Latasopt

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LATASTOP (LATASOPT)

Composition:

Active substance: latanoprost;

1 ml of solution contains latanoprost 0.05 mg;

Excipients: sodium hydrogen phosphate dodecahydrate; sodium dihydrogen phosphate dihydrate; sodium chloride; benzalkonium chloride; purified water.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colourless or almost colourless solution.

Pharmacotherapeutic group

Ophthalmological agents. Anti-glaucoma preparations and miotics. Prostaglandin analogues. ATC code S01E E01.

Pharmacological Properties

Pharmacodynamics

The active substance of the medicinal product, latanoprost, a prostaglandin F2α analog, is a selective prostaglandin FP receptor agonist that reduces intraocular pressure by increasing the outflow of aqueous humor. In humans, the reduction in intraocular pressure begins approximately 3–4 hours after administration of latanoprost, with maximum effect observed at 8–12 hours. The hypotensive effect lasts for at least 24 hours.

Preclinical studies have shown that latanoprost is effective as monotherapy. Furthermore, clinical studies on the combined use of latanoprost have demonstrated its efficacy in combination with beta-adrenergic blockers (timolol). Short-term (1 or 2 weeks) studies have shown 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.

Latanoprost did not cause fluorescein leakage into the posterior segment of pseudophakic human eyes during short-term treatment.

No clinically significant pharmacological effects of latanoprost on the cardiovascular and respiratory systems have been observed at clinical doses.

Children

The efficacy of latanoprost in pediatric patients (≤18 years of age) was demonstrated in a 12-week, double-masked, clinical study comparing latanoprost with timolol, involving 107 patients diagnosed with ocular hypertension and childhood glaucoma. In this study, gestational age of newborns was 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 investigator’s discretion) twice daily. The primary efficacy endpoint was mean reduction in intraocular pressure (IOP) from baseline at week 12. Mean IOP reductions in the latanoprost and timolol groups were similar. Across all studied age groups (birth to 3 years, 3 to 12 years, and 12 to 18 years), mean IOP reductions at week 12 were comparable between patients receiving latanoprost and those receiving timolol. However, efficacy data for latanoprost in the age group from birth to 3 years were derived 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 use in preterm neonates (born before 36 weeks of gestation) are lacking.

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

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

Table

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

SP – standard error.

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

Pharmacokinetics

Absorption

Latanoprost (molecular weight 432.58) is an isopropyl ester of the active moiety, i.e., a prodrug which is inactive per se but becomes biologically active after hydrolysis to form latanoprost acid. The prodrug penetrates well through the cornea, and all of the drug reaching the aqueous humor is hydrolyzed during passage through the cornea.

Distribution

Studies in humans have shown that maximum concentration in the aqueous humor is reached approximately 2 hours after topical administration.

Metabolism and elimination

Practically no metabolism of latanoprost acid occurs in the eye. The main metabolism of latanoprost takes place in the liver. The elimination half-life in blood plasma is 17 minutes.

Children

An open-label pharmacokinetic study of plasma concentrations of latanoprost acid was conducted in adult patients and pediatric patients (from newborns to children up to 18 years of age) with ocular hypertension and glaucoma. Patients in all age groups received treatment with 0.005% latanoprost, 1 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; however, the safety margin for latanoprost with regard to systemic adverse effects remained wide. The median time required to reach maximum plasma concentration was 5 minutes after dosing with latanoprost across all age groups. The median elimination half-life in plasma was short (less than 20 minutes) and similar in both pediatric and adult patients, indicating no 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 pediatric glaucoma.

Contraindications

Hypersensitivity to the active substance or to any of the other components of the medicinal product.

Interaction with other medicinal products and other forms of interaction

Comprehensive data on the interaction of latanoprost with other medicinal products are lacking.

Paradoxical increases 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 colour due to increased brown pigment in the iris. Patients should be informed about the possibility of a permanent change in eye colour before initiating treatment. Treatment of one eye only may lead to permanent heterochromia.

Colour change has been observed predominantly in patients with mixed iris colour, for example, blue-brown, grey-brown, yellow-brown or green-brown. In clinical trials with latanoprost, colour change usually occurred within the first 8 months of treatment, less frequently during the second or third year, and was not observed after the fourth year of treatment. 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 an open 5-year safety study of latanoprost, increased iris pigmentation was recorded in 33% of patients (see section "Adverse reactions"). Colour changes of the iris are mostly mild and often not noticeable from a clinical point of view. The incidence of cases in patients with mixed iris colour ranged from 7% to 85%, with patients having yellow-brown iris colour showing the highest frequency. Eye colour changes were not observed in patients with uniformly blue eyes and were rare in patients with uniformly grey, green or brown eyes.

The colour change occurs due to increased melanin content in the iris stromal melanocytes, not due to an increase in the number of melanocytes. Typically, brown pigmentation around the pupil spreads concentrically towards the periphery of the affected eye, although the entire iris or parts of it may become more brownish. After discontinuation of treatment, further intensification of brown iris pigmentation was not observed. Currently, clinical studies have not provided data indicating that this phenomenon is associated with any symptoms or pathological changes.

No changes in iris nevi or freckles were observed under the influence of treatment. In clinical studies, no pigment accumulation in the trabecular meshwork or any other part of the anterior chamber of the eye was observed. Results from 5 years of clinical use of latanoprost indicate that increased iris pigmentation does not lead to clinical complications, and its use may be continued in case of iris pigmentation changes. However, patients should undergo regular examinations, and if the clinical situation requires, treatment should be discontinued.

Experience with the use of latanoprost 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 inflammatory eye diseases. Latanoprost has no or only minimal effect on the pupil; however, data on its use 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 during the perioperative period of cataract surgery are limited. The drug should be used with caution in such patients.

The drug should be used with caution in patients with a history of herpetic keratitis, but its use should be avoided in cases of active keratitis caused by herpes simplex virus and in patients with recurrent herpetic keratitis in their history, particularly if associated with prostaglandin analogues.

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

The drug may be used with caution in patients with known risk factors for development of iritis/uveitis.

Experience with the use of latanoprost in patients with bronchial asthma is limited, although some cases of asthma exacerbation and/or dyspnoea have been reported during the post-marketing period. Until sufficient clinical experience is accumulated, the drug should be used with caution in patients with bronchial asthma (see also section "Adverse reactions").

Skin pigmentation changes in the periorbital area have been observed, with most cases reported in patients from Japan. Available data suggest that skin pigmentation changes in the periorbital area are not permanent and in some cases resolved during continued latanoprost treatment.

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.

Preservative

The medicinal product contains benzalkonium chloride, commonly used as a preservative in ophthalmic preparations. According to limited available data, there are no differences in the adverse reaction profile between children and adults. However, in general, children's eyes are more sensitive to irritants than adults. Due to irritation, treatment compliance may be impaired in children. Reports indicate that benzalkonium chloride may cause eye irritation, dry eye symptoms, and may affect the tear film and corneal surface. The medicinal product should be used with caution in patients with dry eye and in patients with potential corneal damage. Careful monitoring of patients is necessary during prolonged use.

Contact lenses

Contact lenses may absorb benzalkonium chloride; therefore, they should be removed before administration of the medicinal product and may be reinserted 15 minutes after instillation (see section "Instructions for use and dosage").

Use during pregnancy or breastfeeding

Pregnancy

The safety of latanoprost use in pregnant women has not been established. Its pharmacological action poses a potential risk to pregnancy, the fetus, or the newborn. Therefore, the drug should not be used during pregnancy.

Breastfeeding period

Latanoprost and its metabolites may pass into breast milk; therefore, women who are breastfeeding should either discontinue the drug or stop breastfeeding.

Ability to influence reaction speed when driving or operating machinery

Lataspot has a minor influence on the ability to drive or operate machinery. As with other ophthalmic preparations, instillation of eye drops may cause temporary blurred vision. Patients should not drive or operate machinery until this effect has subsided.

Administration and Dosage

The medicinal product is intended for topical administration (into the conjunctival sac).

Adults (including elderly patients)

The recommended dose is 1 drop in the affected eye once daily. The optimal effect is achieved when the medicinal product is administered in the evening.

The medicinal product should not be used more frequently than once daily, as it has been shown that more frequent administration reduces the effectiveness of intraocular pressure reduction.

If a dose is missed, treatment should be continued by administering the next dose at the usual time.

As with any ophthalmic drops, to reduce potential systemic absorption after instillation, it is recommended to press on the lacrimal sac in the area of the medial canthus of the eye (punctal occlusion) for 1 minute. This should be done immediately after instilling each drop.

Contact lenses should be removed before instilling the drops and may be reinserted 15 minutes after administration.

When using multiple topical ophthalmic agents, the products should be administered at least 5 minutes apart.

Children

The medicinal product may be used in pediatric patients at the same dosage as in adults.

Data on efficacy and safety of the medicinal product in patients 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 from birth to 3 years of age, primarily suffering from primary congenital glaucoma, surgical intervention (e.g., trabeculotomy/goniotomy) remains the primary treatment approach.

Long-term safety of latanoprost use in children has not been established.

Overdose

Symptoms

Apart from eye irritation and conjunctival hyperemia, no other ocular adverse effects have been reported with latanoprost overdose.

Treatment

The information below may be helpful in case of accidental ingestion of the medicinal product. Each bottle contains 125 mcg of latanoprost. More than 90% is metabolized during first-pass liver 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 sweating.

No bronchoconstriction was observed in patients with mild to moderate bronchial asthma when latanoprost doses 7 times higher than the clinical dose were administered topically into the eyes.

In case of overdose, symptomatic treatment should be administered.

Adverse Reactions

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

Adverse events are categorized according to frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Infections and parasitic diseases:

Rare – Herpetic keratitis*§.

Nervous system disorders:

Uncommon – Headache*, dizziness*.

Eye disorders:

Very common – Increased iris pigmentation, mild to moderate conjunctival hyperemia, ocular 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 lashes);
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*, distichiasis, iris cyst*§, local skin reaction on eyelids, darkening of palpebral skin of eyelids, ocular mucous membrane pemphigoid*§;
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*.

* Adverse reaction to latanoprost identified in the post-marketing period.
§ Frequency of adverse reaction to latanoprost estimated using the "Rule of Three".

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

Children

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

Reporting suspected adverse reactions

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

Shelf life.

3 years. After opening the bottle, use within 28 days.

Storage conditions.

Store at 2–8°C in the original packaging and in a place inaccessible to children. After first opening, store the bottle at a temperature not exceeding 25°C.

Packaging.

2.5 ml in a dropper bottle; 1 dropper bottle in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICINE ILAC SAN. VE TIC. A.S.
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of business operations.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.