Latoprost rt

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LATOPROST RT (LATOPROST RT)

Composition:

Active substance: latanoprost;

1 ml of eye drops contains 50 mcg of latanoprost;

Excipients: potassium sorbate, boric acid, disodium edetate, castor oil, macrogol hydroxystearate, propylene glycol, sodium borate, water for injections, hydrochloric acid, sodium hydroxide.

Pharmaceutical form. Eye drops.

Main physico-chemical properties: semi-transparent solution from almost white to pale yellow in colour.

Pharmacotherapeutic group.

Anti-glaucoma agents and miotics. Prostaglandin analogues.

ATC code S01E E01.

Pharmacological properties.

Pharmacodynamics.

The active ingredient of the medicinal product, latanoprost, is a prostaglandin F2α analog and acts as a selective prostaglandin FP receptor agonist, reducing intraocular pressure (IOP) by increasing the outflow of aqueous humor. The reduction in IOP in humans 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. In addition, clinical studies on the combined use of latanoprost have demonstrated its efficacy when used 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 concomitantly 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 aqueous humor production. No effect of latanoprost on the blood-ocular barrier has been observed.

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

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

Children.

The efficacy of latanoprost in pediatric patients (≤ 18 years of age) was demonstrated in a 12-week, double-masked, clinical trial comparing latanoprost with timolol in 107 patients diagnosed with ocular hypertension or pediatric glaucoma. In this study, gestational age at birth 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 IOP from baseline at week 12. Mean reductions in IOP were similar between the latanoprost and timolol 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 comparable between latanoprost and timolol groups. However, efficacy data for latanoprost in the birth to 3 years age group were based on only 13 patients, and significant efficacy was not demonstrated in the 4 patients in the birth to 1 year subgroup. 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 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 in patients with PCG 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 that observed in adults.

Reduction in IOP (mm Hg) 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 substance, i.e. a prodrug that is inactive per se but becomes biologically active after hydrolysis to form latanoprost acid.

Prodrugs penetrate well through the cornea, and all the drug reaching the intraocular fluid is hydrolyzed during passage through the cornea.

Distribution.

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

Biotransformation and elimination.

Metabolism of latanoprost acid in the eye is negligible. The main metabolism occurs in the liver. In humans, the plasma half-life is 17 minutes.

Paediatric population.

An open-label pharmacokinetic study of latanoprost acid plasma concentration was conducted in adult patients and paediatric 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, 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, a wide safety margin for latanoprost with regard to systemic adverse effects was maintained. The median time to reach maximum plasma concentration after latanoprost dosing was 5 minutes across all age groups. The median plasma half-life was short (less than 20 minutes) and similar in both paediatric 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 glauoma.

Contraindications.

Known hypersensitivity to any component 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 increase in IOP has 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 only one eye may lead to permanent heterochromia.

Color change is observed predominantly in patients with mixed iris color, such as blue-brown, gray-brown, yellow-brown, or green-brown. In clinical trials with latanoprost, color changes usually occurred within the first 8 months of treatment, rarely during the second or third year, and were not observed after the fourth year of treatment. 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 an open-label 5-year safety study, increased iris pigmentation was recorded in 33% of patients (see section "Adverse reactions"). Iris color changes are mostly mild and often clinically unnoticeable. The incidence of cases in patients with mixed iris color ranged from 7% to 85%, with patients having yellow-brown iris color showing the highest frequency. Eye color changes were not observed in patients with uniformly blue iris color and were rare in patients with uniformly gray, green, or brown iris color.

The color change occurs due to increased melanin content in the stromal melanocytes of the iris, 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, although the entire iris or parts of it may become more brown. After discontinuation of treatment, further increase in brown iris pigmentation has not been observed. To date, clinical studies have not provided evidence that this phenomenon is associated with any symptoms or pathological changes.

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

Experience with 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 minimal effect on the pupil, but data on its use during acute attacks of angle-closure glaucoma are lacking. Therefore, the medicinal product 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 medicinal product should be used with caution in such patients.

The medicinal product should be used with caution in patients with a history of herpetic keratitis and should be avoided in patients with active herpetic keratitis caused by herpes simplex virus and in patients with recurrent herpetic keratitis in their history, especially those associated with prostaglandin analogs.

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

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

Experience with latanoprost in patients with bronchial asthma is limited, although some cases of asthma exacerbation and/or dyspnea have been reported during the post-marketing period. Until sufficient clinical experience is accumulated, the medicinal product 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 may disappear in some cases during continued latanoprost treatment.

Latanoprost may gradually change the eyelashes and vellus hair around the treated eye and adjacent areas, including increased length, thickness, pigmentation, and number of eyelashes or vellus hairs, as well as misdirected eyelash growth. Changes in eyelashes are reversible and resolve after discontinuation of the medicinal product.

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 medicinal product should not be used during pregnancy.

Breastfeeding period. Latanoprost and its metabolites may pass into breast milk; therefore, women who are breastfeeding should discontinue the use of the medicinal product or stop breastfeeding.

Fertility. Animal studies have shown that latanoprost has no significant effect on fertility in either males or females.

Ability to affect reaction speed when driving or operating machinery.

Latanoprost has a minor influence on the ability to drive or operate machinery. Like other ophthalmic solutions, the medicinal product may cause transient blurred vision. Until this effect subsides, patients should not drive or operate machinery.

Method of Administration and Dosage.

Adults (including elderly patients)

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

The medication should not be used more frequently than once daily, as it has been shown that more frequent administration reduces the effectiveness in lowering intraocular pressure.

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 at the medial canthus of the eye (punctal occlusion) for one minute. This should be done immediately after instilling each drop.

Before instilling ophthalmic drops, contact lenses should be removed and may be reinserted 15 minutes after administration.

When using multiple locally acting ophthalmic agents, the medications should be administered at least 5 minutes apart.

Children

The medication 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 from birth to 3 years of age, primarily suffering from primary congenital glaucoma, surgical intervention (e.g., trabeculotomy/goniotomy) remains the first-line therapy.

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

Overdose.

Apart from eye irritation and conjunctival hyperemia, no other ocular adverse effects have been reported in cases of overdose.

The following information may be helpful in case of accidental ingestion of the medication. Each bottle contains 125 mcg of latanoprost. More than 90% is metabolized during the first pass through the liver. Intravenous infusion of the drug at a dose of 3 mcg/kg did not cause any symptoms in healthy volunteers, whereas doses of 5.5–10 mcg/kg caused nausea, abdominal pain, dizziness, increased fatigue, flushing, and sweating.

However, when ophthalmic doses of latanoprost up to 7 times higher than the clinical dose were administered to patients with moderate bronchial asthma, bronchoconstriction was not observed.

In case of overdose, symptomatic treatment should be administered.

Adverse Reactions

Most adverse reactions are related to the eye. In an open-label 5-year safety study of latanoprost, iris pigmentation changes were recorded in 33% of patients (see section "Special Warnings and Precautions for Use"). Other ophthalmological adverse events were generally transient and occurred after administration.

Adverse reactions are categorized by 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), frequency not known (cannot be estimated from available data).

Infections and infestations:

Rare — Herpetic keratitis*§.

Gastrointestinal disorders:

Uncommon — Nausea, vomiting.

Nervous system disorders:

Uncommon — Headache*, dizziness*.

Eye disorders:

Very common — Increased pigmentation of the iris, mild to moderate conjunctival hyperemia, eye irritation (burning sensation with feeling of "sand in the eye", itching, stinging, foreign body sensation), changes in eyelashes and vellus hair of the 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 the eyelids, darkening of the peripalpebral skin of the eyelids, ocular conjunctival pseudopemphigoid*§;

Very rare — Periorbital changes and eyelid changes leading to deepening of the eyelid sulcus.

Cardiac disorders:

Uncommon — Angina pectoris, tachycardia;

Very rare — Unstable angina*.

Respiratory, thoracic and mediastinal disorders:

Uncommon — Bronchial asthma*, dyspnea*;

Rare — Exacerbation of bronchial asthma.

Skin and subcutaneous tissue disorders:

Uncommon — Skin rash;

Rare — Itching.

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 the adverse reaction to latanoprost was estimated according to the "Rule of Three".

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

Children

In two short-term clinical studies (≤12 weeks) involving 93 (25 and 68) pediatric patients, the safety profile of latanoprost 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"). In pediatric patients, adverse events such as nasopharyngitis and increased body temperature were observed more frequently than in adults.

Reporting of Adverse Reactions

Reporting suspected adverse reactions after medicine authorization is highly important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, patients, or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

2.5 ml in a bottle; 1 bottle per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

San Pharmaceuticals Industries Ltd.

Manufacturer's address and location of operations.

Baroda Highway, Halol, Gujarat, 389350, India.