Latanoprost (Drops) Instructions for Use

ATC Code

S01EE01 (Latanoprost)

Active Substance

Latanoprost (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiglaucoma drug

Pharmacotherapeutic Group

Antiglaucoma agent – synthetic prostaglandin F_2α analogue

Pharmacological Action

Latanoprost, a prostaglandin F_2α analogue, is a selective agonist of FP (prostaglandin F) receptors and reduces intraocular pressure (IOP) by increasing the outflow of aqueous humor, mainly through the uveoscleral pathway, as well as through the trabecular meshwork.

IOP reduction begins approximately 3-4 hours after drug administration, and the maximum effect is noted after 8-12 hours. The hypotensive effect lasts about 24 hours.

Latanoprost does not have a significant effect on the production of aqueous humor or on the blood-ophthalmic barrier.

When used in therapeutic doses, Latanoprost does not have a significant pharmacological effect on the cardiovascular and respiratory systems.

Pharmacokinetics

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

Absorption and Distribution

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

Studies in humans have shown that C_max in the aqueous humor is reached 2 hours after instillation. After instillation in monkeys, Latanoprost is distributed mainly 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 active form of latanoprost is practically not metabolized in the eye but undergoes biotransformation in the liver.

T_1/2 from plasma is 17 min. 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 in the urine.

Pharmacokinetics in Special Patient Groups

Children. Pharmacokinetic studies of latanoprost were conducted in 22 adults and 25 children (aged 0-18 years) with ocular hypertension and glaucoma. All age groups received Latanoprost at a concentration of 0.005%, one drop in each eye for at least 2 weeks. Latanoprost exposure is approximately 2 times higher in children aged 3 to 12 years compared to adult patients and 6 times higher in children under 3 years of age.

However, the safety profile of the drug does not differ between children and adults (see the “Overdose” section). In all age groups, the duration of maintaining C_max of latanoprost acid in blood plasma is 5 min. The T_1/2 of latanoprost acid in children is the same as in adults (<20 min). At steady-state concentration, there is no accumulation of latanoprost acid in the blood plasma.

Indications

• Reduction of elevated intraocular pressure in adults and children (over 1 year of age) with open-angle glaucoma or ocular hypertension.

ICD codes

Dosage Regimen

Drops

Adults (including the elderly)

1 drop into the affected eye(s) once a day. The optimal effect is achieved when the drug is used in the evening.

The drug should not be instilled more than once a day, as it has been shown that more frequent administration reduces the hypotensive effect. If one dose is missed, treatment should be continued according to the usual regimen.

As with the use of any eye drops, to reduce the possible systemic effect of the drug, it is recommended to press on the lower lacrimal point, located at the inner corner of the eye on the lower eyelid, for 1 minute immediately after instillation of each drop. This procedure must be performed directly after instillation.

Before instillation, contact lenses must be removed and reinserted no earlier than 15 minutes after administration (see also the “Special Precautions” section).

If several ophthalmic dosage forms are used simultaneously, their application should be separated by a 5-minute interval.

Children

Latanoprost is used in children at the same dose as in adults. There are no data on the use of the drug in premature infants (gestational age <36 weeks). Data in children under 1 year of age are very limited.

Adverse Reactions

Most adverse reactions were noted from the organ of vision. In an open 5-year safety study, iris pigmentation developed in 33% of patients (see the “Special Precautions” section). Other adverse reactions from the organ of vision are usually transient and noted immediately after instillation.

The grading of adverse reactions by frequency of occurrence was as follows: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000) and very rare (<1/10000); frequency not known (cannot be estimated from the available data).

Infections and infestations frequency not known – herpetic keratitis.

From the organ of vision very common – iris hyperpigmentation, conjunctival hyperemia, mild to moderate eye irritation (burning sensation, gritty feeling, itching, tingling, and foreign body sensation), eyelash changes (increased length, thickness, number, and pigmentation); common – transient punctate epithelial erosions (mostly asymptomatic), blepharitis, eye pain; uncommon – eyelid edema, eye dryness, keratitis, blurred vision, conjunctivitis; rare – iritis/uveitis (mainly in predisposed patients), macular edema, eyelid edema, corneal edema, corneal erosion, periorbital edema, darkening of the eyelid skin, eyelid skin reactions, change in eyelash growth direction, thickening, darkening and lengthening of eyelashes, distichiasis, photophobia; very rare – changes in the periorbital area and eyelash area leading to deepening of the upper eyelid sulcus; frequency not known – iris cyst, conjunctival pseudopemphigoid.

From the nervous system frequency not known – dizziness, headache.

From the heart uncommon – angina pectoris, palpitations; frequency not known – unstable angina.

From the respiratory system rare – bronchospasm (including exacerbation of the disease in patients with a history of bronchial asthma), dyspnea.

From the skin and subcutaneous tissues uncommon – rash; rare – skin itching; very rare – darkening of the eyelid skin and local skin reactions on the eyelids.

From the musculoskeletal system frequency not known – myalgia, arthralgia.

General disorders and administration site conditions very rare – chest pain.

Children

According to the results of two short-term (<12 weeks) clinical studies in 93 children, the safety profile of latanoprost in children did not differ from the safety profile in adults. The safety profile between different age groups in children is comparable. Compared to the adult population, nasopharyngitis and fever were most frequently reported in children.

Contraindications

• Hypersensitivity to latanoprost or other components of the drug;
• Age under 1 year (efficacy and safety not established);
• Pregnancy;
• Breastfeeding period.

With caution

Aphakia, pseudophakia with rupture of the posterior lens capsule; patients with risk factors for macular edema (cases of macular edema, including cystoid, have been described during treatment with latanoprost); inflammatory, neovascular glaucoma (due to lack of sufficient experience with the drug); bronchial asthma; history of herpetic keratitis.

The use of the drug should be avoided in patients with active herpetic keratitis and recurrent herpetic keratitis, especially associated with the use of prostaglandin F_2α analogues.

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

There are limited data on the use of the drug in patients scheduled for cataract surgery. In this regard, the drug should be used with caution in this group of patients.

Use in Pregnancy and Lactation

Pregnancy

The safety of latanoprost use during pregnancy in women has not been established. Latanoprost may have toxic effects on the course of pregnancy, the fetus, and the newborn. Use during pregnancy is contraindicated.

Breastfeeding period

Latanoprost and its metabolites may pass into breast milk. Use during breastfeeding is contraindicated. If it is necessary to use the drug, breastfeeding should be discontinued.

Fertility

No effect of latanoprost on male and female fertility was found in animal studies.

Pediatric Use

The use of the drug is contraindicated in children under 1 year of age.

Special Precautions

Latanoprost 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 irreversible change in eye color. Use of the medicinal product in one eye may cause irreversible heterochromia.

Such a change in eye color was predominantly noted in patients with unevenly colored irises, namely: hazel-blue, gray-brown, yellow-brown, and green-brown. In latanoprost studies, darkening generally began within the first 8 months of treatment, rarely during the second or third year, and was not observed after four years of treatment.

The progression of iris pigmentation decreased over time and stabilized after 5 years. There are no data on increased pigmentation over 5 years. In an open 5-year safety study of latanoprost, iris pigmentation developed in 33% of patients (see “Adverse Reactions”). In most cases, the change in iris color was minor and often not clinically detectable. The frequency ranged from 7% to 85% in patients with heterochromic irises, predominating in patients with yellow-brown irises. No changes were observed in patients with uniformly colored blue irises; in rare cases, changes were noted with uniformly colored gray, green, and brown irises.

The change in eye color is due to an increase in melanin content in the stromal melanocytes of the iris, not an increase in the number of melanocytes themselves. Typically, brown pigmentation appears around the pupil and spreads concentrically to the periphery of the iris. In this case, the entire iris or its parts become brown. After discontinuation of therapy, no further pigmentation was noted. According to available clinical data, the color change was not associated with any symptoms or pathological disorders.

The drug does not affect nevi and lentigo of the iris. According to the results of 5-year clinical studies, no accumulation of pigment in the sclero-corneal trabecular meshwork or other parts of the anterior chamber of the eye was noted. It has been shown that darkening of the iris does not lead to undesirable clinical consequences, so the use of latanoprost can be continued if such darkening occurs. Nevertheless, such patients should be under regular observation and, depending on the clinical situation, treatment may be discontinued.

Experience with the use of latanoprost in the treatment of angle-closure and congenital glaucoma, pigmentary glaucoma, and open-angle glaucoma in patients with pseudophakia is limited.

There is no information on the use of latanoprost in the treatment of secondary glaucoma due to inflammatory eye diseases and neovascular glaucoma.

Latanoprost does not affect pupil size.

Since information on the use of latanoprost in the postoperative period of cataract extraction is limited, caution should be exercised when using the drug in this category of patients.

Caution should be exercised when using latanoprost in patients with a history of herpetic keratitis. In acute herpetic keratitis, as well as in the case of a history of chronic recurrent herpetic keratitis, the appointment of latanoprost should be avoided.

Macular edema, including cystoid, has been observed during therapy with latanoprost, mainly in patients with aphakia, pseudophakia, rupture of the posterior lens capsule, or in patients with risk factors for cystoid macular edema (in particular, diabetic retinopathy and retinal vein occlusion). Caution should be exercised when using latanoprost in patients with aphakia, pseudophakia with rupture of the posterior capsule or anterior chamber intraocular lenses, as well as in patients with known risk factors for cystoid macular edema.

Caution should be exercised when using latanoprost in patients with risk factors for the development of iritis/uveitis.

Experience with the use of latanoprost in patients with bronchial asthma is limited, but in a number of cases in the post-registration period, exacerbation of asthma and/or the appearance of shortness of breath were noted. Caution should be exercised when using latanoprost in this category of patients (see also the “Adverse Reactions” section).

Cases of darkening of the skin of the periorbital area have been reported, which in a number of patients were reversible with continued latanoprost therapy.

Latanoprost can cause gradual changes in eyelashes and vellus hair, such as lengthening, thickening, increased pigmentation, increased density, and change in the direction of eyelash growth. Eyelash changes were reversible and resolved after discontinuation of therapy.

The drug Latanoprost contains benzalkonium chloride, often used as a preservative in ophthalmic medicinal products. Benzalkonium chloride can cause eye irritation, punctate keratopathy and/or toxic ulcerative keratopathy, and can also be absorbed by soft contact lenses and discolor them. Careful monitoring of patients with dry eye syndrome or other corneal diseases during long-term use of the drug is required. Before using the drug, contact lenses must be removed and reinserted no earlier than 15 minutes after instillation (see also the “Dosage Regimen” section).

Use in pediatrics

Information on the efficacy and safety of latanoprost use in children under one year of age is limited. There is no experience with the use of the drug in premature infants (gestational age less than 36 weeks).

There is no information on the safety of long-term use of latanoprost in children. For primary congenital glaucoma in children from 0 to 3 years of age, surgical intervention (goniotomy/trabeculotomy) remains the standard treatment method.

Effect on ability to drive vehicles and operate machinery

As with the use of other ophthalmic medicinal products, temporary visual impairment is possible; until it is restored, it is not recommended to drive vehicles or operate machinery.

Overdose

Symptoms

Apart from irritation of the eye mucosa (conjunctival or episcleral hyperemia), other adverse reactions from the organ of vision with an overdose of latanoprost have not been described.

In case of accidental oral ingestion of latanoprost, the following information should be considered: one 2.5 ml bottle contains 125 mcg of latanoprost. More than 90% of latanoprost is metabolized during the “first pass” through the liver. Intravenous infusion at a dose of 3 mcg/kg in healthy volunteers did not cause any symptoms, but at doses of 5.5-10 mcg/kg, nausea, abdominal pain, dizziness, fatigue, “flushing” and sweating were observed. Intravenous administration of latanoprost to monkeys at a dose of 500 mcg/kg did not cause significant effects on the cardiovascular system.

Intravenous administration of latanoprost to monkeys caused transient bronchospasm. In patients with moderate bronchial asthma, instillation of latanoprost into the eyes at a dose 7 times the therapeutic dose did not cause bronchospasm.

Treatment

In case of overdose, symptomatic treatment is carried out.

Drug Interactions

With simultaneous instillation into the eyes of two prostaglandin analogues, a paradoxical increase in IOP has been described, therefore the simultaneous use of two or more prostaglandins, their analogues or derivatives is not recommended.

In vitro studies have shown that when eye drops containing thimerosal are mixed with eye drops containing Latanoprost, a precipitate is formed. If it is necessary to use these drugs simultaneously, a 5-minute interval between their instillation should be observed.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature from 2°C (35.6°F) to 8°C (46.4°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date indicated on the packaging.

After opening, the bottle should be stored at a temperature not exceeding 25°C (77°F). The shelf life after opening the bottle is 28 days.

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.