XALOPTIC ECO

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KSALOPTIK ECO (XALOPTIC ECO)

Composition:

Active substance: latanoprost;

1 ml of solution contains 50 mcg of latanoprost;

Excipients: polysorbate 80; disodium edetate; sodium chloride; disodium phosphate; sodium dihydrogen phosphate monohydrate; sodium hydroxide; hydrochloric acid, diluted; water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: colorless, clear liquid.

Pharmacotherapeutic group.

Anti-glaucoma agents and miotics. Prostaglandin analogues.

ATC code S01E E01.

Pharmacological properties.

Pharmacodynamics.

The active substance latanoprost, a prostaglandin F2α analogue, is a selective agonist of FP prostaglandin receptors, reducing intraocular pressure (IOP) by increasing the outflow of aqueous humor. Reduction of IOP in humans begins approximately 3–4 hours after administration and reaches its maximum at 8–12 hours. The pressure-lowering effect persists for at least 24 hours.

Studies indicate that the primary mechanism of action is increased uveoscleral outflow.

Preclinical studies have shown that latanoprost is effective as monotherapy. Furthermore, clinical studies on combined use of the drug have been conducted. These included studies demonstrating that latanoprost is effective in combination with beta-adrenergic blockers (timolol). Short-term (1 or 2 weeks) studies show that the effect of latanoprost is additive when used in combination with adrenergic agonists (dipivefrin), oral carbonic anhydrase inhibitors (acetazolamide), and at least partially additive when used with cholinergic agonists (pilocarpine).

Clinical studies have shown that latanoprost does not significantly affect the production of intraocular fluid. No effect of latanoprost on the blood-ocular barrier has been observed.

During short-term treatment, latanoprost did not cause fluorescein leakage into the posterior segment of the eye in pseudophakic patients.

It has been established that, at clinical doses, latanoprost has no significant pharmacological effect on the cardiovascular and respiratory systems.

Children

The efficacy of latanoprost in pediatric patients aged ≤ 18 years was demonstrated in a 12-week, double-masked, clinical study comparing latanoprost with timolol in 107 patients diagnosed with ocular hypertension and childhood glaucoma. In this study, neonatal gestational age had to be at least 36 weeks. Patients received either 0.005% latanoprost once daily or 0.5% timolol (or 0.25% for patients under 3 years of age, at the investigator’s discretion) twice daily. The primary efficacy endpoint was the mean reduction in IOP from baseline at week 12 of the study. Mean reductions in IOP were similar between the latanoprost and timolol treatment groups. Across all age subgroups studied (birth to 3 years, 3 to 12 years, and 12 to 18 years), mean IOP reductions at week 12 were similar between patients receiving latanoprost and those receiving timolol. However, efficacy data for latanoprost in the age group from birth to 3 years were obtained from only 13 patients, and no significant efficacy was demonstrated in the 4 patients representing the birth to 1 year age group in the clinical study. Data on the use of the drug in preterm neonates (born before 36 weeks of gestation) are lacking.

IOP reduction outcomes in the subgroup of patients with primary congenital glaucoma (PCG)/infantile glaucoma were similar between patients receiving latanoprost and those receiving timolol. Results in the non-PCG subgroup (i.e., patients with, for example, juvenile open-angle glaucoma, aphakic glaucoma) and PCG patients were comparable.

IOP reduction outcomes in the subgroup of patients with primary congenital glaucoma/infantile glaucoma (PCG) were similar between patients receiving latanoprost and those receiving timolol. Results in the non-PCG subgroup (i.e., patients with, for example, juvenile open-angle glaucoma, aphakic glaucoma) and PCG patients were comparable.

The effect on IOP was evident after the first week of treatment (see table) and was maintained throughout the 12-week study period, similar to observations in adults.

Reduction of IOP (mmHg) at week 12 of the study according to active treatment group and initial diagnosis

Table 1

SP – standard error.

†Adjusted mean based on analysis of covariance (ANCOVA) model.

Pharmacokinetics.

Latanoprost (molecular weight 432.58) is an isopropyl ester of the active substance, i.e. a prodrug that is inactive itself but becomes biologically active after hydrolysis to form latanoprost acid.

Absorption.

The prodrug is well absorbed through the cornea, and all of the drug reaching the aqueous humor of the eye is hydrolyzed during passage through the cornea.

Distribution.

Studies show that maximum drug concentration in the aqueous humor of humans is reached approximately 2 hours after topical administration.

Biotransformation and elimination.

Latanoprost acid is practically not metabolized in the eye. The main metabolism occurs in the liver. The elimination half-life in human plasma is 17 minutes.

Children.

An open-label pharmacokinetic study of plasma concentrations of latanoprost acid was conducted in 22 adult patients and 25 pediatric patients (from newborns to children up to 18 years of age) with intraocular hypertension and glaucoma. Patients in all age groups received treatment with 0.005% latanoprost, one drop in each eye, for at least 2 weeks. Systemic exposure to latanoprost acid was approximately twice as high in patients aged 3 to <12 years and six times higher in children under 3 years of age compared to adult patients, but the drug still maintained a wide safety margin regarding the occurrence of systemic adverse effects. The median time required to reach peak plasma concentration of the drug was 5 minutes after dosing across all age groups. The median elimination half-life of the drug from plasma was short (less than 20 minutes) and similar in both pediatric and adult patients, indicating absence of accumulation of latanoprost acid in the systemic circulation at steady state.

Clinical characteristics.

Indications.

Reduction of elevated intraocular pressure in adult patients, including elderly patients, with open-angle glaucoma and elevated intraocular pressure.

Reduction of elevated intraocular pressure in pediatric patients with elevated intraocular pressure and childhood glaucoma.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Comprehensive data on interaction with other medicinal products are lacking.

Cases of paradoxical increase in intraocular pressure have been reported following concomitant ocular administration of two prostaglandin analogs. Therefore, concomitant use of two or more prostaglandins, prostaglandin analogs, or their derivatives is not recommended.

Drug interaction studies have been conducted only in adult patients.

Special precautions for use.

Latanoprost may cause a gradual change in eye color due to increased brown pigment in the iris. Patients should be informed about the possibility of a permanent change in eye color before initiating treatment. Treatment of one eye only may lead to irreversible heterochromia.

This change in eye color is observed predominantly in patients with mixed-color irises, i.e., blue-brown, gray-brown, yellow-brown, or green-brown eyes.

The color change usually begins within the first 8 months of treatment, but in a small number of patients, it may occur later. The progression of iris pigmentation decreases over time and stabilizes after 5 years. The effect of increased pigmentation after 5 years of latanoprost treatment has not been evaluated. In a 5-year safety study of latanoprost, increased iris pigmentation was recorded in 33% of patients (see section "Adverse reactions"). Changes in iris color are minor in most cases and often clinically unnoticeable. The incidence in patients with mixed iris color ranged from 7% to 85%, with patients having yellow-brown iris color showing the highest frequency.

Changes in eye color have not been observed in patients with uniformly blue eyes and are rare in patients with uniformly gray, green, or brown eyes.

The color change occurs due to increased melanin content in melanocytes of the iris stroma, not due to an increase in the number of melanocytes. Typically, brown pigmentation starts around the pupil and spreads concentrically toward the periphery of the affected eye, but the entire iris or parts of it may become more brown. No further increase in brown pigment in the iris was observed after discontinuation of treatment. Currently, clinical studies have not provided evidence that this phenomenon is associated with

any symptoms or pathological changes.

The use of the drug has not affected iris nevi or freckles. Pigment accumulation in the trabecular meshwork or elsewhere in the anterior chamber has not been observed. Results from 5 years of clinical use suggest that increased iris pigmentation does not lead to clinical complications, and latanoprost treatment may be continued even if iris pigmentation changes occur. However, patients should undergo regular examinations, and if the clinical situation requires, treatment with latanoprost should be discontinued.

Experience with latanoprost use is limited in chronic angle-closure glaucoma, open-angle glaucoma in pseudophakic patients, and pigmentary glaucoma. Currently, there are no data on the use of latanoprost in inflammatory or neovascular glaucoma or in ocular inflammatory diseases. Latanoprost has no effect or only minimal effect on the pupil; however, data on the use of the drug during acute attacks of angle-closure glaucoma are lacking. Therefore, the drug should be used with caution in such conditions until more data become available.

Data on the use of latanoprost before and after cataract surgery are limited. Latanoprost should be used with caution in such patients.

Latanoprost should be used with caution in patients with a history of herpetic keratitis, but its use should be avoided in cases of active herpetic keratitis caused by herpes simplex virus and in patients with a history of recurrent herpetic keratitis, especially if associated with prostaglandin analogs.

Cases of macular edema have been reported (see section "Adverse reactions"), primarily in aphakic patients, pseudophakic patients with posterior capsule rupture or anterior chamber lenses, and in patients with known risk factors for cystoid macular edema (such as diabetic retinopathy and retinal vein occlusion). Latanoprost should be used with caution in aphakic patients, pseudophakic patients with posterior capsule rupture or anterior chamber lenses, and in patients with known risk factors for cystoid macular edema.

Latanoprost may be used with caution in patients with known risk factors predisposing to iritis/uveitis.

There is no experience with the use of the drug in patients with severe bronchial asthma, although some cases of asthma exacerbation and/or dyspnea have been reported during the post-marketing period. Until sufficient clinical experience is accumulated, the drug should be prescribed to patients with bronchial asthma with caution (see also section "Adverse reactions").

Changes in skin color in the periorbital area have been observed, with most cases reported in Japanese patients. Current data suggest that skin pigmentation changes in the periorbital area are not permanent and, in some cases, may resolve during continued treatment with Xalatan ECO.

Latanoprost may gradually change the eyelashes and vellus hair around the treated eye and adjacent areas; these changes include increased length, thickness, pigmentation, and number of eyelashes or vellus hairs, as well as misdirected eyelash growth. Changes in eyelashes are reversible and disappear after discontinuation of the drug.

Use during pregnancy or breastfeeding.

Pregnancy

The safety of this medicinal product for use during pregnancy has not been established. Its pharmacological action poses a potential risk to pregnancy, the fetus, or the newborn. Therefore, latanoprost should not be used during pregnancy.

Period of breastfeeding

Latanoprost and its metabolites may pass into breast milk; therefore, mothers who are breastfeeding should either discontinue treatment with Xalatan ECO or stop breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

The use of eye drops, as with other ophthalmic medicinal products, may cause temporary blurred vision. Until this effect subsides, patients should not drive vehicles or operate machinery.

Method of Administration and Dosage

Recommended dosage for adults (including elderly patients) is 1 drop in the affected eye once daily. The optimal effect is achieved when latanoprost is administered in the evening.

The latanoprost dose should not exceed the recommended single dose, as more frequent administration has been shown to reduce the intraocular pressure (IOP)-lowering effect.

If a dose is missed, the next dose should be administered according to the regular schedule.

To minimize systemic absorption following ocular instillation, it is recommended to apply digital pressure to the lacrimal sac at the inner canthus of the eye (nasolacrimal duct occlusion) for approximately one minute. This should be performed immediately after instillation of the drops.

Contact lenses should be removed prior to instillation and may be reinserted 15 minutes after administration.

If a patient is using multiple topical ophthalmic products, they should be administered with an interval of at least 5 minutes between each. Ophthalmic ointments should be used last.

Instructions for Use

The following steps should be performed to ensure correct use of the Xalatan Eco dropper bottle:

1. Wash hands thoroughly and assume a comfortable position before using the medication.
2. Remove the protective cap (Figure 1).
3. Hold the bottle upside down, placing the thumb on the shoulder and the other fingers on the base of the bottle (Figure 2). Before first use, "prime" the bottle by pressing on the shoulder and base several times (approximately 10 times) until the first drop appears.
4. Tilt the head backward and gently pull down the lower eyelid to create a pouch between the eyeball and eyelid.
5. Position the dropper tip close to the eye, but avoid contact between the tip and the eye, eyelids, or fingers.
6. Gently press on the shoulder and base of the bottle to release one single drop into the eye, then release the lower eyelid (Figure 3).
7. Immediately after instillation, apply pressure to the nasolacrimal duct (Figure 4) for approximately 1 minute (by pressing a finger against the inner corner of the eye near the nose), close the eye, and keep it closed during this time.
8. If the physician has prescribed administration in the conjunctival sac of the other eye, repeat steps 4–7.
9. After instillation, replace the cap on the bottle.

Figure 1. Figure 2. Figure 3. Figure 4.

Children

Xalatan Eco eye drops may be used in pediatric patients at the same dosage as in adults. Data on efficacy and safety of the drug in children under 1 year of age are very limited (4 patients) (see section "Pharmacological Properties"). There are no available data on use in preterm infants (born before 36 weeks of gestation).

In children aged from birth to 3 years, primarily affected by primary congenital glaucoma, surgical intervention (e.g., trabeculotomy/goniotomy) remains the first-line treatment. Long-term safety of the drug use in children has not been established.

Overdose

Other adverse reactions beyond ocular irritation and conjunctival hyperemia are not known in cases of latanoprost overdose.

The following information may be useful in case of accidental ingestion of Xalatan Eco. One bottle contains 125 mcg of latanoprost. More than 90% is metabolized during first-pass hepatic metabolism. Intravenous infusion of latanoprost at a dose of 3 mcg/kg in healthy volunteers did not cause any symptoms; however, at doses of 5.5–10 mcg/kg, it caused nausea, abdominal pain, dizziness, increased fatigue, flushing, and increased sweating.

However, local ocular administration of latanoprost doses 7 times higher than the clinical dose of Xalatan Eco did not result in bronchospasm in patients with moderate bronchial asthma.

In cases of latanoprost overdose, treatment should be symptomatic.

Adverse Reactions

Most adverse events are related to the eye. In an open-label 5-year study of latanoprost, iris pigmentation changes were observed in 33% of patients (see section "Special Warnings and Precautions for Use"). Other ocular adverse events are usually temporary and occur after drug instillation.

Adverse events are categorized according to frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from available data).

Infections and parasitic diseases

Rare: Herpetic keratitis.

Nervous system disorders

Uncommon: Headache, dizziness.

Ocular disorders

Very common: Increased iris pigmentation; mild or moderate conjunctival hyperemia, eye irritation (burning sensation with feeling of "sand in the eyes", itching, stinging, foreign body sensation); changes in eyelashes and vellus hair of eyelids (increased length, thickness, pigmentation, and number of eyelashes).

Common: Punctate keratitis, mostly asymptomatic; blepharitis; eye pain; photophobia; conjunctivitis.

Uncommon: Eyelid edema; dry eye; keratitis; blurred vision; macular edema, including cystoid macular edema; uveitis.

Rare: Iritis; corneal edema; corneal erosion; periorbital edema; trichiasis (misdirected eyelash growth, sometimes causing eye irritation); distichiasis (presence of an additional row of eyelashes near the orifices of Meibomian glands); iris cyst; local skin reaction on eyelids; darkening of palpebral skin of eyelids; ocular conjunctival pseudopemphigoid.

Very rare: Periorbital changes and eyelid changes leading to deepening of the eyelid fold.

Cardiac disorders

Uncommon: Angina pectoris; tachycardia.

Very rare: Unstable angina.

Respiratory, thoracic and mediastinal disorders

Uncommon: Bronchial asthma, dyspnea.

Rare: Exacerbation of bronchial asthma.

Gastrointestinal disorders

Uncommon: Nausea, vomiting.

Skin and subcutaneous tissue disorders

Uncommon: Skin rash.

Rare: Pruritus.

Musculoskeletal and connective tissue disorders

Uncommon: Myalgia, arthralgia.

General disorders and administration site conditions

Uncommon: Chest pain.

Very rare cases of corneal calcification have been reported with ophthalmic solutions containing phosphate in some patients with significantly damaged corneas.

Children

In two short-term clinical studies (≤ 12 weeks) involving 93 pediatric patients (25 and 68), the safety profile of the drug was similar to that in adults, and no new adverse events were identified. Short-term safety profiles were also similar across different pediatric subgroups (see section "Pharmacological Properties"). The following adverse events occurred more frequently in pediatric patients than in adults: nasopharyngitis and increased body temperature.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

2 years.

After first opening of the bottle:

30 days – for 2.5 ml packaging; 90 days – for 7.5 ml packaging.

Storage conditions

Store at temperatures not exceeding 25 °C.

Do not freeze.

Keep out of reach and sight of children.

Packaging

2.5 ml or 7.5 ml in a bottle. One bottle per cardboard box.

Prescription status

Prescription only.

Manufacturer

Lomapharm GmbH.

Manufacturer's address and place of business

Langes Feld 5, Emmerthal, Niedersachsen, 31860, Germany.