TRAVATAN 40 micrograms/ml eye drops, solution

1 ml of solution contains 40 micrograms of travoprost.

Excipients: benzalkonium chloride 0.15 mg, polyoxyethylene hydrogenated castor oil 40 (HCO-40) 5 mg (see section 4.4.)

For a full list of excipients, see section 6.1.

Eye drops, solution .

Clear, colourless solution.

Decrease of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma (see section 5.1).

For ocular use.

Use in adults, including the elderly

The dose is one drop of TRAVATAN in the conjunctival sac of the affected eye(s) once daily. Optimal effect is obtained if the dose is administered in the evening.

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).

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.

When substituting another ophthalmic antiglaucoma agent with TRAVATAN, the other agent should be discontinued and TRAVATAN should be started the following day.

Paediatric patients

The efficacy and safety of TRAVATAN in patients below the age of 18 years have not been established and its use is not recommended in these patients until further data become available.

Use in hepatic and renal impairment

TRAVATAN 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 dosage adjustment is necessary in these patients.

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.

Hypersensitivity to the active substance or to any of the excipients.

TRAVATAN 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 be 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 TRAVATAN has been reported in 0.4% of patients.

TRAVATAN 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.

TRAVATAN 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 TRAVATAN 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 Travatan 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.

Skin contact with TRAVATAN must be avoided as transdermal absorption of travoprost has been demonstrated in rabbits .

Benzalkonium chloride, which is commonly used as a preservative in ophthalmic products, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since TRAVATAN contains benzalkonium chloride, close monitoring is required with frequent or prolonged use.

In patients with known predisposing risk factors for iritis/uveitis, TRAVATAN can be used with caution.

Prostaglandins and prostaglandin analogues are biologically active materials 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

TRAVATAN contains benzalkonium chloride which may cause irritation and is known to discolour soft contact lenses. Contact with soft contact lenses is to be avoided.

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

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

No interaction studies have been performed.

Women of child-bearing potential/contraception

TRAVATAN 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/new-born child. TRAVATAN should not be used during pregnancy unless clearly necessary.

Lactation

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. The use of TRAVATAN by breast-feeding mothers is not recommended.

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 machinery.

In clinical studies involving over 4200 patients, TRAVATAN was administered once daily as monotherapy or adjunctive therapy to timolol 0.5%. No serious ophthalmic or systemic undesirable effects related to TRAVATAN were reported in any of the clinical studies. The most frequently reported treatment-related undesirable effect with TRAVATAN monotherapy was hyperaemia of the eye (22.3%), which included ocular, conjunctival, or scleral hyperaemia. Hyperaemia was mild in 83.0% of those patients who experienced it. Almost all patients (98%) who experienced hyperaemia did not discontinue therapy as a result of this event. In phase III clinical studies ranging from 6 to 12 months in duration, hyperaemia decreased over time.

The following undesirable effects were assessed to be treatment-related (with TRAVATAN monotherapy) and are classified according to the following convention: very common (1/10), common >1/100 to <1/10), uncommon >1/1,000 to 1/100), rare >1/10,000 to 1/1000), or very rare (1/10,000). Within each frequency grouping, undesirable effects are presented in decreasing order of seriousness.

Infections and infestations:

Uncommon: herpes simplex

Immune system disorders:

Uncommon: hypersensitivity, seasonal allergy

Nervous system disorders:

Common: headache

Uncommon: dysgeusia

Eye disorders:

Very common: conjunctival hyperaemia, ocular hyperaemia

Common: punctate keratitis, anterior chamber cell, anterior chamber flare, eye pain, photophobia, eye discharge, ocular discomfort, eye irritation, abnormal sensation in eye, foreign body sensation in eyes, visual acuity reduced, vision blurred, dry eye, eye pruritus, lacrimation increased, erythaema of eyelid, eyelid oedema, eyelids pruritis, growth of eyelashes, iris hyperpigmentation, eyelash discolouration

Uncommon: corneal erosion, iridocyclitis, iritis, uveitis, visual field defect, keratitis, anterior chamber inflammation, eye swelling, corneal staining, photopsia, blepharitis, conjunctival oedema, conjunctivitis allergic, conjunctival disorder, conjunctivitis, conjunctival follicles, hypoaesthesia eye, ectropion, keratoconjunctivitis sicca, madarosis, cataract, eye allergy, eyelid pain, eyelid disorder, eyelid margin crusting, scleral hyperaemia, asthenopia

Cardiac disorders:

Uncommon: heart rate irregular, palpitations, heart rate decreased

Vascular disorders:

Uncommon: blood pressure decreased, blood pressure increased, hypotension

Respiratory, thoracic and mediastinal disorders:

Uncommon: dysponea, asthma, respiratory disorder, pharyngolaryngeal pain, cough, dysphonia, nasal congestion, throat irritation

Gastrointestinal disorders:

Uncommon: peptic ulcer reactivated, gastrointestinal disorder, constipation

Skin and subcutaneous tissue disorders:

Common: skin hyperpigmentation (periocular)

Uncommon: dermatitis allergic, periorbital oedema, dermatitis contact, erythaema, hair colour changes, hair texture abnormal, hypertrichosis

Musculoskeletal, connective tissue and bone disorders:

Uncommon: shoulder pain

General disorders and administrative site conditions:

Uncommon: asthenia, malaise

Adverse reactions identified from post-marketing experience that have not been reported previously in clinical trials with TRAVATAN as monotherapy include the following.

Ocular: macular oedema (see also section 4.4)

Systemic: bradycardia, tachycardia, asthma aggravated, vertigo, tinnitus, PSA increased, hair growth abnormal.

No cases of overdose have been reported. A topical overdose is not likely to occur or to be associated with toxicity. A topical overdose of TRAVATAN may be flushed from the eye(s) with lukewarm water. Treatment of a suspected oral ingestion is symptomatic and supportive.

Pharmacotherapeutic Group: Ophthalmologicals – antiglaucoma preparations and

miotics – prostaglandin analogues

ATC code: S01E E04

Mechanism of action

Travoprost, a prostaglandin F_2α analogue, is a highly selective full agonist which 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 the intraocular pressure in man starts about 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.

Data on adjunctive administration of TRAVATAN with timolol 0.5% and limited data with brimonidine 0.2% were collected during clinical trials that showed an additive effect of TRAVATAN with these glaucoma medications. No clinical data are available on adjunctive use with other ocular hypotensive medications.

Secondary pharmacology

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

Absorption

Travoprost is an ester prodrug. It is absorbed through the cornea where the isopropyl ester is hydrolysed to the active free acid. Studies in rabbits have shown peak concentrations of 20 ng/g of the free acid in aqueous humour one to two hours after topical dosing of TRAVATAN. Aqueous humour concentrations declined with a half-life of approximately 1.5 hours.

Distribution

Following topical ocular administration of TRAVATAN to healthy volunteers, low systemic exposure to active free acid was demonstrated. Peak active free acid plasma concentrations of 25 pg/ml or less were observed between 10 and 30 minutes post-dose. Thereafter, plasma levels declined rapidly to below the 10 pg/ml assay quantitation limit before 1 hour post-administration. Due to the low plasma concentrations and rapid elimination following topical dosing, the elimination half-life of active free acid in man could not be determined.

Metabolism

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.

Excretion

Travoprost free acid and its metabolites are mainly excreted by the kidneys. TRAVATAN 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 dosage adjustment is necessary in these patients.

In ocular toxicity studies in monkeys, administration of travoprost at a dose of 0.45 microgram, twice a day, was shown to induce increased palpebral fissure. 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 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, 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 ³Htravoprost. 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).

Benzalkonium chloride

Polyoxyethylene hydrogenated castor oil 40 (HCO-40)

Trometamol

Disodium edetate

Boric acid (E284)

Mannitol (E421)

Sodium hydroxide and/or hydrochloric acid (to adjust pH)

Purified water

None known.

Specific in vitro interaction studies were performed with TRAVATAN and medicinal products containing thiomersal. No evidence of precipitation was observed.

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.

Cartons containing 1 or 3 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/1/01/199/001-002

Date of first authorisation :27.11.2001

Date of last renewal: 27.11.2006