Unilat

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT UNILAT (UNILAT)

Composition:

Active substance: 1 ml of solution contains latanoprost 50 mcg;

Excipients: sodium chloride, sodium dihydrogen phosphate monohydrate, anhydrous sodium hydrogen phosphate, benzalkonium chloride, concentrated hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Eye drops.

Main physico-chemical properties: clear, colorless solution free from mechanical particles.

Pharmacotherapeutic group. Ophthalmological agents. Anti-glaucoma and miotic agents. Prostaglandin analogues. Latanoprost. ATC code S01E E01.

Pharmacological Properties

Pharmacodynamics

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

Preclinical studies have shown the efficacy of the drug as monotherapy. In addition, clinical studies on combination therapy have demonstrated that latanoprost is effective 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 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 aqueous humor. 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 the drug in pediatric patients (≤18 years of age) was demonstrated in a 12-week, double-masked, clinical study comparing latanoprost with timolol in 107 patients diagnosed with elevated intraocular pressure or pediatric glaucoma. In this study, gestational age of neonates 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 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 patients receiving latanoprost and those receiving timolol. However, efficacy data for latanoprost in the birth to 3 years age group were based on only 13 patients, and no significant efficacy was demonstrated in the 4 patients representing the birth to 1 year age group in the clinical trial. 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 latanoprost and timolol treatment groups. Results in the non-PCG subgroup (i.e., patients with, for example, juvenile open-angle glaucoma, aphakic glaucoma) were comparable to those in PCG patients.

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.

SP – standard error.

*Adjusted calculated value 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 latanoprost acid.

Prodrugs penetrate well through the cornea, and all the drug that reaches 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. Practically no metabolism of latanoprost acid occurs in the eye. The main metabolism of the drug takes place in the liver. In humans, the plasma half-life 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 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 despite this, a wide safety margin for systemic adverse effects was maintained. The median time required to reach peak plasma concentration of the drug was 5 minutes after dosing across all age groups. The median plasma half-life of the drug 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 patients with open-angle glaucoma and elevated intraocular pressure.

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

Contraindications.

Known hypersensitivity to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Comprehensive data on interaction with other medicinal products are lacking. Paradoxical increase in intraocular pressure 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

The drug may cause a gradual change in eye color due to increased brown pigmentation in the iris. Patients should be informed about the possibility of permanent eye color change prior to initiating treatment. Treatment of only one eye may lead to permanent heterochromia.

Color change is predominantly observed in patients with mixed iris coloration, such as blue-brown, gray-brown, yellow-brown, or green-brown. In clinical studies with latanoprost, iris color changes typically 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. Progression of iris pigmentation decreases over time and stabilizes after 5 years. The effect of enhanced 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 (see section "Adverse reactions"). Iris color changes are mostly mild and often clinically insignificant. The incidence of such changes in patients with mixed iris color ranged from 7% to 85%, with the highest frequency observed in patients with yellow-brown iris color. 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 stromal melanocytes of the iris, 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 brownish. After discontinuation of treatment, further progression of 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 therapy. Clinical studies have not shown pigment accumulation in the trabecular meshwork or any other part of the anterior chamber of the eye. Results from 5 years of clinical use indicate that increased iris pigmentation does not lead to clinical complications, and treatment may be continued in case of iris pigmentation changes. However, patients should undergo regular ophthalmic examinations, and if clinically indicated, treatment should be discontinued.

Experience with the drug 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 the drug in inflammatory or neovascular glaucoma or in ocular inflammatory diseases. The drug has no or minimal effect on the pupil, but data on its use during acute attacks of angle-closure glaucoma are lacking. Therefore, latanoprost should be used with caution in such conditions until more data become available.

Data on the use of the drug during the perioperative period of cataract surgery are limited. Latanoprost 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 herpetic keratitis caused by herpes simplex virus and in patients with a history of recurrent herpetic keratitis, particularly when 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.

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

Experience with the drug 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 drug should be prescribed 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 Japanese patients. Available data suggest that periorbital skin pigmentation changes are not permanent and may resolve during continued treatment.

Latanoprost may gradually alter 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 drug.

Preservative. The drug contains benzalkonium chloride, commonly used as a preservative in ophthalmic preparations. According to limited available data, there are no differences in the adverse effect profile between children and adults. However, overall, children's eyes are more sensitive to irritants than those of adults. Irritation may disrupt treatment compliance in children. Reports indicate that benzalkonium chloride may cause ocular irritation, dry eye symptoms, and may affect the tear film and corneal integrity. Careful monitoring of patients is required during prolonged use.

Contact lenses. Contact lenses may absorb benzalkonium chloride; therefore, they should be removed before applying the drug and may be reinserted 15 minutes after instillation (see section "Dosage and administration").

Use during pregnancy or breastfeeding.

Pregnancy. The safety of this medicinal product 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.

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

Effects on ability to drive or operate machinery.

The drug has negligible influence on the ability to drive or operate machinery. As with other ophthalmic preparations, instillation of eye drops may cause transient blurred vision. Until this effect resolves, patients should refrain from driving or operating machinery.

Method of Administration and Dosage.

Recommended dosage for adults, including elderly patients.

Recommended therapy: 1 drop in the affected eye once daily. Optimal effect is achieved when the medication is administered in the evening.

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

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

Method of administration.

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

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

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

Children.

The drug 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 treatment.

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

Overdose.

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

Treatment. The information below may be useful in case of accidental ingestion. Each vial 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, hot flashes, and increased sweating.

No bronchospasm was observed in patients with mild bronchial asthma when doses of latanoprost up to 7 times higher than the clinical dose were administered topically to 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, iris pigmentation changes were observed in 33% of patients (see section "Special Warnings and Precautions for Use"). Other ocular adverse events are usually transient and occur upon instillation of the medication.

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

Infections and infestations

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, sensation of sand in the eye, 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 of the eyelids; darkening of the palpebral skin of the eyelids; pseudopemphigoid of the ocular conjunctiva*§.

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.

Skin and subcutaneous tissue disorders

Uncommon: Skin rash.

Rare: Itching.

Musculoskeletal and connective tissue disorders

Uncommon: Myalgia*, arthralgia*.

Gastrointestinal disorders

Uncommon: Nausea, vomiting.

General disorders and administration site conditions

Uncommon: Chest pain*.

* Adverse reaction identified during the post-marketing period.

§ Frequency of the adverse reaction was estimated using the "Rule of Three".

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

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 observed in adults, and no new adverse reactions were identified. Short-term safety profiles were also similar across different pediatric subgroups (see section "Pharmacological Properties"). In pediatric patients, nasopharyngitis and increased body temperature were reported 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 are encouraged to report any suspected adverse reactions.

Shelf life. 2 years.

The shelf life of the product after first opening of the container is 28 days.

Storage conditions

Store in the original packaging, protected from light and out of reach of children.

Prior to first opening: Store at 2°C – 8°C. Do not freeze.

After first opening: Store at a temperature not exceeding 25°C.

After first opening, store for no more than 28 days.

Packaging

2.5 ml in a dropper bottle. One dropper bottle in a cardboard box.

Prescription status Prescription only.

Manufacturer TOV "UNIMED PHARMA" / "UNIMED PHARMA Ltd."

Manufacturer's address and place of business

Orieskova 11, 821 05 Bratislava, Slovak Republic.