SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Hamituf 40 micrograms/mL eye drops, solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of solution contains 40 micrograms of travoprost.

Excipient(s) with known effect:

Each mL of solution contains 10 microgram of polyquaternium-1, 7.5 mg of propylene glycol, 2 mg of macrogolglycerol hydroxystearate 40 (see section 4.4.)

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Eye drops, solution. (Eye drops)

Clear, colourless solution.

pH 6.3 to 7.3;

osmolality 265 - 320 mOsmol/kg

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

4.2 Posology and method of administration

Posology

Use in adults, including elderly population

The dose is one drop of Hamituf 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 medicinal product withtravoprost eye drops, the other medicinal product should be discontinued and travoprost eye drops should be started the following day.

Patients with 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.

Paediatric population

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

Method of Administration For ocular use.

For patients who wear contact lenses, please refer to section 4.4.

After cap is removed, if the tamper evident snap collar is loose, remove before using the medicinal product. 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.

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

Eye colour change

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.

Periorbital and eye lid changes

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. Periorbital and lid changes including deepening of the eyelid sulcus have also 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 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. Travoprost should therefore be used with caution in patients with active intraocular inflammation.

Aphakic patients

Macular oedema has been reported during treatment with prostaglandin F2a analogues. 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.

Iritis/uveitis

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

Contact with the skin

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

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.

Contact lenses

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

Excipients

Hamituf contains propylene glycol which may cause skin irritation.

Hamituf contains macrogolglycerol hydroxystearate 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 the 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.

Fertility

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

4.7 Effects on ability to drive and use machines

Travoprost has no or negliglible influence on the ability to drive and use machines. 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.

4.8 Undesirable effects

Summary of the safety profile

In clinical trials with travoprost eye drops , the most common adverse reactions were hyperaemia and iris hyperpigmentation, occurring in approximately 20% and 6% of pateients respectively.

Tabulated list of adverse reactions

The following adverse reactions 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) or not known (frequency cannot be estimated from the available data). Within each frequency group, adverse reactions are presented in decreasing order of seriousness. The adverse reactions were obtained from clinical studies and post-marketing data with travoprost eye drops.

System Organ Class	Frequency	Adverse reactions
Infections and infestations	Rare	herpes simplex, keratitis herpetic
Immune system disorders	Uncommon	hypersensitivity, seasonal allergy
Phychiatric disorders	Not known	depression, anxiety
Nervous system disorder	Uncommon	headache, dizziness, visual field defect
	Rare	dysgeusia
Eye disorders	Very common	ocular hyperaemia
	Common	iris hyperpigmentation, eye pain, ocular discomfort, dry eye, eye

		pruritus, eye irritation
	Uncommon	corneal erosion, uveitis, iritis, anterior chamber inflammation, keratitis, punctate keratitis, photophobia, eye discharge, blepharitis, erythema of eyelid, periorbital oedema, eyelids pruritus, visual acuity reduced, vision blurred, lacrimation increased, conjunctivitis, ectropioncataract, eyelid margin crusting, growth of eyelashes,
	Rare	eyelash discolouration, asthenopia
		iridocyclitis, eye inflammation, photopsia, eczema eyelids, conjunctival oedema, halo vision, conjunctival follicles, hypoaesthesia
	Not known	eye, meibomianitis, anterior chamber pigmentation, mydriasis, eyelash thickening
		macular oedema, sunken eyes
Ear and labyrinth disorders	Not known	vertigo, tinnitus
Cardiac disorders	Uncommon	palpitations
	Rare	heart rate irregular, heart rate decreased
	Not known	chest pain, bradycardia, tachycardia
Vascular disorders	Rare	blood pressure diastolic decreased, blood pressure systolic increased, hypotension, hypertension
Respiratory, thoracic and	Uncommon	dyspnoea, asthma, nasal congestion,
mediastinal disorder		throat irritation
	Rare	respiratory disorder, oropharyngeal pain, cough, dysphonia
	Not known	asthma aggravated
Gastrointestinal disorders	Rare	peptic ulcer reactivated, gastrointestinal disorder, constipation, dry mouth
	Not known	diarrhea, abdominal pain, nausea
Skin and subcutaneous	Uncommon	skin hyperpigmentation (periocular),
tissue disorders		skin discolouration, hair texture

		abnormal, hypertrichosis
	Rare	dermatitis allergic, dermatitis contact, erythema, rash, hair colour changes, madarosis
	Not known	pruritus, hair growth abnormal
Musculoskeletal and	Rare	musculoskeletal pain
connective tissue disorders	Not known	arthralgia
Renal and urinary disorders	Not known	dysuria, urinary incontinence
General disorders and administrative site conditions	Rare	asthenia
Investigations	Not known	prostatic specific antigen increased

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.

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 F2a 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.

Clinical efficacy and safety

In a clinical trial, patients with open-angle glaucoma or ocular hypertension who were treated with travoprost eye drops (polyquaternium preserved) dosed once-daily in the evening demonstrated 8 to 9 mmHg reductions (approximately 33%) in intraocular pressure from 24 to 26 mmHg baseline. 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).

Travoprost eye drops 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.

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 postdose. 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 halflife 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 F2„ 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 (180 pg/ml and 30 pg/ml plasma, respectively) at exposures 1.2 to 6 times the clinical exposure (up to 25 pg/ml).

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Boric acid (E284)

Sodium chloride Mannitol (E421)

Macrogolglycerol hydroxystearate 40

Polyquaternium-1

Propylene glycol (E1520)

Sodium hydroxide (E524) and/or hydrochloric acid (E507) (for pH adjustment) Purified water

6.2 Incompatibilities

Not applicable.

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

6.3 Shelf life

2 years

Discard 4 weeks after first opening.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

Keep the bottle in the outer carton in order to protect from light.

6.5 Nature and contents of container

Transparent LDPE bottles with transparent LDPE dropper insert and light blue, tamper-proof HDPE screw cap.

Pack sizes:

1 x 2.5 ml, 3 x 2.5 ml, 6 x 2.5 ml Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

ALFRED E. TIEFENBACHER (GmbH & Co KG.) Van-der-Smissen-Strasse 1 22767 Hamburg Germany

8    MARKETING AUTHORISATION NUMBER(S)

PL 17683/0132

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/02/2015

10    DATE OF REVISION OF THE TEXT

11/02/2015