IZBA 30mcg / ml ophthalmic drops solution medication leaflet

IZBA 30 micrograms/mL eye drops, solution

One mL of solution contains 30 micrograms of travoprost.

One mL of solution contains 7.5 mg propylene glycol and 2 mg polyoxyethylene hydrogenated castoroil 40 (HCO-40) (see section 4.4).

For the full list of excipients, see section 6.1.

Eye drops, solution (eye drops).

Clear, colourless solution.

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

Decrease of elevated intraocular pressure in paediatric patients aged 3 years to <18 years with ocularhypertension or paediatric glaucoma (see section 5.1).

Use in adults, including elderly patients

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

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

If more than one topical ophthalmic medicinal product is being used, the medicinal products must beadministered at least 5 minutes apart.

If a dose is missed, treatment should be continued with the next dose as planned. The dose should notexceed one drop in the affected eye(s) daily.

When substituting another ophthalmic antiglaucoma medicinal product with IZBA, the othermedicinal product should be discontinued and IZBA should be started the following day.

Travoprost 30 µg/mL has not been studied in patients with hepatic or renal impairment. However,travoprost 40 µg/mL has been studied in patients with mild to severe hepatic impairment and inpatients with mild to severe renal impairment (creatinine clearance as low as 14 mL/min). No dosageadjustment is necessary in these patients (see section 5.2). Therefore, no need for dose adjustment atthe lower concentration of active ingredient is anticipated.

IZBA can be used in paediatric patients from 3 years to <18 years at the same posology as in adults(see section 5.1).

The safety and efficacy of IZBA in children below the age of 3 years have not been established.

Currently available data are described in section 5.1 but no recommendation on a posology below theage of 3 years can be made.

For ocular use.

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

The patient should remove the protective overwrap immediately prior to initial use. To preventcontamination of the dropper tip and solution, care must be taken not to touch the eyelids, surroundingareas or other surfaces with the dropper tip of the bottle.

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

Eye colour change

IZBA may gradually change the eye colour by increasing the number of melanosomes (pigmentgranules) in melanocytes. Before treatment is instituted, patients must be informed of the possibility ofa permanent change in eye colour. Unilateral treatment can result in permanent heterochromia. Thelong-term effects on the melanocytes and any consequences thereof are currently unknown. Thechange in iris colour occurs slowly and may not be noticeable for months to years. The change in eyecolour 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 withbrown eyes. Typically, the brown pigmentation around the pupil spreads concentrically towards theperiphery in affected eyes, but the entire iris or parts of it may become more brownish. Afterdiscontinuation 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

IZBA has been reported in 0.2% of patients.

Periorbital and lid changes including deepening of the eyelid sulcus have been observed withprostaglandin analogues.

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

There is no experience of IZBA in inflammatory ocular conditions; nor in neovascular, angle-closure,narrow-angle or congenital glaucoma and only limited experience in thyroid eye disease, inopen-angle glaucoma of pseudophakic patients and in pigmentary or pseudoexfoliative glaucoma.

IZBA 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 isrecommended when using IZBA in aphakic patients, pseudophakic patients with a torn posterior lenscapsule 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, IZBA should be used with caution.

Contact with the skin

Skin contact with IZBA must be avoided as transdermal absorption of travoprost has beendemonstrated in rabbits.

Prostaglandins and prostaglandin analogues are biologically active materials that may be absorbedthrough the skin. Women who are pregnant or attempting to become pregnant should exerciseappropriate precautions to avoid direct exposure to the contents of the bottle. In the unlikely event ofcoming in contact with a substantial portion of the contents of the bottle, thoroughly cleanse theexposed area immediately.

Contact lenses

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

IZBA contains propylene glycol which may cause skin irritation.

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

No long-term safety data are available in the paediatric population.

No interaction studies have been performed.

Travoprost must not be used in women of childbearing age/potential unless adequate contraceptivemeasures are in place (see section 5.3).

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

Travoprost should not be used during pregnancy unless clearly necessary.

It is unknown whether travoprost from eye drops is excreted in human breast milk. Animal studieshave shown excretion of travoprost and metabolites in breast milk. The use of travoprost bybreast-feeding mothers is not recommended.

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

IZBA has no or negligible 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 orusing machines.

In a clinical trial of 3 months duration (N=442) involving IZBA as monotherapy, the most commonadverse reaction observed was hyperaemia of the eye (ocular or conjunctival) reported inapproximately 12% of the patients.

The following adverse reactions were assessed to be related with IZBA monotherapy and areclassified 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 <1/1,000) and very rare(<1/10,000). Within each frequency grouping in Table 1, adverse reactions are presented indecreasing order of seriousness.

Table 1 Travoprost 30 µg/mL eye drops, solution

System Organ class Frequency Adverse reaction

Eye disorders Very common ocular hyperaemia

Common dry eye, eye pruritus, ocular discomfort

Uncommon punctate keratitis, anterior chamberinflammation, blepharitis, eye pain,photophobia, visual impairment, vision blurred,conjunctivitis, eyelid oedema, eyelid margincrusting, eye discharge, dark circles undereyes, growth of eyelashes, eyelash thickening

Skin and subcutaneous Uncommon pruritus, rashtissue disorders

The following adverse reactions were assessed to be related with travoprost 40 µg/mL eye drops,solution (either benzalkonium chloride [BAK] or Polyquad-preserved) and are classified according tothe following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to<1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated fromthe available data). Within each frequency grouping in Table 2, adverse reactions are presented indecreasing order of seriousness.

Table 2 Travoprost 40 µg/mL eye drops, solution

System Organ class Frequency Adverse reaction

Immune system disorders Uncommon hypersensitivity, seasonal allergy

Psychiatric disorders Not known depression, anxiety, insomnia

Nervous system disorders Uncommon headache

Rare dysgeusia, dizziness, visual field defect

Eye disorders Very common ocular hyperaemia

Common iris hyperpigmentation, eye pain, oculardiscomfort, dry eye, eye pruritus, eye irritation

Uncommon corneal erosion, uveitis, iritis, anterior chamberinflammation, keratitis, punctate keratitis,photophobia, eye discharge, blepharitis,erythema of eyelid, periorbital oedema, eyelidspruritus, visual acuity reduced, vision blurred,lacrimation increased, conjunctivitis, ectropion,cataract, eyelid margin crusting, growth ofeyelashes

Rare iridocyclitis, ophthalmic herpes simplex, eyeinflammation, photopsia, eczema eyelids,conjunctival oedema, halo vision, conjunctivalfollicles, hypoaesthesia eye, trichiasismeibomianitis, anterior chamber pigmentation,mydriasis, asthenopia, eyelashhyperpigmentation, eyelash thickening

Not known macular oedema, lid sulcus deepened

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, arrhythmia

Vascular disorders Rare blood pressure diastolic decreased, bloodpressure systolic increased, hypotension,hypertension

Respiratory, thoracic and Uncommon cough, nasal congestion, throat irritationmediastinal disorders Rare dyspnoea, asthma, respiratory disorder,oropharyngeal pain, dysphonia, rhinitis allergic,nasal dryness

Not known asthma aggravated, epistaxis

Gastrointestinal disorders Rare peptic ulcer reactivated, dry mouthgastrointestinal disorder, constipation

Not known diarrhoea, abdominal pain, nausea, vomiting

Skin and subcutaneous tissue Uncommon skin hyperpigmentation (periocular), skindisorders discolouration, hair texture abnormal,hypertrichosis

Rare dermatitis allergic, , dermatitis contact,erythema, rash, hair colour changes, madarosis

Not known Pruritus, hair growth abnormal

Musculoskeletal and connective Rare musculoskeletal pain, arthralgiatissue disorders

Renal and urinary disorders Not known dysuria, urinary incontinence

General disorders and Rare astheniaadministration site conditions

Investigations Not known prostatic specific antigen increased

In a 3-month phase 3 study and a 7-day pharmacokinetic study, involving 102 paediatric patientsexposed to travoprost 40 micrograms/mL eye drops, solution, the types and characteristics of adversereactions reported were similar to what has been observed in adult patients. The short-term safetyprofiles in the different paediatric subsets were also similar (see section 5.1). The most frequentadverse reactions reported in the paediatric population were ocular hyperaemia (16.9%) and growth ofeyelashes (6.5%). In a similar 3-month study in adult patients, these events occurred at an incidence of11.4% and 0%, respectively.

Additional adverse reactions reported in paediatric patients in the 3-month paediatric study (n=77)compared to a similar trial in adults (n=185) included erythema of eyelid, keratitis, lacrimationincreased, and photophobia, all reported as single events with an incidence of 1.3% versus 0.0% seenin adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

A topical overdose is not likely to occur or to be associated with toxicity. A topical overdose oftravoprost may be flushed from the eye(s) with lukewarm water. Treatment of a suspected oralingestion is symptomatic and supportive.

Pharmacotherapeutic group: Ophthalmologicals, antiglaucoma preparations and miotics, ATC code:

S01EE04

Travoprost, a prostaglandin F2 analogue, is a highly selective full agonist which has a high affinity forthe prostaglandin FP receptor, and reduces the intraocular pressure by increasing the outflow ofaqueous humour via trabecular meshwork and uveoscleral pathways. Reduction of the intraocularpressure in man starts about 2 hours after administration and maximum effect is reached after12 hours. Significant lowering of intraocular pressure can be maintained for periods exceeding24 hours with a single dose.

In a clinical trial, patients with open-angle glaucoma or ocular hypertension treated with IZBA dosedonce-daily in the evening, demonstrated intraocular pressure lowering equivalent to travoprost40 µg/mL eye drops, solution at all on-therapy visits and time points (95% CI within ±1.0 mmHg).

The mean reduction from baseline in IOP ranged from 7.1 to 8.2 mmHg as summarised in Table 3.

The mean percent reductions in IOP from baseline to each study visit and assessment time pointranged from 28.4% to 30.7%.

Table 3 IOP change from baseline (mmHg) for IZBA

Visit 8 AM 10 AM 4 PM

Week 2 Mean -8.0 -7.3 -7.1(N=442) 95% CI (-8.3, -7.7) (-7.6, -7.0) (-7.4, -6.8)

Week 6 Mean -8.1 -7.4 -7.2(N=440*) 95% CI (-8.4, -7.9) (-7.6, -7.1) (-7.5, -6.9)

Month 3 Mean -8.2 -7.5 -7.1(N=432*) 95% CI (-8.6, -7.9) (-7.9, -7.2) (-7.4, -6.8)

*One subject had missing data at 8 AM at Week 6; one had missing data at 4 PM at Month 3.

An improved safety profile has been observed for IZBA when compared to the marketed travoprost40 µg/mL eye drops, solution (benzalkonium chloride preserved or polyquaternium-1 perserved). Themost common adverse reaction associated with both IZBA and travoprost 40 µg/mL eye drops,solution is hyperaemia. Hyperaemia (ocular or conjunctival) was observed in 11.8% of patients(N=442) exposed to IZBA compared with 14.5% observed for patients exposed to travoprost40 µg/mL eye drops, solution, benzalkonium chloride preserved.

Secondary pharmacology

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

Travoprost 40 µg/mL eye drops, solution preserved with polyquaternium-1 induced minimal ocularsurface toxicity, compared to eye drops preserved with benzalkonium chloride, on cultured humancorneal cells and following topical ocular administration in rabbits.

IZBA has not been specifically studied in a clinical trial involving paediatric subjects. However, amodelling approach demonstrated that IOP lowering would be expected to be equivalent in paediatricpatients aged 3 years and above using both IZBA and TRAVATAN (travoprost 40 micrograms/mLeye drops, solution). The studies used in the model were two dose response trials, one Phase III studyusing IZBA and a paediatric study using TRAVATAN (travoprost 40 micrograms/mL eye drops,solution).

The efficacy of TRAVATAN (travoprost 40 micrograms/mL eye drops, solution) in paediatric patientsfrom 2 months to less than 18 years of age was demonstrated in a 12-week, double-masked clinicalstudy of travoprost compared with timolol in 152 patients diagnosed with ocular hypertension orpaediatric glaucoma. Patients received either travoprost 0.004% once daily or timolol 0.5% (or 0.25%for subjects younger than 3 years old) twice daily. The primary efficacy endpoint was the intraocularpressure (IOP) change from baseline at Week 12 of the study. Mean IOP reductions in the travoprostand timolol groups were similar (see Table 4).

In the age groups 3 to <12 years (n=36) and 12 to <18 years (n=26), mean IOP reduction at Week 12in the travoprost group was similar to that in the timolol group. Mean IOP reduction at Week 12 in the2 months to <3 years of age group was 1.8 mmHg in the travoprost group and 7.3 mmHg in thetimolol group. IOP reductions for this group were based on only 6 patients in the timolol group and9 patients in the travoprost group where 4 patients in the travoprost group versus 0 patients in thetimolol group had no relevant mean IOP reduction at Week 12. No data are available for children lessthan 2 months old.

The effect on IOP was seen after the second week of treatment and was consistently maintainedthroughout the 12 week period of study for all age groups.

Table 4 Comparison of Mean IOP Change from Baseline (mmHg) at Week 12

Travoprost Timolol

Mean Mean Mean

N (SE) N (SE) Differencea (95% CI)53 -6.4 60 -5.8 -0.5 (-2.1, 1.0)(1.05) (0.96)

SE = Standard Error; CI = Confidence Interval;aMean difference is travoprost - timolol. Estimates based on least squares means derived from astatistical model that accounts for correlated IOP measurements within patient where primarydiagnosis and baseline IOP stratum are in the model.

Travoprost is an ester prodrug. It is absorbed through the cornea where the isopropyl ester ishydrolysed to the active free acid. Studies in rabbits have shown peak concentrations of 20 ng/g of thefree acid in aqueous humour one to two hours after topical dosing of travoprost 40 µg/mL eye drops,solution. Aqueous humour concentrations declined with a half-life of approximately 1.5 hours.

Following topical ocular administration of travoprost 40 µg/mL eye drops, solution to healthyvolunteers, low systemic exposure to active free acid was demonstrated. Peak active free acid plasmaconcentrations 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 hourpost-administration. Due to the low plasma concentrations and rapid elimination following topicaldosing, the elimination half-life of active free acid in man could not be determined.

Metabolism is the major route of elimination of both travoprost and the active free acid. The systemicmetabolic pathways parallel those of endogenous prostaglandin F2 which are characterised byreduction of the double bond in position C13-C14, oxidation of the 15-hydroxyl and -oxidativecleavages of the upper side chain.

Travoprost free acid and its metabolites are mainly excreted by the kidneys. Travoprost 40 µg/mL eyedrops, solution has been studied in patients with mild to severe hepatic impairment and in patientswith mild to severe renal impairment (creatinine clearance as low as 14 mL/min). No dosageadjustment is necessary in these patients.

A pharmacokinetic study of TRAVATAN (travoprost 40 micrograms/mL eye drops, solution) inpaediatric patients aged 2 months to <18 years demonstrated low plasma exposure to travoprost freeacid, with concentrations ranging from below the 10 pg/mL assay limit of quantitation (BLQ) to54.5 pg/mL.

In ocular toxicity studies in monkeys, administration of travoprost at a dose of 0.45 microgram, twicea day, was shown to induce increased palpebral fissure. Topical ocular administration of travoprost tomonkeys at concentrations of up to 0.012% to the right eye, twice daily for one year resulted in nosystemic toxicity.

Increased palpebral fissure observed in monkeys were not seen in rabbits or in the clinical trials withtravoprost products and is considered to be species specific.

Reproduction toxicity studies have been undertaken in rat, mice and rabbit by systemic route. Findingsare 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 theclinical 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 ratsadministered 3H-travoprost. Reproduction and development studies have demonstrated a potent effecton 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).

Travoprost is considered a persistent, bioaccumulative and toxic (PBT) substance. Hence, despite thevery small amounts of travoprost used by patients in eye drops, a risk to the environment cannot beexcluded.

Polyquaternium-1

Polyoxyethylene hydrogenated castor oil 40 (HCO-40)

Boric acid (E284)

Mannitol (E421)

Sodium chloride

Propylene glycol (E1520)

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

Purified water

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

2 years.

Discard 4 weeks after first opening.

This medicinal product does not require any special storage conditions.

IZBA is packaged in a 4 mL syndiotactic polypropylene (sPP) oval bottle with polypropylene (PP)dispensing plugs and closures presented in an overwrap. Each 4 mL bottle will contain 2.5 mL ofsolution.

Cartons containing 1 or 3 bottles.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements. It should be noted that travoprost is considered a PBT substance (see section 5.3).

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/13/905/001-002

Date of first authorisation: 20 February 2014

Date of latest renewal: 14 November 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu