Xalatan

INSTRUCTIONS for medical use of the medicinal product XALATAN® (XALATAN®)

Composition:

Active substance: latanoprost;

1 ml of ophthalmic solution contains 50 mcg of latanoprost;

Excipients: sodium chloride, sodium dihydrogen phosphate monohydrate, anhydrous sodium hydrogen phosphate, benzalkonium chloride solution, water for injections.

Pharmaceutical form. Ophthalmic solution.

Main physicochemical properties: clear, colorless solution.

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

Pharmacological properties.

Pharmacodynamics.

The active substance, latanoprost, a prostaglandin F2α analogue, 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 of the drug, with maximum effect observed after 8–12 hours. The hypotensive effect lasts for at least 24 hours.

Preclinical studies have shown that Xalatan® is effective as monotherapy. In addition, clinical studies on combination therapy have been conducted. 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 aqueous humor. No effect of latanoprost on the blood-aqueous 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 effect of latanoprost on the cardiovascular or respiratory systems has been observed at clinically used doses.

Children.

The efficacy of Xalatan® 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 ocular hypertension or childhood glaucoma. In this study, gestational age at birth had to be 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 age subgroups studied (from birth to 3 years, 3 to 12 years, and 12 to 18 years), mean IOP reductions at week 12 were similar between patients treated with latanoprost and those treated with timolol. However, efficacy data for latanoprost in the age group from birth to 3 years were obtained 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. Outcomes in the non-PCG subgroup (i.e., patients with, for example, juvenile open-angle glaucoma, aphakic glaucoma) were similar 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 that observed in adults.

SP – standard error.

†Adjusted estimated value based on the 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 enters 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. However, a wide safety margin for systemic adverse effects was maintained. The median time to reach peak plasma concentration after dosing was 5 minutes across all age groups. The median plasma elimination half-life 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.

Known hypersensitivity to any component of the Xalatan® medicinal product.

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 after 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.

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

Color change is predominantly observed in patients with mixed iris color, such as blue-brown, gray-brown, yellow-brown, or green-brown. In clinical studies with latanoprost, color changes typically occurred during 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 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 (see section "Adverse reactions"). Iris color changes are mostly mild and often clinically insignificant. The incidence of cases in patients with mixed iris color ranged from 7% to 85%, with the highest frequency observed in patients with yellow-brown iris color. No change in eye color was observed in patients with uniformly blue eyes, and such changes 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 treated eye, although the entire iris or parts of it may become more brown. No further increase in brown iris pigmentation has been observed after discontinuation of treatment. Currently, 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 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 indicate that increased iris pigmentation does not lead to clinical complications, and treatment with Xalatan® may be continued if iris pigmentation changes occur. However, patients should undergo regular examinations, and treatment with Xalatan® should be discontinued if the clinical situation so requires.

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

Data on the use of Xalatan® during the perioperative period of cataract surgery are limited. This medication should be used with caution in such patients.

Xalatan® should be used with caution in patients with a history of herpetic keratitis. However, 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 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 patients with known risk factors for cystoid macular edema (such as diabetic retinopathy and retinal vein occlusion). Xalatan® should be used with caution in aphakic patients, pseudophakic patients with posterior capsule rupture or anterior chamber lenses, and patients with known risk factors for cystoid macular edema.

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

Experience with the use of 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 to patients with bronchial asthma (see also section "Adverse reactions").

Changes in skin color in the periorbital area have been observed, with most cases reported in Japanese patients. Available data suggest that skin pigmentation changes in the periorbital area are not permanent and, in some cases, may resolve during continued treatment with Xalatan®.

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 drug.

Preservative.

Xalatan® contains benzalkonium chloride, a commonly used 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 reactive to irritants than those of adults. Irritation may lead to non-compliance with the treatment regimen in children. Reports indicate that benzalkonium chloride may cause eye irritation, dry eye symptoms, and may affect the tear film and corneal surface. It should be used with caution in patients with dry eye and in patients who may have corneal damage. Careful monitoring of patients is required during prolonged use.

Contact lenses.

Contact lenses may absorb benzalkonium chloride; therefore, they should be removed before applying Xalatan® 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 for use during pregnancy has not been established. Its pharmacological action poses a potential risk to pregnancy, the fetus, or the newborn. Therefore, Xalatan® 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 Xalatan® or stop breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Xalatan® has a negligible effect on the ability to drive or operate machinery. As with other ophthalmic preparations, instillation of eye drops may cause transient blurred vision. Patients should not drive or operate machinery until this effect has resolved.

Method of Administration and Dosage.

Recommended dosage for adults, including elderly patients.

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

Xalatan® 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, treatment should be continued with the next dose at the usual time.

Method of administration.

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

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

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

Children. Xalatan® may be used in pediatric patients at the same dosage as in adults.

Data on the efficacy and safety of Xalatan® 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 aged from birth to 3 years, primarily suffering from primary congenital glaucoma, surgical intervention (e.g., trabeculotomy/goniotomy) remains the first-line treatment.

The long-term safety of Xalatan® in pediatric patients has not been established.

Overdose.

Symptoms.

Apart from eye irritation and conjunctival hyperemia, no other ocular adverse effects have been reported following overdose of Xalatan®.

Treatment.

The following information may be useful in case of accidental ingestion of Xalatan®. One vial contains 125 mcg of latanoprost. More than 90% is metabolized during first-pass through the liver. Intravenous infusion of latanoprost 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, hot flushes, and sweating.

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

In case of overdose of Xalatan®, symptomatic treatment should be administered.

Side effects.

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

Adverse events are categorized according to frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), 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 pigmentation of the iris; mild to moderate conjunctival hyperemia; eye irritation (burning sensation with feeling of "sand in the eye", itching, stinging, and foreign body sensation); changes in eyelashes and vellus hair of the eyelids (increased length, thickness, pigmentation, and number of eyelashes).

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 palpebral skin of the eyelids; ocular conjunctival pseudopemphigoid*§.

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: Itching.

Musculoskeletal and connective tissue disorders

Uncommon: Myalgia*, arthralgia*.

General disorders and administration site conditions

Uncommon: Chest pain*.

* Adverse reaction to the drug identified during the post-marketing period.

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

There have been very rare reports of corneal calcification associated with the 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 was similar to that 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, the following adverse events occurred more frequently than in adults: nasopharyngitis and increased body temperature.

Reporting suspected adverse reactions.

Reporting of 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. 3 years.

Storage conditions. Store at 2–8 °C in the original packaging, out of the reach of children. After first opening, store the bottle at a temperature not exceeding 25 °C and use within 4 weeks.

Packaging. 2.5 ml in a polyethylene bottle. 1 bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Pfizer Manufacturing Belgium/Pfizer Manufacturing Belgium.

Manufacturer's address and place of business.

Rijksweg 12, Puurs-Sint-Amands, 2870, Belgium/Rijksweg 12, Puurs-Sint-Amands, 2870, Belgium.