plasma only during the first hour after ocular administration of DuoTrav. Timolol can be measured in human aqueous humour after ocular administration of timolol and in plasma for up to 12 hours after ocular administration of DuoTrav.

Biotransformation

Metabolism is the major route of elimination of both travoprost and the active free acid. The systemic metabolic pathways parallel those of endogenous prostaglandin F_2α which are characterised by reduction of the 13-14 double bond, oxidation of the 15-hydroxyl and β-oxidative cleavages of the upper side chain.

Timolol is metabolised by two pathways. One route yields an ethanolamine side chain on the thiadiazole ring and the other giving an ethanolic side chain on the morpholine nitrogen and a second similar side chain with a carbonyl group adjacent to the nitrogen. The plasma t_1/2 of timolol is 4 hours after ocular administration of DuoTrav.

Elimination

Travoprost free acid and its metabolites are mainly excreted by the kidneys. Less than 2% of an ocular dose of travoprost was recovered in urine as free acid. Timolol and its metabolites are primarily excreted by the kidneys. Approximately 20% of a timolol dose is excreted in the urine unchanged and the remainder excreted in urine as metabolites.

In monkeys, administration of DuoTrav twice–daily was shown to induce increased palpebral fissure and to increase iris pigmentation similar to that observed with ocular administration of prostanoids.

DuoTrav preserved with polyquaternium-1 induced minimal ocular surface toxicity, compared to eye drops preserved with benzalkonium chloride, on cultured human corneal cells and following topical ocular administration in rabbits.

Travoprost

Topical ocular administration of travoprost to monkeys at concentrations of up to 0.012% to the right eye, twice daily for one year resulted in no systemic toxicity.

Reproduction toxicity studies with travoprost have been undertaken in rat, mice and rabbit by systemic route. Findings are related to FP receptor agonist activity in uterus with early embryolethality, post-implantation loss, and foetotoxicity. In pregnant rat, systemic administration of travoprost at doses more than 200 times the clinical dose during the period of organogenesis resulted in an increased incidence of malformations. Low levels of radioactivity were measured in amniotic fluid and foetal tissues of pregnant rats administered ³H-travoprost. Reproduction and development studies have demonstrated a potent effect on foetal loss with a high rate observed in rats and mice (180 pg/ml and 30 pg/ml plasma, respectively) at exposures 1.2 to 6 times the clinical exposure (up to 25 pg/ml).

Timolol

Non-clinical data revealed no special hazard for humans with timolol based on conventional studies of safety pharmacology, repeat dose toxicity, genotoxicity, carcinogenic potential. Reproduction toxicity studies with timolol showed delayed foetal ossification in rats with no adverse effects on postnatal development (7000 times the clinical dose) and increased foetal resorptions in rabbits (14000 times the clinical dose).

Polyquaternium-1

Mannitol (E421)

Propylene glycol (E1520)

Polyoxyethylene hydrogenated castor oil 40 (HCO-40)

Boric acid

Sodium chloride

Sodium hydroxide and/ or hydrochloric acid (for pH adjustment)

Purified water

Not applicable.

3 years.

Discard 4 weeks after first opening.

This medicinal product does not require any special storage conditions.

2.5 ml oval bottle with dispensing plug and screw cap, all polypropylene presented in an overwrap.

Pack sizes of 1, 3 or 6 bottles.

Not all pack sizes may be marketed.

No special requirements.

Alcon Laboratories (UK) Ltd.,

Boundary Way,

Hemel Hempstead,

Herts HP2 7UD

United Kingdom

EU/1/06/338/001-3

Date of first authorisation: 24/04/06

Date of last renewal: 07/10/10

24^th March 2011