Leaflet AKANTIOR 0.8mg / ml ophthalmic drops single dose solution

AKANTIOR 0.8 mg/mL eye drops, solution in single-dose container

Each mL of solution contains 0.8 mg polihexanide (0.08% w/w). One drop (about 0.032 g) contains onaverage 0.025 mg polihexanide.

Each drop of the solution contains approximately 0.4 mg phosphates which is equivalent to 11 mg/mL.

For the full list of excipients, see section 6.1.

Eye drops, solution in single-dose container (eye drops)

Clear, colourless solution, practically free of visible particles.pH: 5.6 - 6.0

Osmolality: 270 - 330 mOsmol/kg

AKANTIOR is indicated for the treatment of Acanthamoeba keratitis in adults and children from12 years of age.

AKANTIOR should be prescribed by physicians experienced in the diagnosis and treatment of

Acanthamoeba keratitis.

AKANTIOR should be started as early as possible in the course of Acanthamoeba infection.

Adults and children from 12 years of age

The recommended dose is 1 drop of AKANTIOR in the affected eye according to the followingregimen:

Intensive 19-day treatment phase:

* 16 times a day at 1-hour intervals, daytime only, for five days

* 8 times a day at 2-hour intervals, daytime only, for further seven days

* 6 times a day at 3-hour intervals, daytime only, for further seven days

Continuation treatment phase:

* 4 times a day at 4-hour intervals, until cure (i.e. corneal healing, absence of cornealinflammation or no evidence of infection) and for no longer than 12 months.

Reinitiation of intensive treatment.

The 19-day intensive regimen phase may be reinitiated if a deterioration (or exacerbation) of ocularinflammation occurs during the continuation treatment phase and Acanthamoeba culture is negative.

Treatment with AKANTIOR should be stopped if deterioration is accompanied by a positive culture.

AKANTIOR should be discontinued in patients with failure to achieve cure within 12 months oftreatment start.

The safety and efficacy of AKANTIOR in children younger than 12 years has not yet beenestablished. No data are available.

No dose adjustment is required in patients 65 years of age and older.

For ocular use.

For single use only.

The contents of the single-dose container must be used immediately after opening.

Patients should be instructed:

* To avoid contact between the single-dose container tip and the eye or eyelids.

* To use the solution immediately after opening the single-dose container and to discard itafterwards.

* To instil AKANTIOR at least 5 minutes after any other ophthalmic product.

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

Subjects with urgent need of ocular surgery due to advanced Acanthamoeba keratitis.

AKANTIOR may cause mild to moderate eye discomfort (such as eye pain) and eye redness.

The patient should be advised to contact the doctor in case of concern or a severe eye reaction.

No data are available on the use of AKANTIOR in subjects with immunodeficiency disorders orrequiring systemic immunosuppressive therapy.

AKANTIOR contains phosphates. Cases of corneal calcification have been reported very rarely inassociation with the use of phosphate containing eye drops in some patients with significantlydamaged corneas.

No interaction studies have been performed.

Local interactions with other medicinal products cannot be excluded.

If more than one topical ophthalmic product is being used, AKANTIOR must be administered at least5 minutes after the last administration.

As systemic absorption of polihexanide after use of AKANTIOR is negligible or not detectable, nointeractions with systemic medicinal products are expected.

There are no data from the use of polihexanide in pregnant women.

Animal studies using oral administration do not indicate direct or indirect harmful effects with respectto reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of AKANTIOR during pregnancy.

It is unknown whether polihexanide is excreted in human milk.

A decision must be made as to whether to discontinue breast-feeding or to discontinue/abstain from

AKANTIOR therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

There are no data on the effects of polihexanide on human fertility.

AKANTIOR has minor influence on the ability to drive and use machines, as it may cause temporaryblurred vision or other visual disturbances, which is expected to last a few minutes after instillation. Ifblurred vision occurs at instillation, the patient must wait until the vision clears before driving or usingmachines.

The most common adverse reactions are eye pain (13.0%) and ocular hyperaemia (11.6%).

The most serious are corneal perforation (1.4%), corneal transplant (1.4%) and visual impairment(1.4%), which are also part of the natural history of the disease.

The adverse reactions listed below were observed in clinical trials in patients treated with AKANTIORwith a reasonable possibility of causality to the medicinal product.

Adverse reactions are presented according to MedDRA system organ classification (SOC and

Preferred Term Level).

They are classified according to the subsequent convention: very common (≥ 1/10); common (≥ 1/100to < 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 from available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions observed in clinical trial 043/SI

System organ class Frequency Adverse reactions

Infections and infestations Common Conjunctivitis

Eye infection

Eye disorders Very common Eye pain

Ocular hyperaemia

Common Corneal perforation

Visual impairment

Ulcerative keratitis

Corneal epithelium defects

Corneal infiltrates

Punctate keratitis

Tearing

Conjunctival hyperaemia

Eye inflammation

Eye irritation

Photophobia

Conjunctival papillae

Eye pruritus

Eye discharge

Eye swelling

Foreign body sensation

Ocular discomfort

Dry eye

General disorders and Common Condition aggravatedadministration site conditions Application site pain

Application site discomfort

Product intolerance

Application site pruritus

Injury, poisoning and procedural Common Persistent epithelial defectcomplications Toxicity to various agents

Surgical and medical procedures Common Corneal transplant

Adverse reactions reported in phosphate containing eye drops

Cases of corneal calcification have been reported very rarely in association with the use of phosphatecontaining eye drops in some patients with significantly damaged corneas.

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.

No information is available on overdose in humans; overdose is unlikely to occur after ocularadministration.

If overdose occurs, treatment should be symptomatic and supportive.

Pharmacotherapeutic group: Ophthalmologicals, other antiinfectives, ATC code: S01AX24

Acanthamoeba keratitis is a severe, progressive corneal infection characterized by intense pain,photophobia, and is sight threatening. Acanthamoeba keratitis is an ultra-rare disease primarilyaffecting contact lens wearers with an incidence of 1-4 per million. Results from a cohort of 227patients in a retrospective study indicated substantial variations in the way patients are treated; acombination of polihexanide 0.2 mg/ml and propamidine 1.0 mg/ml was used in 45 patients and57.8% of patients were cured within one year.

Pharmacodynamics were not tested in the scope of clinical trials.

Polihexanide acts on both the active trophozoite and dormant cystal forms of Acanthamoeba.

Polihexanide is a polycationic polymer composed of hexamethylene biguanide units and has a dual-targeted mechanism of action that involves:

* Disruption of Acanthamoeba cell membranes. Polihexanide, positively charged, binds to thephospholipid bilayer of the trophozoites membrane, negatively charged, causing membranedamage, cell lysis and death due to leakage of essential cell components. Polihexanide is alsoable to penetrate the ostiole of the encysted Acanthamoeba to exert the same effect. This actiononly marginally affects the neutral phospholipids in mammalian cell membrane.

* DNA binding. Once polihexanide has passed through the cell membrane, it condenses anddamages Acanthamoeba chromosomes. Polihexanide interacts extensively with the DNAphosphate backbone to block the Acanthamoeba DNA replication process. This mechanism isrestricted to Acanthamoeba cells as polihexanide is unable to penetrate the nucleus ofmammalian cells.

The absolute efficacy of AKANTIOR was determined by comparing results observed in a randomised,double-blind, active-controlled phase III clinical trial with historical control data on subjects whoreceived no treatment. These subjects were identified through a systematic literature review (n=56); theclinical resolution rate with no surgery in this historical control was 19.6% (95%CI: 10.2%, 32.4%).

The remaining 80.4% of patients required surgery (keratoplasty 38/56: 67.9% [48.0%, 83.0%]),enucleation 4/56: 7.1% [3.0%, 18.0%]) or minor surgery 4/56: 7.1% [1.0%, 29.0%])).

The treatment effect (percentage of patients cured without surgery) of AKANTIOR versus absence oftreatment (historical control) is shown in Table 2. A study effect of 30.7% (95%CI: 14.2%; 47.2%)was also estimated based on results observed for the chosen comparator in study 043 and the expandedretrospective study published by Papa et al. 2020. By performing a crude adjustment method of addingthis estimated value of 30.7%, the estimated placebo effect would reach a hypothetical clinicalresolution of 50.3% (95%CI: 36.6%; 64.1%).

Table 2. Absolute efficacy of AKANTIOR

Treatment AKANTIOR + placebo No treatment

Source Phase III clinical trial Historical control

N. 66 56

Cured 56 11

Clinical resolution rate (binomialexact 95% CI) 84.8% (73.9%, 92.5%) 19.6% (10.2%, 32.4%)

Clinical resolution rate including30.7% study effect (binomial exact 84.8% (73.9%, 92.5%) 50.3 % (36.6%, 64.1%)95%CI)

Treatment effect-mean difference(binomial exact 95%CI) unadjusted 65.2% (49.3%, 77.5%)

Treatment effect-mean difference(binomial exact 95%CI) adjusting for 34.5% (16.8%,49.8%)a study effect

CI=confidence interval

The phase III clinical trial was conducted using, as active control, 0.2 mg/ml polihexanide plus 1mg/ml propamidine . In total, 135 patients with Acanthamoeba keratitis and no history of previousanti-amoebic treatment were enrolled in this trial. Subjects requiring urgent surgical intervention foradvanced Acanthamoeba keratitis in either eye (e.g., for advanced corneal thinning/melting etc.) wereexcluded. The overall mean age was 36.5 years; 58.2% patients were female. Four patients were aged15-17 years and two patients were aged > 65 years.

Patients were randomised 1:1 to receive AKANTIOR plus placebo (n = 69) or a combination ofpolihexanide 0.2 mg/mL plus propamidine 1 mg/mL (n = 66). Both treatment arms followed the samedosing regimen with an intensive 19-day treatment (16 times daily for 5 days, 8 times daily for 7 days,6 times daily for a further 7 days) during the daytime only, followed by 4 times daily treatment untilresolution of corneal inflammation. The investigators also received instructions when to stop orreinitiate treatment (see section 4.2). Treatment was allowed for a maximum of one year.

Of the 135 patients enrolled, 127 (66 AKANTIOR and 61 comparator-arm) had a confirmed diagnosisof Acanthamoeba keratitis by in vivo confocal microscopy, PCR, or culture. The intention-to-treat(ITT) population included 127 patients, and the per protocol (PP) population included 119 subjects (62

AKANTIOR and 57 comparator-arm).

The primary efficacy endpoint was the clinical resolution rate within 12 months from randomisation.

Patients requiring an increase of the dose due to worsening of the condition (n=4), all of them in themonotherapy treatment group, were counted as treatment failure in the primary analysis. Analyseswere performed on the ITT population.

Clinical resolution was defined as no corneal inflammation requiring treatment, no or mildconjunctival inflammation, no limbitis, scleritis or anterior chamber inflammation, and no relapsewithin 30 days of discontinuing all topical therapy given for Acanthamoeba keratitis.

The clinical resolution rate obtained in the study is shown in Table 3.

Table 3. Primary efficacy analysis: cure rate within 12 months

Treatment n Cured % cured Difference in proportion(95%CI) rate (95%CI)

AKANTIOR + placebo 66 56 84.8% (73.9%, 92.5%)0.2 mg/ml polihexanide + -0.04 (-0.15, 0.08)1 mg/ml propamidine 61 54 88.5% (77.8%, 95.3%)

CI=confidence interval

The median time-to-cure was 140 days (95%CI=117,150) for 0.8 mg/ml polihexanide and 114 days(91,127) for the control arm (p=0.0442, log rank test).

Overall, 2 subjects had corneal transplantation, both in the 0.8 mg/ml polihexanide + placebotreatment group (1 was coded as “Corneal infiltrates” and therefore, it was not included in therespective table as “Corneal transplant”). There were small differences in the proportion of treatmentfailures (prematurely withdrawn subjects) between treatments: 10/66 (15.2%) in the group treated with0.8 mg/ml polihexanide and 7/61 (11.5%) in the group treated with 0.2 mg/ml polihexanide plus 1mg/ml propamidine.

The European Medicines Agency has waived the obligation to submit the results of studies with

AKANTIOR in all subsets of the paediatric population with Acanthamoeba keratitis (see section 4.2for information on paediatric use).

Pharmacokinetics were not studied.

AKANTIOR is intended for topical ophthalmic application. The systemic absorption of polihexanideis expected to be negligible after topical administration to the eye.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

A 26-week toxicity study using daily administration (16 times/day at approximately 1-hour intervalsfrom day 1 to day 5, 8 times/day at approximately 2-hour intervals from day 6 to week 3 and4 times/day at approximately 4-hour intervals from week 4 to week 26) of polihexanide 0.8 mg/mLeye drops was conducted in rabbits. The study did not indicate any local or systemic effects of thetreatment. No indications of a systemic effect of polihexanide 0.8 mg/mL eye drops were observedduring 26 weeks of treatment period. Post mortem macroscopic and histopathological examinationsperformed at the end of the study did not reveal treatment-related changes.

There was no evidence of genotoxicity in in vitro and in vivo studies.

There was no evidence of embryo-foetal toxicity in oral studies in the rat and the rabbit.

Sodium dihydrogen phosphate monohydrate

Disodium phosphate dodecahydrate

Sodium chloride

Purified water

Not applicable.

2 years.

After opening the sachet

Once the outer sachet has been opened, the single-dose containers must be used within 28 days (afterthis period, any unused single-dose containers must be discarded).

After opening the single-dose container

The contents of the single dose container must be used immediately after opening.

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

AKANTIOR is contained in low density polyethylene (LDPE) single-dose containers filled with0.3 mL solution.

The single-dose containers are moulded in 5-unit sealed strips which in turn are wrapped in apolyester/aluminium/polyethylene sachet and packaged inside a carton box.

* 20 single-dose containers

* 30 single-dose containers

* multipack containing 120 (4 packs of 30) single-dose containers

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

SIFI S.p.A.

Via Ercole Patti, 3695025 Aci Sant’Antonio (CT)

Italy

EU/1/24/1840/001

EU/1/24/1840/002

EU/1/24/1840/003

Date of first authorisation:

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

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