Prolatan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROLATAN (PROLATAN)

Composition:

Active substance: latanoprost;

1 ml of solution contains 0.05 mg of latanoprost;

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

Pharmaceutical form. Eye drops.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. 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 humour. Reduction in intraocular pressure in humans begins approximately 3–4 hours after administration of the drug, 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 combined use of the drug have been conducted. These included studies demonstrating the efficacy of latanoprost when used in combination with beta-adrenergic blockers (timolol). Short-term (1–2 weeks) studies have shown that the effect of latanoprost is additive when used in combination with adrenergic agonists (dipivalyl epinephrine), oral carbonic anhydrase inhibitors (acetazolamide), and at least partially additive when used with cholinergic agonists (pilocarpine).

Clinical studies have shown that latanoprost has no statistically significant effect on aqueous humour production. No effect of latanoprost on the blood-aqueous barrier has been demonstrated.

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 and respiratory systems has been observed at clinical doses.

Children

The efficacy of latanoprost in pediatric patients aged ≤ 18 years was demonstrated in a 12-week, double-masked, clinical study comparing latanoprost with timolol in 107 patients diagnosed with elevated intraocular pressure or childhood 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 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 similar between latanoprost and timolol groups. However, efficacy data for latanoprost in the birth to 3 years age group were derived from only 13 patients, and no significant efficacy was demonstrated in the 4 patients who represented 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 latanoprost and timolol groups. Results in the non-PCG subgroup (i.e., patients with, for example, juvenile open-angle glaucoma, aphakic glaucoma) were consistent with 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 calculated value based on analysis of covariance (ANCOVA) model.

Pharmacokinetics.

Latanoprost (molecular weight 432.58) is a prodrug (in the form of isopropyl ester) that is inactive in itself but becomes biologically active after hydrolysis to form latanoprost acid.

The prodrug penetrates well through the cornea, and all of it that enters the intraocular fluid is hydrolyzed during passage through the cornea.

Studies in humans have shown that maximum concentration in the intraocular fluid is reached approximately 2 hours after topical administration. 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 latanoprost acid plasma concentration 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 reactions 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 elimination half-life of the drug from plasma 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 (IOP) 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 childhood glaucoma.

Contraindications.

Known hypersensitivity to any component of the drug.

Interaction with other medicinal products and other types of interactions.

Comprehensive data on drug 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.

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

Changes in eye colour are predominantly observed in patients with mixed iris colour, such as blue-brown, grey-brown, yellow-brown, or green-brown. In clinical trials with latanoprost, colour changes usually occurred within the first 8 months of treatment, less frequently 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 (see section "Adverse reactions"). Iris colour changes are mostly mild and often clinically insignificant. The incidence of cases in patients with mixed iris colour ranged from 7% to 85%, with the highest frequency observed in patients with yellow-brown iris colour. Changes in eye colour were not observed in patients with uniformly blue iris colour and were rare in patients with uniformly grey, green, or brown iris colour.

The colour change occurs due to increased melanin content in the iris stromal melanocytes, not due to an increase in melanocyte number. 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. No further increase in brown iris pigmentation has been observed after discontinuation of treatment. 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 observed 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 if iris pigmentation changes occur. However, patients should undergo regular ophthalmological examinations, and treatment should be discontinued if clinically indicated.

Experience with latanoprost in chronic angle-closure glaucoma, open-angle glaucoma in pseudophakic patients, and pigmentary glaucoma is limited. Currently, there are no data on the use of the medicinal product in inflammatory or neovascular glaucoma or in inflammatory eye diseases. The medicinal product has no or minimal effect on the pupil, but data on its use during acute attacks of angle-closure glaucoma are lacking. Therefore, caution is recommended when using the medicinal product in such conditions until more data become available.

Data on the use of the medicinal product 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. 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 if associated with prostaglandin analogues.

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). The medicinal product 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.

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

Experience with the medicinal product 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 prescribed with caution to patients with bronchial asthma (see also section "Adverse reactions").

Changes in skin pigmentation 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 disappear in some cases during continued 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.

Preservative

The medicinal product contains benzalkonium chloride, commonly used as a preservative in ophthalmic preparations. According to limited available data, there are no differences in the adverse reaction profile between children and adults. However, ocular response to irritants is generally stronger in children than in adults. Due to irritation, treatment compliance may be impaired in children. Reports indicate that benzalkonium chloride may cause ocular irritation, dry eye symptoms, and may affect the tear film and corneal surface. Caution is required in patients with dry eye and in those with potential corneal damage. Careful monitoring is necessary during prolonged use.

Contact lenses

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

Use during pregnancy or breastfeeding.

Pregnancy

The safety of this medicinal product 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 breastfeeding before treatment with this medicinal product.

Reproductive function (fertility)

Based on animal studies, latanoprost does not affect fertility in males or females.

Women planning pregnancy

The physician should be immediately informed if a patient plans to become pregnant or suspects she is pregnant while using latanoprost 0.005% ophthalmic solution. The medicinal product should be used in women of reproductive age only under medical supervision.

Contraception in males and females

No data available.

Ability to affect reaction speed when driving vehicles or operating machinery.

The medicinal product has a minor influence on reaction speed when driving vehicles or operating machinery. As with other ophthalmic preparations, instillation of eye drops may cause temporary blurred vision. Patients should refrain from driving or operating machinery until this effect subsides.

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 the medication is administered in the evening.

The medication should not be used more frequently than once daily, as more frequent administration has been shown to reduce the effectiveness of intraocular pressure reduction.

If a dose is missed, treatment should be continued with the next dose at the usual time. As with any ophthalmic drops, to minimize potential systemic absorption, it is recommended to press on the lacrimal sac in the area of the medial canthus of the eye (nasolacrimal occlusion) for one minute immediately after instillation. This should be performed every time right after drop administration.

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

When using multiple ophthalmic topical agents, other than latanoprost, they should be administered with an interval of at least 5 minutes between each.

Children

The medication may be used in pediatric patients at the same dosage as in adults.

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

The safety of long-term use in children has not been established.

Overdose.

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

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

However, when latanoprost doses up to 7 times higher than the clinical dose were administered topically to the eyes of patients with moderate bronchial asthma, no bronchoconstriction was observed.

In case of overdose, symptomatic treatment should be administered.

Side effects

Most side effects 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 ocular side effects are usually temporary and occur after administration of the drug.

Side effects are categorized according to frequency: 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 parasitic diseases

Rare: Herpetic keratitis*§.

Nervous system disorders

Uncommon: Headache*; dizziness*.

Eye disorders

Very common: Increased iris pigmentation; mild to moderate conjunctival hyperemia; eye irritation (burning sensation with feeling of "sand in the eyes", 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 on eyelids; darkening of palpebral skin of eyelids; pseudopemphigoid of ocular conjunctiva*§.

Very rare: Periorbital changes and eyelid changes leading to deepening of eyelid folds.

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 identified during the post-marketing period.

§ Frequency of adverse reaction was 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 reactions were identified. Short-term safety profiles in different pediatric subgroups were also similar (see section "Pharmacological properties"). Adverse reactions observed more frequently in pediatric patients than in adults include nasopharyngitis and increased body temperature.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at 2–8°C in a protected from light place.

After opening, store the bottle for no more than 4 weeks at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging. 2.5 ml in a bottle with dropper; 1 or 3 bottles per cardboard box.

Prescription status. Prescription only.

Manufacturer.

SENTISS PHARMA PVT. LTD., India /
SENTISS PHARMA PVT. LTD., India.

Manufacturer's address and place of business.

Village Khera Nihla, Tehsil Nalagarh, Distt. Solan, Himachal Pradesh, 174 101, India /
Village Khera Nihla, Tehsil Nalagarh, Distt. Solan, Himachal Pradesh, 174 101, India.

Marketing Authorization Holder.

SENTISS PHARMA PVT. LTD., India /
SENTISS PHARMA PVT. LTD., India.

Contact details for the Marketing Authorization Holder's Pharmacovigilance Contact Person (for reporting all suspected adverse reactions and lack of efficacy, 24/7): 0681291858 (mobile), 0445850460 (telephone/fax), [email protected].

Address of the Marketing Authorization Holder.

212/D-1, Ashirwad Commercial Complex, Green Park, New Delhi, 110016, India /
212/D-1, Ashirwad Commercial Complex, Green Park, New Delhi, 110016, India.