Catiolanze^® (Drops) Instructions for Use

Marketing Authorization Holder

Santen, Oy (Finland)

Manufactured By

Excelvision (France)

Quality Control Release

SANTEN, OY (Finland)

Contact Information

SANTEN LLC (Russia)

ATC Code

S01EE01 (Latanoprost)

Active Substance

Latanoprost (Rec.INN registered by WHO)

Dosage Form

Catiolanze®

Eye drops 50 mcg/1 ml: single-dose pipette containers 0.3 ml 30 pcs.

Dosage Form, Packaging, and Composition

Eye drops in the form of a white liquid.

Excipients: medium-chain triglycerides, cetalkonium chloride, polysorbate 80, glycerol, water for injections.

0.3 ml – single-use polyethylene pipette containers^× (5) – sealed sachets made of laminated aluminum foil (6) – cardboard cartons.

^× connected in 1 strip of 5 single-dose pipette containers.

Clinical-Pharmacological Group

Antiglaucoma drug – synthetic prostaglandin F2α analogue

Pharmacotherapeutic Group

Drugs used in ophthalmology; antiglaucoma drugs and miotic agents; prostaglandin analogues

Pharmacological Action

Mechanism of action

The active substance Latanoprost, a prostaglandin F_2α analogue, is a selective agonist of prostanoid FP receptors, which reduces IOP by enhancing the outflow of aqueous humor.

Studies show that the main mechanism of action of the drug is the enhancement of uveoscleral outflow of aqueous humor. In addition, a slight increase in outflow facility (reduction in outflow resistance) has also been described.

Pharmacodynamic effects

IOP reduction in humans begins approximately 3-4 hours after drug application, and the maximum effect is achieved after 8-12 hours. The hypotensive effect persists for at least 24 hours.

Basic studies have shown that Latanoprost is effective as monotherapy. Furthermore, clinical studies on combination use have been conducted. These include studies demonstrating the efficacy of latanoprost in combination with beta-adrenergic receptor antagonists (timolol). Short-term (1 or 2 weeks) studies show that the effect of latanoprost is additive in combination with adrenergic agonists (dipivefrine epinephrine), oral carbonic anhydrase inhibitors (acetazolamide), and at least partially additive with cholinergic agonists (pilocarpine).

Latanoprost does not have a significant effect on the production of aqueous humor. Latanoprost does not affect the blood-aqueous barrier. During short-term use in pseudophakic patients, Latanoprost did not cause fluorescein leakage into the posterior segment of the eye. Latanoprost at therapeutic doses does not have a significant pharmacological effect on the cardiovascular or respiratory systems.

Clinical efficacy and safety

The efficacy and safety of the drug Catiolanze^® were evaluated in one pivotal phase III study.

The phase III study was a single-masked, randomized, controlled non-inferiority efficacy and safety study of Catiolanze^® eye drop emulsion, compared with a latanoprost eye drop solution containing the preservative benzalkonium chloride. The study involved 386 adult patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). The primary endpoint was the maximum and minimum change in IOP from baseline in the treatment groups over the 12-week treatment period, with a non-inferiority margin of 1.5 mmHg initially set. Baseline demographic data and disease characteristics were similar between patient groups, with an overall mean age (SD) of 63.1 years (11.16). The majority (61.5%) of patients were female, and 96.4% were Caucasian. Primary OAG was diagnosed in 75.8% (n=291) of patients and OHT in 21.1% (n=81); the remaining patients were diagnosed with pseudoexfoliative glaucoma (2.1%) and pigmentary glaucoma (1.0%).

Efficacy

The primary efficacy endpoint was met, as non-inferiority of Catiolanze^® compared to the 0.005% latanoprost solution containing preservative was demonstrated at week 12 (see Table 2). The mean difference between the Catiolanze^® group and the preservative-containing latanoprost solution group at peak and trough levels was -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 patients with a baseline CFS score ≥1 on the modified Oxford Scale was assessed as a key secondary efficacy endpoint. Catiolanze^® demonstrated superiority compared to the control group in improving the CFS score at week 12.

Table 1. Efficacy Results: Mixed Model for Repeated Measures 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 squares mean; MMRM – mixed model for repeated measures; SE – standard error.
The analysis applies to all patients from the full analysis population with a baseline CFS score ≥1 regarding CFS test results. Statistical significance (P<0.05) is highlighted in bold.

Efficacy Results: Change in Mean Baseline IOP with Standard Error (SE) by Visit and Analysis Time Point (Study Eye, Open Population)

Children

Studies of Catiolanze^® eye drop emulsion in children have not been conducted.

The efficacy and safety of the preservative-containing latanoprost eye drop solution have been studied in children. The efficacy of latanoprost in children under 18 years of age was demonstrated in a 12-week double-blind clinical study of latanoprost compared to timolol in 107 patients with ocular hypertension and pediatric glaucoma. The gestational age of newborns had to be at least 36 weeks. Patients received either Latanoprost 50 mcg/ml once daily or timolol 0.5% (or 0.25% for children under 3 years) twice daily. The primary efficacy endpoint was the mean reduction in IOP from baseline after 12 weeks of treatment.

The mean IOP reduction in the latanoprost and timolol groups was similar. In all age groups studied (0 to <3 years, 3 to <12 years, and 12 to 18 years), the mean IOP reduction at week 12 in the latanoprost group was similar to that in the timolol group. However, efficacy data for latanoprost in the age group 0 to 3 years were obtained from only 13 patients receiving Latanoprost, and efficacy in the 4 patients in the age group 0 to 1 year was not confirmed. There are no data on the use of the drug in premature infants (gestational age <36 weeks).

IOP reduction in patients in the primary congenital glaucoma (PCG) subgroup was similar in the latanoprost group and the timolol group. In the subgroup of patients without PCG (e.g., juvenile open-angle glaucoma, aphakic glaucoma), the results were the same as in the PCG patient subgroup.

The effect on IOP was observed after the first week of treatment (see Table 2) and persisted throughout the 12-week study period, as in adults.

Table 2. IOP Reduction (mmHg) at Week 12 by Active Treatment Group and Baseline Diagnosis

SE – standard error.
* adjusted estimate based on analysis of covariance (ANCOVA) model.

Preclinical safety data

Ophthalmic and systemic toxicity of latanoprost has been investigated in several animal species. Generally, Latanoprost is well tolerated with a safety margin of at least 1000-fold between the therapeutic dose for ocular instillation and systemic toxicity. High doses of latanoprost, approximately 100 times the therapeutic dose/kg body weight, administered intravenously to unanesthetized monkeys, increased respiratory rate, probably reflecting transient bronchospasm. Studies in animals did not reveal sensitizing properties of latanoprost.

When latanoprost was administered at doses up to 100 mcg/eye/day into the eyes of rabbits or monkeys, no toxic effects on the eyes were detected (the therapeutic dose is approximately 1.5 mcg/eye/day). However, in monkeys, Latanoprost caused increased iris pigmentation. The mechanism of increased pigmentation appears to be stimulation of melanin production in iris melanocytes without any proliferative changes. The change in iris color may be permanent.

In chronic ophthalmic toxicity studies, administration of latanoprost at a dose of 6 mcg/eye/day caused an increase in the palpebral fissure. This effect was reversible and occurred at doses exceeding therapeutic ones. This effect has not been observed in humans.

In a 28-day ophthalmic toxicity study, administration of Catiolanze^® twice daily for 28 days did not reveal local or systemic toxic effects in rabbits. Plasma concentrations of latanoprost acid were negligible 15 minutes after the last instillation of Catiolanze^®.

In bacterial reverse mutation tests, a mouse lymphoma gene mutation test, and a mouse micronucleus test, no genotoxicity of latanoprost was detected. Chromosomal aberrations were observed in an in vitro study with human lymphocytes. Similar effects have been noted with prostaglandin F_2α, a naturally produced prostaglandin, indicating that this is a class-specific effect.

In additional mutagenicity studies to assess DNA repair synthesis in vitro/in vivo in rats, a negative result was obtained, indicating the absence of mutagenic activity of latanoprost. Carcinogenicity studies in mice and rats did not reveal any carcinogenic potential of the drug.

Studies in animals did not reveal any effect of latanoprost on male or female fertility. In an embryotoxicity study in rats, no embryotoxicity was observed with intravenous administration of latanoprost at doses of 5, 50, and 250 mcg/kg/day. However, in rabbits, Latanoprost caused embryo lethality at doses of 5 mcg/kg/day and higher.

Latanoprost at a dose of 5 mcg/kg/day (approximately 100 times the clinical dose) caused marked embryofetal toxicity, characterized by an increased incidence of late resorptions and abortions, as well as reduced fetal weight.

No teratogenic potential was detected.

Pharmacokinetics

Latanoprost (molecular weight 432.58) is a prodrug, esterified with an isopropyl group, which is itself inactive but becomes biologically active after hydrolysis to the acid form.

Absorption

The prodrug is well absorbed through the cornea and is completely hydrolyzed upon entry into the aqueous humor.

Distribution

Studies of latanoprost in humans show that C_max in the aqueous humor is reached 2 hours after topical application. After topical application in monkeys, Latanoprost is distributed predominantly in the anterior chamber of the eye, conjunctiva, and eyelids. Only a small amount of latanoprost reaches the posterior chamber of the eye.

Metabolism and excretion

The acid form of latanoprost is practically not metabolized in the eye. The main metabolism of the drug occurs in the liver. The T_1/2 from human plasma is 17 minutes. Animal studies have shown that the main metabolites (1,2-dinor- and 1,2,3,4-tetranor metabolites) have no (or low) biological activity and are excreted mainly by the kidneys.

Children

An open pharmacokinetic study of plasma concentrations of latanoprost acid was conducted in 22 adults and 25 children (aged 0-18 years) with ocular hypertension and glaucoma. Patients of all age groups received Latanoprost at a dose of 50 mcg/ml, one drop in each eye for at least 2 weeks. Systemic exposure to latanoprost acid was approximately 2 times higher in children aged 3 to 12 years and 6 times higher in children under 3 years of age compared to adult patients; while a wide safety margin regarding the occurrence of systemic adverse effects was maintained (see section “Overdose”). The mean time to C_max in plasma was 5 minutes after drug instillation in all age groups. The mean plasma T_1/2 was short (<20 minutes), similar in children and adults, preventing accumulation of latanoprost in the acid form in plasma at steady-state concentration.

Indications

• Reduction of elevated intraocular pressure in adult patients with open-angle glaucoma and ocular hypertension;
• Reduction of elevated intraocular pressure and treatment of pediatric glaucoma in children and adolescents aged 4 to 18 years.

ICD codes

Dosage Regimen

The recommended dose is 1 drop into the affected eye(s) once daily. The optimal effect is achieved when Catiolanze^® is applied in the evening.

The drug should not be used more than once a day, as more frequent administration reduces the hypotensive effect.

If one dose is missed, treatment should be continued with the next dose according to the usual schedule.

Children

Children from 0 to 4 years

The safety and efficacy of Catiolanze^® in children aged 0 to 4 years have not been established. Available data are provided in the sections “Pharmacological Action”, “Pharmacokinetics” and “Adverse Reactions”, but dosing recommendations cannot be provided.

Children from 4 to 18 years

The dosage regimen for children and adolescents aged 4 to 18 years is the same as for adults.

Method of administration

Topically, as instillations into the conjunctival sac.

For single use only.

The single-dose pipette container contains a sufficient amount of the drug for instillation into both eyes.

As with the use of any other eye drops, to reduce possible systemic absorption of the drug after instillation of each drop, it is recommended to compress the lacrimal sac at the medial canthus (punctal occlusion) for one minute. This procedure must be performed immediately after instillation of each drop.

Before instilling the drug, contact lenses must be removed and reinserted no earlier than 15 minutes after administration.

If more than one topical ophthalmic drug is used, the medications should be administered at least 5 minutes apart. Catiolanze^® should be administered last.

Catiolanze^® is a sterile white emulsion. The contents of one individual single-dose pipette container should be used immediately after opening for administration into the affected eye(s). Since the sterility of the drug is already compromised after opening the individual single-dose pipette container, any remaining contents must be discarded immediately after administration.

Instructions for medical use of the drug Catiolanze^®

1. Wash your hands and sit or stand comfortably.
2. Open the aluminum sachet which contains 5 single-dose pipette containers for single use.
3. Remove one single-dose pipette container from the aluminum sachet, leaving the remaining pipette containers in the sachet.
4. Gently shake the single-dose pipette container.
5. Unscrew the cap (Figure 1).

1. Gently pull down the lower eyelid of the affected eye with your finger (Figure 2).

1. Tilt your head back and look at the ceiling.
2. Bring the tip of the single-dose pipette container close to the eye, do not touch the eye with the tip of the pipette container.
3. Gently squeeze out one drop of the drug into the eye, then release the lower eyelid.
4. Blink several times to distribute the drug over the entire eye.
5. After applying Catiolanze^®, gently press your finger on the inner corner of the affected eye near the nose. Hold your finger for 1 minute, with your eyes closed (Figure 3). This is where a small duct is located through which tears drain from the eyes to the nose. Pressing on this point closes the opening of this drainage canal. This helps prevent Catiolanze^® from entering the systemic circulation.

1. If, as prescribed by the doctor, the patient uses the drug in both eyes, repeat steps 6-11 for the other eye.
2. Discard the single-use dropper tube after use. Do not store it for reuse.

Adverse Reactions

Summary of the safety profile

Most adverse reactions (ARs) were related to the organ of vision. In an open 5-year safety study of latanoprost eye drops solution, iris pigmentation developed in 33% of patients (see section “Special Precautions”). Other ocular ARs were generally transient and occurred upon instillation of the drug.

Safety data for Catiolanze^® were obtained from a study involving 330 patients. The most common ARs were eye hyperemia (1.6%) and conjunctival injection (1.0%). No serious ARs specific to Catiolanze^® were identified during the studies.

Data on the safety of long-term use of Catiolanze^® were obtained from a phase III study conducted over 360 days involving 118 patients. The long-term safety profile did not differ from the profile observed during the first 3 months of treatment. The most frequent ocular ARs reported with long-term use were eye hyperemia and conjunctival injection (4.4%), abnormal eye sensation (2.2%), and eyelash growth (2.2%).

Tabulated list of adverse reactions

Table 1 presents ARs to latanoprost eye drops (preserved solution) identified during clinical studies and post-marketing surveillance. ARs observed with a different frequency during clinical studies of Catiolanze^® eye drop emulsion are marked in Table 3 with the superscript ^“2”.

ARs are classified by frequency as follows: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1,000 to <1/100), rare (from ≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Table 3

¹AR was identified in the post-marketing period.
² Frequency of AR was assessed based on the results of studies of Catiolanze^® eye drop emulsion.

Children

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

Short-term safety profiles in various pediatric subgroups were also similar (see sections “Pharmacodynamics” and “Dosage and Administration”). ARs that were observed more frequently with preserved latanoprost in children compared to adults included nasopharyngitis and pyrexia.

Specific studies of Catiolanze^® in children have not been conducted.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to latanoprost or to any of the excipients of the drug.

Use in Pregnancy and Lactation

Pregnancy

The safety of this medicinal product during human pregnancy has not been established. Catiolanze^® may have potentially hazardous pharmacological effects on the course of pregnancy, the fetus, or the newborn.

Therefore, Catiolanze^® should not be used during pregnancy, or in women of childbearing potential not using contraception.

Breast-feeding

Latanoprost and its metabolites may pass into breast milk. Therefore, Catiolanze^® should not be used during breast-feeding or breast-feeding should be discontinued.

Fertility

No effect of Catiolanze^® on male or female fertility was found in animal studies (see subsection “Non-clinical safety data”).

Pediatric Use

Contraindicated for use in children aged 0 to 4 years (safety and efficacy have not been established).

Special Precautions

Eye color change

Catiolanze^® may gradually change eye color by increasing the amount of brown pigment in the iris. Before starting treatment, patients should be informed about the possible permanent change in eye color. Treatment of only one eye may cause permanent heterochromia.

Such eye color change was more frequently observed with latanoprost use in patients with mixed-color irides, namely: blue-brown, grey-brown, yellow-brown, and green-brown. In latanoprost studies, iris color change usually occurred within the first 8 months of treatment, rarely during the second or third year, and was not observed after the fourth year of treatment. The rate of progression of iris pigmentation decreases over time and stabilizes within five years. The effect of increased pigmentation beyond five years has not been evaluated. In an open 5-year safety study of latanoprost, iris pigmentation developed in 33% of patients (see section “Adverse Reactions”). The iris color change was mostly slight and often not clinically detectable. The incidence of iris color change in patients with differently colored irides ranges from 7 to 85%, predominating in patients with yellow-brown irides. No changes were observed in patients with uniformly blue eyes, and changes were rarely observed in patients with uniformly grey, green, or brown eyes.

Eye color change during latanoprost treatment is due to an increase in melanin content in the stromal melanocytes of the iris, not an increase in the number of melanocytes. Typically, brown pigmentation around the pupil spreads concentrically towards the periphery of the affected eyes, but the entire iris or parts of it may become more brownish. After discontinuation of latanoprost treatment, no further increase in brown iris pigment was observed. Based on clinical data available to date, the color change has not been associated with any symptoms or pathological disorders.

Latanoprost treatment had no effect on nevi or freckles of the iris. Pigment accumulation in the trabecular meshwork or other parts of the anterior chamber of the eye was not observed in clinical studies. According to the results of 5-year clinical studies of latanoprost, increased iris pigmentation does not lead to negative clinical consequences; therefore, if iris pigmentation develops, treatment with Catiolanze^® can be continued. Nevertheless, such patients should be regularly monitored, and if the clinical situation requires it, treatment with Catiolanze^® may be discontinued.

Chronic angle-closure glaucoma

Experience with latanoprost in chronic angle-closure glaucoma and open-angle glaucoma in pseudophakic patients and pigmentary glaucoma is limited. There is no experience with latanoprost in the treatment of inflammatory and neovascular glaucoma or inflammatory eye conditions. Latanoprost has no or negligible effect on pupil size, but there is no experience in acute attacks of angle-closure glaucoma. Therefore, Catiolanze^® should be used with caution in such patients.

Cataract surgery

Due to limited information on the use of latanoprost in the postoperative period after cataract extraction, caution should be exercised when using Catiolanze^® in these patients.

Patients with a history of herpetic keratitis, aphakia, pseudophakia

Caution should be exercised when using Catiolanze^® in patients with a history of herpetic keratitis, and it should be avoided in cases of active herpetic keratitis and in patients with a history of recurrent herpetic keratitis, especially associated with the use of prostaglandin analogues.

Macular edema and cystoid macular edema

Cases of macular edema have been reported with latanoprost use (see section “Adverse Reactions”), mainly in aphakic patients, pseudophakic patients with torn posterior lens capsule, or with anterior chamber intraocular lenses, and in patients with risk factors for cystoid macular edema (such as diabetic retinopathy and retinal vein occlusion). Catiolanze^® should be used with caution in patients with aphakia, pseudophakia, torn posterior lens capsule, or anterior chamber intraocular lenses, and in patients with known risk factors for cystoid macular edema.

Iritis/Uveitis

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

Patients with bronchial asthma

Experience with latanoprost in patients with bronchial asthma is limited, but some cases of asthma exacerbation and/or dyspnea associated with latanoprost use have been reported in the post-marketing period. Therefore, Latanoprost should be used with caution in patients with asthma until sufficient clinical experience is accumulated (see also section “Adverse Reactions”).

Periorbital skin discoloration

Skin discoloration in the periorbital region has been observed with latanoprost use, with most reports coming from Japanese patients. Current experience suggests that periorbital skin discoloration is reversible and in some cases resolves despite continued latanoprost treatment.

Eyelash changes

Latanoprost may gradually change eyelashes and vellus hair in the treated eye and surrounding area, including increased length, thickness, pigmentation, increased number of eyelashes or hairs, and changed direction of eyelash growth. Eyelash changes are reversible after discontinuation of latanoprost treatment.

Other

Concomitant use of Latanoprost with prostaglandins, prostaglandin analogues, or prostaglandin derivatives is not recommended (see section “Drug Interactions”).

Excipients

Catiolanze^® contains cetalkonium chloride, which may cause eye irritation.

Considering the possible effect of cetalkonium chloride on contact lenses, contact lenses should be removed before bedtime instillation of the eye drops and reinserted after waking up.

Effect on ability to drive and use machines

Catiolanze^® has a minor influence on the ability to drive and use machines.

As with other ophthalmic preparations, temporary blurred vision may occur after instillation of Catiolanze^®. Until vision is clear, driving vehicles or operating machinery is not recommended.

Overdose

Overdose from ocular instillation is unlikely. In case of overdose with Catiolanze^®, treatment should be symptomatic.

Symptoms besides eye irritation and conjunctival injection, other ocular adverse reactions from latanoprost overdose via ocular instillation are unknown.

Treatment symptomatic therapy.

Children

The principles described above apply to the treatment of overdose in children.

Drug Interactions

Interaction studies in adult patients have not been conducted.

Paradoxical elevation of IOP has been reported after concomitant ophthalmic administration of two prostaglandin analogues. Therefore, concomitant ophthalmic use of two or more prostaglandins, prostaglandin analogues, or prostaglandin derivatives is not recommended.

Children

No interaction studies have been conducted in children.

Storage Conditions

Store at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

After first opening the laminated aluminum foil pouch, use within 28 days; store in the original packaging (laminated aluminum foil pouch) to protect from light and evaporation.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.