SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Travoprost Pharmathen 40 micrograms/ml eye drops, solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution contains 40 micrograms of Travoprost.

Average active substance/drop: 0.97 - 1.4 pg

Excipients with known effect: benzalkonium chloride 150 micrograms/ml, macrogol glycerol hydroxy stearate 40 5 mg/ml (see section 4.4.).

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Eye drops, solution.

Clear, colourless solution. pH: 5.5-7.0

Osmolality: 266-294 mOsm/Kg

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

4.2    Posology and method of administration

Use in adults, including the elderly population

The dose is one drop of Travoprost Pharmathen 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 Travoprost Pharmathen, the other agent should be discontinued and Travoprost should be started the following day.

Paediatric population

The efficacy and safety of Travoprost 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.

Hepatic and 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 dosage adjustment is necessary in these patients.

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.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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 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 Travoprost has been reported in 0.4% of patients.

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 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 Travoprost 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 Travoprost 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 Travoprost Pharmathen contains benzalkonium chloride, close monitoring is required with frequent or prolonged use.

In patients with known predisposing risk factors for iritis/uveitis, Travoprost 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

Travoprost Pharmathen 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 Travoprost Pharmathen and wait 15 minutes after instillation of the dose before reinsertion.

Travoprost Pharmathen contains Macrogol glycerol hydroxy stearate 40 which may cause skin reactions.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6 Fertility, pregnancy and lactation

Women of child-bearing potential/contraception

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

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

In clinical studies involving over 4400 patients, Travoprost was administered once daily as monotherapy or adjunctive therapy to timolol 0.5%. No serious ophthalmic or systemic undesirable effects related to the product were reported in any of the clinical studies. The most frequently reported treatment-related undesirable effect with Travoprost monotherapy was hyperaemia of the eye (22%), which included ocular, conjunctival, or scleral hyperaemia. Hyperaemia was mild in 83.6% 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. In a post approval long-term clinical study of 5 years duration involving 502 patients, Travoprost was administered once daily. No serious ophthalmic or systemic undesirable effects related to Travoprost were reported in the clinical study. The most frequently reported treatment-related undesirable effect with Travoprost was iris hyperpigmentation (29.5%) (see section 4.4). Hyperaemia of the eye assessed as related to the use of Travoprost was reported at an incidence of 10.0% with 2% of patients reporting hyperemia of the eye discontinuing study participation due to the undesirable effect.

The following undesirable effects were assessed to be treatment-related (with Travoprost 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.

System Organ Classification	Frequency	Preferred Term
Infections and infestations	Uncommon	herpes simplex, keratitis herpetic
Immune system disorders	Uncommon	hypersensitivity, drug hypersensitivity, seasonal allergy
Nervous system disorders	Common	headache
	Uncommon	dysgeusia, dizziness, visual field defect
Eye disorders	Very common	ocular hyperaemia, iris hyperpigmentation

	Common	punctate keratitis, anterior chamber inflammation, eye pain, photophobia, eye discharge, ocular discomfort, visual acuity reduced, vision blurred, dry eye, eye pruritus, lacrimation increased, erythema of eyelid, eyelid oedema, growth of eyelashes, eyelash discolouration
	Uncommon	corneal erosion, uveitis, keratitis, eye inflammation, photopsia, blepharitis, conjunctival oedema, halo vision, conjunctivitis, conjunctival follicles, hypoaesthesia eye, meibomianitis, ectropion, anterior chamber pigmentation, mydriasis, cataract, eyelid margin crusting, asthenopia
Cardiac disorders	Uncommon	heart rate irregular, palpitations, heart rate decreased
Vascular disorders	Uncommon	blood pressure decreased, blood pressure increased, hypotension, hypertension
Respiratory, thoracic and mediastinal disorders	Uncommon	dyspnoea, asthma, respiratory disorder, oropharyngeal pain, cough, dysphonia, nasal congestion, throat irritation
Gastrointestinal disorders	Uncommon	peptic ulcer reactivated, gastrointestinal disorder, constipation
	Common	skin hyperpigmentation (periocular)
Skin and subcutaneous tissue disorders	Uncommon	dermatitis allergic, periorbital oedema, dermatitis contact, erythema, rash, hair colour changes, hair texture abnormal, hypertrichosis, madarosis
Musculoskeletal, connective tissue and bone disorders	Uncommon	musculoskeletal 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 Travoprost as monotherapy include the following.

Ocular: macular oedema (see also section 4.4), sunken eyes

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

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 (Website: www.mhra.gov.uk/yellowcard).

4.9 Overdose

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 Travoprost may be flushed from the eye(s) with lukewarm water. Treatment of a suspected oral ingestion is symptomatic and supportive.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Ophthalmologicals - antiglaucoma preparations and

miotics - prostaglandin analogues ATC code: S01E E04 Mechanism of action

Travoprost, a prostaglandin F_2a 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 Travoprost with timolol 0.5% and limited data with brimonidine 0.2% were collected during clinical trials that showed an additive effect of Travoprost 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)

5.2 Pharmacokinetic properties

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 Travoprost. Aqueous humour concentrations declined with a half-life of approximately 1.5 hours.

Distribution

Following topical ocular administration of Travoprost 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.

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_2a which are characterised by reduction of the 13-14 double bond, oxidation of the 15-hydroxyl and P-oxidative cleavages of the upper side chain.

Elimination

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

5.3 Preclinical safety data

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 ³H - Travoprost. Reproduction and development studies have demonstrated a potent effect on foetal loss with a high rate observed in rats and mice at plasma levels of 180 pg/ml and 30 pg/ml, respectively corresponding to 1.2 to 6 times the clinical exposure (up to 25 pg/ml).

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Benzalkonium chloride

Macrogol glycerol hydroxy stearate 40

Trometamol

Disodium edetate

Boric acid (E284)

Mannitol (E421)

Sodium hydroxide Water for injection

6.2    Incompatibilities

None known.

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

Shelf life

3 years

Discard 4 weeks after first opening.

6.4 Special precautions for storage

Before opening, keep bottle in overwrap pouch in order to protect from moisture.

After first opening, this medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Translucent polypropylene (PP) 5 ml bottle with a transparent low density polyethylene (LDPE) dropper and a white high density polyethylene (HPDE) tamper-proof screw cap, presented in a polyethylene terephthalate/ aluminium/polyethylene (PET/Alu/PE) overwrap. Each bottle contains 2.5 ml eye drops.

Pack sizes: Cartons containing 1 or 3 bottles.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Pharmathen S.A.

Dervenakion 6, Pallini, Attiki, 153 51 Greece

8    MARKETING AUTHORISATION NUMBER(S)

PL 17277/0318

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/04/2014

10 DATE OF REVISION OF THE TEXT

11/04/2014