Latanox®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LATANOX®

Composition:

Active substance: latanoprost;

1 ml of the preparation contains latanoprost – 0.05 mg;

Excipients: benzalkonium chloride, sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate, sodium chloride, purified water.

Pharmaceutical form. Eye drops.

Main physicochemical properties: colorless clear liquid.

Pharmacotherapeutic group. Anti-glaucoma preparations and miotics. Latanoprost. ATC code S01E E01.

Pharmacological Properties

Pharmacodynamics

Latanoprost is a prostaglandin F2α analog and a selective FP receptor agonist. It reduces intraocular pressure by increasing the outflow of aqueous humor and demonstrates anti-glaucoma activity. The main mechanism of latanoprost's action is related to the enhancement of uveoscleral outflow. It has no significant effect on aqueous humor production and does not affect the blood-ocular barrier. Reduction in intraocular pressure begins 3–4 hours after administration, with maximum effect observed at 8–12 hours. The hypotensive effect lasts for at least 24 hours.

Studies have shown that latanoprost is effective as monotherapy. In addition, clinical studies have been conducted on the combined use of the drug. These included studies demonstrating that latanoprost is effective in combination with beta-adrenergic blockers (timolol). Short-term (1 or 2 weeks) studies indicate 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 leakage of fluorescein into the posterior segment of pseudophakic human eyes during short-term treatment.

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

Pharmacokinetics

Latanoprost (molecular weight 432.58) is an isopropyl ester prodrug, which is inactive per se but becomes biologically active after hydrolysis to form latanoprost acid.

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

Studies in humans have shown that maximum concentration in the intraocular fluid is achieved approximately 2 hours after topical administration. After topical application in monkeys, latanoprost is distributed mainly in the anterior segment, conjunctiva, and eyelids. Only a minimal amount of the drug reaches the posterior segment.

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

Clinical characteristics.

Indications.

Reduction of elevated intraocular pressure in patients with open-angle glaucoma and elevated ocular tonus.

Contraindications.

Individual hypersensitivity to latanoprost, benzalkonium chloride, or other components of the drug.

Interaction with other medicinal products and other forms of interaction.

Comprehensive data on interactions with other medicinal products are lacking.
Paradoxical increase in intraocular pressure has been reported following concomitant ocular administration of two prostaglandin analogues. Therefore, concomitant use of two or more prostaglandins, prostaglandin analogues, or their derivatives is not recommended.

Special precautions for use.

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

This change in eye color is observed predominantly in patients with mixed iris color, for example, blue-brown, gray-brown, yellow-brown, or green-brown. In clinical trials of 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 treatment has not been evaluated. In an open-label 5-year safety study of latanoprost, increased iris pigmentation was recorded in 33% of patients. Iris color changes were 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 eyes and were rare in patients with uniformly gray, green, or brown eyes. The color 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 toward the periphery of the affected eye, although the entire iris or parts of it may become more brown. After discontinuation of treatment, further progression 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 therapy. 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 suggest that increased iris pigmentation does not lead to clinical complications, and treatment with Latanox® may be continued if iris pigmentation changes occur. However, patients should undergo regular examinations, and if the clinical situation requires, treatment with Latanox® 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, Latanox® 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. Latanox® should be used with caution in such patients.

Latanox® 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 a history of recurrent herpetic keratitis, especially if associated with prostaglandin analogs.

Cases of macular edema have been reported, 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).

Latanox® should be used with caution in such patients.

Latanox® may be used cautiously and under monitoring in patients with known risk factors for iritis/uveitis.

Experience with the use of the drug in patients with bronchial asthma is limited, although some cases of bronchial asthma exacerbation and/or dyspnea have been reported during the post-marketing period. Until sufficient clinical experience is accumulated, the drug should be prescribed with caution to patients with bronchial asthma.

Skin pigmentation changes in the periorbital area have been observed, with most cases reported in Japanese patients. Current data indicate that skin pigmentation changes in the periorbital area are not permanent and in some cases resolve during continued treatment with the medication.

Latanoprost may gradually alter 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.

Latanox® contains benzalkonium chloride, commonly used as a preservative in ophthalmic preparations. Reports indicate that benzalkonium chloride may cause punctate keratopathy and/or toxic ulcerative keratopathy; it may also cause eye irritation and alter the color of soft contact lenses. Careful monitoring is required in patients with dry eye or conditions involving corneal damage when latanoprost is used frequently or long-term. Contact lenses may absorb benzalkonium chloride; therefore, they should be removed before applying latanoprost but may be reinserted 15 minutes after instillation.

Use during pregnancy or breastfeeding.

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

Latanoprost and its metabolites may pass into breast milk; therefore, nursing mothers should either discontinue treatment with Latanox® or stop breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Patients who experience temporary blurred vision after instillation of eye drops should not drive or operate machinery for several minutes after administering the medication.

Dosage and Administration

Recommended dosage for adults, including elderly patients

Recommended therapy: 1 drop in the affected eye once daily. The optimal effect is achieved when Latanox® is administered in the evening.

Latanox® should not be used more frequently than once daily, as more frequent administration has been shown to reduce the intraocular pressure-lowering effect.

If a dose is missed, continue treatment with the next dose at the usual time.

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

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

When using multiple ophthalmic agents with local action, the medications should be administered with an interval of at least 5 minutes between them.

Children

There is insufficient experience with the use of Latanox® in children.

Latanox® is not recommended for use in pediatric practice.

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 useful in case of accidental ingestion of Latanox®: one vial 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 in healthy volunteers resulted in a mean plasma concentration 200 times higher than concentrations observed during clinical trials and did not cause any symptoms. However, at doses of 5.5–10 mcg/kg, nausea, abdominal pain, dizziness, fatigue, hot flushes, and increased sweating were observed. In monkeys, intravenous infusion of latanoprost at doses up to 500 mcg/kg did not cause any significant effects on the cardiovascular system. Intravenous administration of latanoprost in monkeys was associated with transient bronchospasm.

However, in patients with mild to moderate bronchial asthma, administration of latanoprost eye doses 7 times higher than the clinical dose of Latanox® did not result in bronchoconstriction. In case of overdose with Latanox®, symptomatic treatment should be administered.

Side effects.

Side effects are categorized according to their frequency of occurrence 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

Not known: herpetic keratitis.

Eye disorders

Very common: increased pigmentation of the iris; mild or 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 (increased length, thickness, pigmentation, and number) (the majority of cases were observed in Japanese patients).

Common: transient punctate epithelial erosions, mostly asymptomatic; blepharitis; eye pain; photophobia.

Uncommon: eyelid edema; dry eyes; keratitis; blurred vision; conjunctivitis.

Rare: iritis/uveitis; macular edema; symptomatic corneal edema and erosions; periorbital edema; misdirected eyelash growth, sometimes causing eye irritation; development of an additional row of eyelashes near the meibomian gland orifices (distichiasis); photophobia.

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

Not known: iris cyst.

Nervous system disorders

Not known: headache, dizziness.

Cardiovascular system disorders

Very rare: worsening of angina in patients with pre-existing heart disease.

Not known: tachycardia.

Respiratory system disorders

Rare: bronchial asthma, exacerbation of bronchial asthma, dyspnea.

Skin and subcutaneous tissue disorders

Uncommon: skin rash.

Rare: local skin reaction on the eyelids; darkening of the palpebral skin of the eyelids.

Musculoskeletal and connective tissue disorders

Not known: myalgia, arthralgia.

Gastrointestinal disorders

Uncommon: nausea, vomiting.

General disorders and administration site conditions

Very rare: chest pain.

Very rare cases of corneal calcification associated with the use of phosphate-containing eye drops have been reported in some patients with significantly damaged corneas.

Shelf life. 2 years.

Storage conditions.

Store at +2°C to +8°C, protected from light and out of reach of children.

An opened bottle should be stored at a temperature not exceeding 25°C for up to four weeks.

Packaging.

2.5 mL solution in a dropper bottle; 1 or 3 dropper bottles in a cardboard box.

Prescription status.

Prescription only.

Manufacturer/Marketing Authorization Holder

Pliva-Lachema d.d.

Manufacturer's address and place of business

Svilno 20, 51000 Rijeka, Croatia.