Catiolanze 50 micrograms/mL eye drops, emulsion

Catiolanze is indicated for the reduction of elevated intraocular pressure (IOP) in adult patients with open angle glaucoma or ocular hypertension.

Catiolanze is indicated for the reduction of elevated IOP in children from 4 years of age and adolescents with elevated IOP and paediatric glaucoma.

Posology

Catiolanze may be used in paediatric patients from 4 years old onwards at the same posology as in adults.

Recommended therapy is one eye drop in the affected eye(s) once daily. Optimal effect is obtained if Catiolanze is administered in the evening.

The dose of Catiolanze should not exceed once daily since it has been shown that more frequent administration decreases the IOP lowering effect.

Missed dose

If one dose is missed, treatment should continue with the next dose as normal.

Paediatric population

The safety of Catiolanze in children aged less than 4 years old has not been established as no data for this formulation (emulsion) are available. Currently available safety data for the active substance latanoprost are described in sections 4.8 and 5.1.

Method of administration

Ocular use.

For single use only.

A single-dose container contains enough eye drops liquid to treat both eyes.

As with any eye drops, it is recommended that the lachrymal sac be compressed at the medial canthus (punctal occlusion) for one minute, in order to reduce possible systemic absorption. This should be performed immediately following the instillation of each drop.

Contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.

If more than one topical ophthalmic medicinal product is being used, the medicinal products must be administered at least 5 minutes apart. Catiolanze should be administered last (see section 4.5).

This medicinal product is a sterile white liquid that does not contain a preservative. The liquid from one individual single-dose container is to be used immediately after opening for administration to the affected eye(s). Since sterility cannot be maintained after the individual single-dose container is opened, any remaining contents must be discarded immediately after administration.

Patients should be instructed:

- to avoid contact between the dropper tip and the eye or eyelids

- to use the eye drops emulsion immediately after first opening the single-dose container and to discard the single-dose after use.

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

Change in eye colour

Catiolanze may gradually change eye colour by increasing the amount of brown pigment in the iris. Before treatment is instituted, patients should be informed of the possibility of a permanent change in eye colour. Unilateral treatment can result in permanent heterochromia.

This change in eye colour has predominantly been seen with latanoprost in patients with mixed coloured irides, i.e. blue-brown, grey-brown, yellow-brown and green-brown. In studies with latanoprost, the onset of the change is usually within the first 8 months of treatment, rarely during the second or third year, and has not been seen after the fourth year of treatment. The rate of progression of iris pigmentation decreases with time and is stable for five years. The effect of increased pigmentation beyond five years has not been evaluated. In an open 5-year latanoprost safety study, 33% of patients developed iris pigmentation (see section 4.8). The iris colour change is slight in the majority of cases and often not observed clinically. The incidence in patients with mixed colour irides ranged from 7 to 85%, with yellow-brown irides having the highest incidence. In patients with homogeneously blue eyes, no change has been observed and in patients with homogeneously grey, green or brown eyes, the change has only rarely been seen.

The colour change with latanoprost treatment is due to increased melanin content in the stromal melanocytes of the iris and not to an increase in number of melanocytes. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become more brownish. No further increase in brown iris pigment has been observed after discontinuation of latanoprost treatment. It has not been associated with any symptom or pathological changes in clinical trials to date.

Neither naevi nor freckles of the iris have been affected by latanoprost treatment. Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not been observed with latanoprost in clinical trials. Based on 5 years clinical experience with latanoprost, increased iris pigmentation has not been shown to have any negative clinical sequelae and Catiolanze can be continued if iris pigmentation ensues. However, patients should be monitored regularly and if the clinical situation warrants, Catiolanze treatment may be discontinued.

Chronic angle closure glaucoma

There is limited experience of latanoprost in chronic angle closure glaucoma, open angle glaucoma of pseudophakic patients and in pigmentary glaucoma. There is no experience of latanoprost in inflammatory and neovascular glaucoma or inflammatory ocular conditions. Latanoprost has no or little effect on the pupil, but there is no experience in acute attacks of closed angle glaucoma.

Therefore, it is recommended that Catiolanze should be used with caution in these conditions until more experience is obtained.

Cataract surgery

There are limited study data on the use of latanoprost during the peri-operative period of cataract surgery. Catiolanze should be used with caution in these patients.

History of herpetic keratitis, aphakic, and pseudophakic patients

Catiolanze should be used with caution in patients with a history of herpetic keratitis, and should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.

Macular oedema and cystoid macular oedema

Reports of macular oedema have occurred with latanoprost (see section 4.8) mainly in aphakic patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema (such as diabetic retinopathy and retinal vein occlusion). Catiolanze should be used with caution in aphakic patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema.

Iritis/ uveitis

Catiolanze should be used with caution in patients with known predisposing risk factors for iritis/uveitis.

Patients with asthma

There is limited experience with latanoprost in patients with asthma, but some cases of exacerbation of asthma and/or dyspnoea were reported with latanoprost in post marketing experience. Asthmatic patients should therefore be treated with caution until there is sufficient experience (see also section 4.8).

Periorbital skin discolouration

Periorbital skin discolouration has been observed with latanoprost, the majority of reports being in Japanese patients. Experience to date shows that periorbital skin discolouration is not permanent and in some cases has reversed while continuing treatment with latanoprost.

Eyelash changes

Latanoprost may gradually change eyelashes and vellus hair in the treated eye and surrounding areas; these changes include increased length, thickness, pigmentation, number of lashes or hairs and misdirected growth of eyelashes. Eyelash changes are reversible upon discontinuation of latanoprost treatment.

Other

Concomitant use of latanoprost with prostaglandins, prostaglandin analogues or prostaglandin derivatives is not recommended (see section 4.5).

Excipient with known effect

Catiolanze contains cetalkonium chloride which may cause eye irritation.

No interaction studies have been performed in adults.

There have been reports of paradoxical elevations in IOP following the concomitant ophthalmic administration of two prostaglandin analogues. Therefore, the use of two or more prostaglandins, prostaglandin analogues or prostaglandin derivatives is not recommended.

Paediatric population

No interaction studies have been performed in the paediatric population.

Pregnancy

The safety of this medicinal product for use in human pregnancy has not been established. It has potential hazardous pharmacological effects with respect to the course of pregnancy, to the unborn or the neonate. Therefore, Catiolanze should not be used during pregnancy.

Breast-feeding

Latanoprost and its metabolites may pass into breast milk. Catiolanze should therefore not be used in breast-feeding women or breast feeding should be stopped.

Fertility

Latanoprost has not been found to have any effect on male or female fertility in animal studies (see section 5.3).

Catiolanze has minor influence on the ability to drive and use machines. In common with other eye preparations, instillation of Catiolanze may cause transient blurring of vision. Until this has resolved, patients should not drive or use machines.

Summary of the safety profile

The majority of adverse reactions relate to the ocular system. In an open 5-year safety study with preserved latanoprost eye drops, solution, 33% of patients developed iris pigmentation (see section 4.4). Other ocular adverse reactions are generally transient and occur on dose administration.

Safety data specific for Catiolanze are available from 330 patients. The most common adverse reactions were ocular hyperaemia (1.6%) and conjunctival hyperaemia (1.0%). There were no serious adverse reactions during the studies specific for Catiolanze.

Long term safety data are available from a Phase 3 study in which 118 patients received Catiolanze at least for 360 days. The long term safety profile did not differ from that observed during the first 3 months of treatment. The most common ocular adverse reactions reported during long term use were ocular and conjunctival hyperaemia (4.4%), abnormal sensation in eye (2.2%) and growth of eyelashes (2.2%).

Tabulated list of adverse reactions

The table below describes adverse reactions for preserved latanoprost eye drops, solution from clinical trials and postmarketing data. Adverse reactions occurring with a different frequency observed in clinical trials with Catiolanze eye drops emulsion product are labelled in the table with ^¥.

The adverse reactions are categorised by frequency as follows: 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), not known (frequency cannot be estimated from the available data).

*ADR identified post-marketing

§ADR frequency estimated using “The Rule of 3”

¥ADR frequency estimated from studies specific to Catiolanze eye drops emulsion

Description of selected adverse reactions

No information is provided.

Paediatric population

In two short term clinical trials (≤12 weeks), involving 93 (25 and 68) paediatric patients treated with preserved latanoprost eye drops, solution, the safety profile was similar to that in adults and no new adverse events were identified.

The short-term safety profiles in the different paediatric subsets were also similar (see section 4.2 and 5.1). Adverse events seen more frequently with preserved latanoprost in the paediatric population as compared to adults were nasopharyngitis and pyrexia.

Catiolanze was not specifically studied in the paediatric population.

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:

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdose is unlikely to occur after ocular administration. If overdose occurs, treatment should be symptomatic.

Symptoms

Apart from ocular irritation and conjunctival hyperaemia, no other ocular side effects are known if latanoprost is overdosed via the ocular route.

Treatment

If overdosage with this medicine occurs, treatment should be symptomatic.

Paediatric population

The principles described above apply to the management of overdose in the paediatric population.

Pharmacotherapeutic group: Ophthalmologicals; Antiglaucoma preparations and miotics.

ATC code: S01EE01

Mechanism of action

The active substance latanoprost, a prostaglandin F_2α analogue, is a selective prostanoid FP receptor agonist which reduces the IOP by increasing the outflow of aqueous humour.

Studies indicate that the main mechanism of action is increased uveoscleral outflow, although some increase in outflow facility (decrease in outflow resistance) has been reported.

Pharmacodynamic effects

Reduction of the IOP starts about three to four hours after administration and maximum effect is reached after eight to twelve hours. Pressure reduction is maintained for at least 24 hours. Pivotal studies have demonstrated that latanoprost is effective as monotherapy. In addition, clinical trials investigating combination use have been performed. These include studies that show that latanoprost is effective in combination with beta-adrenergic antagonists (timolol). Short-term (1 or 2 weeks) studies suggest that the effect of latanoprost is additive in combination with adrenergic agonists (dipivalyl epinephrine), oral carbonic anhydrase inhibitors (acetazolamide) and at least partly additive with cholinergic agonists (pilocarpine).

Latanoprost has no significant effect on the production of aqueous humour. Latanoprost has not been found to have any effect on the blood-aqueous barrier. Latanoprost has not induced fluorescein leakage in the posterior segment of pseudophakic human eyes during short term treatment. Latanoprost in clinical doses has not been found to have any significant pharmacological effects on the cardiovascular or respiratory system.

Clinical efficacy and safety

The efficacy and safety of Catiolanze has been evaluated in one pivotal Phase 3 study.

A Phase 3, single-masked, randomised, controlled non-inferiority study evaluated the efficacy and safety of Catiolanze eye drops emulsion to benzalkonium chloride preserved latanoprost eye drops solution in 386 adults with open angle glaucoma (OAG) or ocular hypertension (OHT). Primary endpoint was the peak and trough change from baseline in IOP between treatment groups over a 12-week treatment period, with a prespecified non inferiority margin of 1.5 mmHg. Baseline demographic and disease characteristics were similar between groups, with an overall mean age (SD) of 63.1 years (11.16). The majority (61.5%) of participants were women and 96.4% were White. 75.8% (n=291) of patients had a primary OAG and 21.1% (n=81) had OHT; the remaining had a pseudo-exfoliative glaucoma (2.1%) and pigmentary glaucoma (1.0%).

Efficacy

The primary endpoint was met as the non-inferiority of Catiolanze versus the preserved latanoprost 0.005% solution was demonstrated at Week 12 (see table 1). The Least square (LS) mean treatment difference between the Catiolanze and the preserved latanoprost solution groups at the peak and trough timepoints were -0.6 (95% CI -1.2, -0.1) and -0.5 (95% CI -1.0, 0.1), respectively.

Change from baseline in corneal fluorescein staining (CFS) score at Week 12 in subjects with baseline CFS ≥1 on the modified Oxford scale was assessed as key secondary endpoint. Catiolanze demonstrated superiority versus the control in terms of improvement in CFS score at Week 12.

Table 1 Efficacy results: MMRM on observed cases (study Eye, full analysis set)

CFS, Corneal fluorescein staining; CI, confidence interval; FAS, full analysis set; n, number of patients; LS mean, Least square mean; MMRN, mixed-effects model for repeated measures; SE, standard error.

The analysis is applied to all patients in the FAS with baseline CFS score ≥1 for CFS.. Statistical significance (P≤0.05) shown in bold.

Figure Efficacy Results: IOP RAW Mean Change from Baseline with SE by Analysis Visit and Timepoint (Study Eye, Open Label Population)

09/16 = 9am/4pm; BL = Baseline; IOP = Intraocular pressure; M = Month; SE = Standard error; W = Week

Paediatric population

Catiolanze eye drops, emulsion was not specifically studied in the paediatric population.

Efficacy and safety of preserved latanoprost eye drops solution has been established in paediatric patients. The efficacy of latanoprost in paediatric patients ≤18 years of age was demonstrated in a 12-week, double-masked clinical study of latanoprost compared with timolol in 107 patients diagnosed with ocular hypertension and paediatric glaucoma. Neonates were required to be at least 36 weeks gestational age. Patients received either latanoprost 50 mcg/mL once daily or timolol 0.5% (or optionally 0.25% for subjects younger than 3 years old) twice daily. The primary efficacy endpoint was the mean reduction in IOP from baseline at Week 12 of the study. Mean IOP reductions in the latanoprost and timolol groups were similar. In all age groups studied (0 to <3 years, 3 to <12 years and 12 to 18 years of age) the mean IOP reduction at Week 12 in the latanoprost group was similar to that in the timolol group. Nevertheless, efficacy data in the age group 0 to <3 years were based on only 13 patients for latanoprost and no relevant efficacy was shown from the 4 patients representing the age group 0 to <1 year old in the clinical paediatric study. No data are available for preterm infants (less than 36 weeks gestational age).

IOP reductions among subjects in the primary congenital glaucoma (PCG) subgroup were similar between the latanoprost group and the timolol group. The non-PCG (e.g. juvenile open angle glaucoma, aphakic glaucoma) subgroup showed similar results as the PCG subgroup.

The effect on IOP was seen after the first week of treatment (see table 2) and was maintained throughout the 12 week period of study, as in adults.

SE: standard error.

†Adjusted estimate based on an analysis of covariance (ANCOVA) model

Latanoprost (mw 432.58) is an isopropyl ester prodrug which per se is inactive, but after hydrolysis to the acid of latanoprost becomes biologically active.

Absorption

The prodrug is well absorbed through the cornea and all latanoprost that enters the aqueous humour is hydrolysed during the passage through the cornea.

Distribution

Studies in man with latanoprost indicate that the peak concentration in the aqueous humour is reached about two hours after topical administration. After topical application in monkeys, latanoprost is distributed primarily in the anterior segment, the conjunctivae and the eyelids. Only minute quantities of the drug reach the posterior segment.

Biotransformation and Elimination

There is practically no metabolism of the acid of latanoprost in the eye. The main metabolism occurs in the liver. The half-life in plasma is 17 minutes in man. The main metabolites, the 1,2-dinor and 1,2,3,4-tetranor metabolites, exert no or only weak biological activity in animal studies and are excreted primarily in the urine.

Paediatric population

An open-label pharmacokinetic study of plasma latanoprost acid concentrations was undertaken in 22 adults and 25 paediatric patients (from birth to <18 years of age) with ocular hypertension and glaucoma. All age groups were treated with latanoprost 50 mcg/mL, one drop daily in each eye for a minimum of 2 weeks. Latanoprost acid systemic exposure was approximately 2-fold higher in 3 to <12 year olds and 6-fold higher in children <3 years old compared with adults, but a wide safety margin for systemic adverse effects was maintained (see section 4.9). Median time to reach peak plasma concentration was 5 minutes post-dose across all age groups. The median plasma elimination half-life was short (<20 minutes), similar for paediatric and adult patients, and resulted in no accumulation of latanoprost acid in the systemic circulation under steady-state conditions.

The ocular as well as systemic toxicity of latanoprost has been investigated in several animal species. Generally, latanoprost is well tolerated with a safety margin between clinical ocular dose and systemic toxicity of at least 1 000 times. High doses of latanoprost, approximately 100 times the clinical dose/kg body weight, administered intravenously to unanaesthetised monkeys have been shown to increase the respiration rate probably reflecting bronchoconstriction of short duration. In animal studies, latanoprost has not been found to have sensitising properties.

In the eye, no toxic effects have been detected with latanoprost doses of up to 100 micrograms/eye/day in rabbits or monkeys (clinical dose is approximately 1.5 micrograms/eye/day). In monkeys, however, latanoprost has been shown to induce increased pigmentation of the iris. The mechanism of increased pigmentation seems to be stimulation of melanin production in melanocytes of the iris with no proliferative changes observed. The change in iris colour may be permanent.

In chronic ocular toxicity studies with latanoprost, administration of latanoprost 6 micrograms/eye/day has also been shown to induce increased palpebral fissure. This effect is reversible and occurs at doses above the clinical dose level. The effect has not been seen in humans.

In a 28-day ocular toxicity study, administration of Catiolanze two times a day for 28 days did not reveal any significant local or systemic toxic effects in rabbits. Plasma concentrations of latanoprost acid were negligible at 15 minutes after the final instillation of Catiolanze.

Latanoprost was found to be negative in reverse mutation tests in bacteria, gene mutation in mouse lymphoma and mouse micronucleus test. Chromosome aberrations were observed in vitro with human lymphocytes. Similar effects were observed with prostaglandin F_2α, a naturally occurring prostaglandin, and indicates that this is a class effect.

Additional mutagenicity studies on in vitro/in vivo unscheduled DNA synthesis in rats were negative and indicate that latanoprost does not have mutagenic potency. Carcinogenicity studies in mice and rats were negative.

Latanoprost has not been found to have any effect on male or female fertility in animal studies. In the embryotoxicity study in rats, no embryotoxicity was observed at intravenous doses (5, 50 and 250 micrograms/kg/day) of latanoprost. However, latanoprost induced embryolethal effects in rabbits at doses of 5 micrograms/kg/day and above.

The dose of 5 micrograms/kg/day (approximately 100 times the clinical dose) caused significant embryofoetal toxicity characterised by increased incidence of late resorption and abortion and by reduced foetal weight.

No teratogenic potential has been detected.

Medium chain triglycerides

Cetalkonium chloride

Polysorbate 80

Glycerol

Water for injections

Not applicable.

3 years

This medicinal product is a sterile white liquid that does not contain a preservative. Sterility cannot be maintained after the individual single-dose container is opened.

Discard any opened individual single-dose container immediately after use.

Store below 30°C.

After opening of the aluminium pouch, the single-dose containers should be kept in the pouch in order to avoid evaporation and protect from light.

Low density polyethylene single-dose containers in a sealed aluminium-polyethylene foil pouch.

Each single-dose container contains 0.3 mL. One pouch contains 5 single-dose containers.

Pack sizes: 30, 60, 90 or 120 single-dose containers.

Not all pack sizes may be marketed.

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