polihexanide: prescribing information – dosing, contraindications, interactions, side effects

AKANTIOR is indicated for the treatment of Acanthamoeba keratitis in adults and children from 12 years of age.

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

Posology

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 following regimen:

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 corneal inflammation 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 ocular inflammation 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.

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

Special populations

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

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

Method of administration

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 it afterwards.
• 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.

Summary of safety profile

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.

Tabulated list of adverse reactions

The adverse reactions listed below were observed in clinical trials in patients treated with AKANTIOR with 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 (≥ 1/100 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 from available data). Within each frequency grouping, adverse reactions 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 administration site conditions
Common
Condition aggravated
Application site pain
Application site discomfort
Product intolerance
Application site pruritus
Injury, poisoning and procedural complications
Common
Persistent epithelial defect
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 phosphate containing eye drops in some patients with significantly damaged corneas.

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 national reporting system listed in Appendix V.

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 or requiring systemic immunosuppressive therapy.

Excipients

AKANTIOR contains phosphates. Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged 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 least 5 minutes after the last administration.

As systemic absorption of polihexanide after use of AKANTIOR is negligible or not detectable, no interactions with systemic medicinal products are expected.

Pregnancy

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 respect to reproductive toxicity (see section 5.3).

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

Breast-feeding

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 of therapy for the woman.

Fertility

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 temporary blurred vision or other visual disturbances, which is expected to last a few minutes after instillation. If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machines.

No information is available on overdose in humans; overdose is unlikely to occur after ocular administration.
If overdose occurs, treatment should be symptomatic and supportive.

5.
PHARMACOLOGICAL PROPERTIES

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 primarily affecting contact lens wearers with an incidence of 1-4 per million. Results from a cohort of 227 patients in a retrospective study indicated substantial variations in the way patients are treated; a combination of polihexanide 0.2 mg/ml and propamidine 1.0 mg/ml was used in 45 patients and 57.8% of patients were cured within one year.

Mechanism of action

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 the phospholipid bilayer of the trophozoites membrane, negatively charged, causing membrane damage, cell lysis and death due to leakage of essential cell components. Polihexanide is also able to penetrate the ostiole of the encysted Acanthamoeba to exert the same effect. This action only marginally affects the neutral phospholipids in mammalian cell membrane.
• DNA binding. Once polihexanide has passed through the cell membrane, it condenses and damages Acanthamoeba chromosomes. Polihexanide interacts extensively with the DNA phosphate backbone to block the Acanthamoeba DNA replication process. This mechanism is restricted to Acanthamoeba cells as polihexanide is unable to penetrate the nucleus of mammalian cells.

Clinical efficacy

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 who received no treatment. These subjects were identified through a systematic literature review (n=56); the clinical 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 of treatment (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 expanded retrospective study published by Papa et al. 2020. By performing a crude adjustment method of adding this estimated value of 30.7%, the estimated placebo effect would reach a hypothetical clinical resolution of 50.3% (95%CI: 36.6%; 64.1%).

Table 2. Absolute efficacy of AKANTIOR
Treatment
AKANTIOR + placebo
No treatment
Source

Pharmacokinetics were not studied.

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