Agloprost

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

Composition:

Active substance: travoprost;

1 ml of solution contains 0.04 mg of travoprost;

Excipients: benzalkonium chloride solution, edetate disodium, polyoxyethylated hydrogenated castor oil, tromethamine, boric acid, mannitol (E 421), concentrated hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colourless solution.

Pharmacotherapeutic group. Medicinal products used in ophthalmology. Anti-glaucoma preparations and miotics. Prostaglandin analogues. ATC code S01E E04.

Pharmacological Properties

Pharmacodynamics

Travoprost, a prostaglandin F2α analogue, is a potent and selective agonist of the prostaglandin FP receptor, with high affinity for FP receptors. It reduces intraocular pressure by increasing the outflow of aqueous humor through the trabecular meshwork and uveoscleral pathways. In humans, the reduction in intraocular pressure begins approximately 2 hours after administration, with maximum effect reached at 12 hours. A significant reduction in intraocular pressure may persist for more than 24 hours following a single dose.

Data on the use of travoprost in combination with 0.5% timolol, and limited data on its use in combination with 0.2% brimonidine, demonstrate an additive effect of travoprost when used concomitantly with these antiglaucoma medications. Clinical data on concomitant use with other ophthalmic hypotensive agents are lacking.

Travoprost significantly increased blood flow to the optic nerve in rabbits after 7 days of topical ocular administration (1.4 mcg once daily).

Non-clinical Safety Data

In ocular toxicity studies in monkeys, administration of travoprost at a dose of 0.45 mcg twice daily caused an increase in palpebral fissure. Topical administration of travoprost to the right eye of monkeys at concentrations up to 0.012% twice daily for 1 year did not result in systemic toxicity.

Toxicological studies on reproductive function were conducted in rats, mice, and rabbits following systemic administration. The findings are related to FP receptor agonist activity in the dam, associated with early embryonic mortality, post-implantation loss, and fetal toxicity. In pregnant rats, systemic administration of travoprost at doses 200 times higher than the therapeutic dose during organogenesis resulted in an increased incidence of developmental abnormalities. Low levels of radioactivity were detected in amniotic fluid and fetal tissues of pregnant rats following administration of 3H-travoprost. Reproductive and fetal development studies revealed an increased risk of fetal loss at high rates in female rats and mice (180 pg/mL and 30 pg/mL in plasma, respectively) at doses 1.2 to 6 times higher than the therapeutic exposure (up to 25 pg/mL).

Pharmacokinetics

Travoprost is an isopropyl ester prodrug. It is absorbed through the cornea, where the isopropyl ester is hydrolyzed to the active free acid. Studies in rabbits showed peak concentrations of 20 ng/mL of the free acid in aqueous humor within 1–2 hours after topical administration of travoprost. Drug concentrations in aqueous humor decline with an elimination half-life of approximately 1.5 hours.

Following ocular instillation of travoprost in healthy volunteers, systemic exposure to the active free acid was low. Peak plasma concentrations of the active free acid were observed within 10–30 minutes after dosing and were at or below 25 pg/mL. Plasma levels rapidly declined within 1 hour after administration to levels below the lower limit of quantification (10 pg/mL). Due to the low plasma concentrations and rapid elimination following topical administration, the elimination half-life of the free active acid in humans has not been determined.

Metabolism is the primary route of elimination for both travoprost and its active free acid. Systemic metabolic pathways are similar to those of endogenous prostaglandin F2α, involving reduction of the 13–14 double bond, oxidation of the 15-hydroxyl group, and β-oxidative cleavage of the upper side chain.

The free acid of travoprost and its metabolites are primarily excreted via the kidneys. The effect of travoprost has been studied in patients with hepatic impairment (mild to severe) and in patients with renal impairment (mild to severe) (creatinine clearance less than 14 mL/min). Dose adjustment in these patients is not required.

Clinical characteristics.

Indications.

To reduce elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

No studies on interactions with other medicinal products have been conducted.

In vitro studies on specific interaction were carried out using travoprost and medicinal products containing thiomersal. No evidence of precipitation was observed.

Special precautions for use.

Travoprost may gradually change eye colour by increasing the number of melanosomes (pigment granules) in melanocytes. Patients should be informed about the possibility of irreversible change in eye colour before initiating treatment. Treating one eye may result in irreversible heterochromia. The long-term effects of travoprost on melanocytes are currently unknown. The change in iris colour occurs slowly and may go unnoticed for months or even years. This change has primarily been observed in patients with mixed iris colour, i.e. blue-brown, grey-brown, yellow-brown, and green-brown; however, this phenomenon has also been observed in patients with brown eyes. Typically, brown pigmentation starts around the pupil and spreads concentrically towards the periphery of the iris of the treated eye, although the entire iris or parts thereof may become more intensely brown. After discontinuation of treatment, no further increase in brown iris pigmentation has been observed.

During controlled clinical trials, darkening of the eyelid skin and/or periorbital area associated with the use of travoprost was reported in 0.4% of patients.

Travoprost may gradually change the structure of eyelashes of the treated eye(s). Such changes were observed in approximately half of patients in clinical trials and included increased length, thickness, pigmentation, and/or number of eyelashes. The mechanism of eyelash structural changes and the long-term consequences of this effect are currently unknown.

Studies in monkeys have shown that travoprost causes slight enlargement of the palpebral fissure. However, this effect was not observed in clinical trials and is considered species-specific.

There is no experience with the use of travoprost in inflammatory eye diseases, neovascular glaucoma, angle-closure glaucoma, narrow-angle or congenital glaucoma. Limited experience exists with its use in eye disorders associated with thyroid dysfunction, open-angle glaucoma in pseudophakic patients, and pigmentary or pseudoexfoliative glaucoma.

Travoprost should be prescribed with caution in patients with aphakia, pseudophakia, or rupture of the posterior lens capsule, or in those with anterior chamber lenses, as well as for treating patients with known risk factors for developing cystoid macular oedema.

Contact of Agluprost with the skin should be avoided, as studies in rabbits have shown transdermal absorption of travoprost.

Travoprost contains hydrogenated polyethylene glycol castor oil, which may cause skin reactions.

Agluprost should be prescribed with caution in patients with known risk factors for iritis/uveitis.

Prostaglandins and their analogues are biologically active substances that may be absorbed through the skin. Therefore, pregnant women or women intending to become pregnant should take appropriate precautions to avoid direct exposure to the contents of the bottle. If a significant amount of the solution comes into contact with the skin, the affected area should be thoroughly washed immediately.

Contact lenses must be removed before instilling Agluprost and may be reinserted no sooner than 15 minutes after instillation.

Use during pregnancy or breastfeeding.

Pregnancy

Travoprost exerts harmful pharmacological effects on pregnant women and/or the foetus/newborn. Agluprost should not be used during pregnancy unless clearly necessary.

Women of childbearing potential/contraception

Agluprost should not be used in women of childbearing potential unless they are using effective contraception (see section "Pharmacological properties").

Breastfeeding

It is unknown whether travoprost from ophthalmic drops passes into human breast milk. Animal studies have shown that travoprost and its metabolites can pass into the milk of lactating females; therefore, Agluprost is not recommended during breastfeeding.

Ability to affect driving and use of machines.

As with any ophthalmic solution, temporary blurred vision or other visual disturbances may affect the ability to drive or operate machinery. If blurred vision occurs immediately after instillation, patients should wait until vision clears before driving or operating machinery.

Method of Administration and Dosage.

For ophthalmic use.

Use in adults, including elderly patients

One drop of Agluprost into the conjunctival sac of the affected eye(s) once daily. The optimal effect is achieved when the dose is administered in the evening.

After instillation, nasolacrimal occlusion or gentle eyelid closure is recommended. This reduces systemic absorption of ophthalmic medications, which may decrease the likelihood of systemic adverse effects.

If more than one topical ophthalmic agent is used, the administration interval between them should be at least 5 minutes.

If a dose is missed, treatment should continue with the next scheduled dose. The daily dose must not exceed one drop in the affected eye(s) once daily.

When switching from another ophthalmic anti-glaucoma medication to Agluprost, discontinue the other medication and start Agluprost the following day.

Use in hepatic and renal impairment

The use of travoprost has been studied in patients with hepatic impairment (mild to severe), as well as in patients with renal impairment (mild to severe) (creatinine clearance below 14 ml/min). Dose adjustment is not required in these patients.

Patients should be advised to open the protective overwrap of the dropper bottle immediately before the first use. To prevent contamination of the dropper tip and solution, care should be taken to avoid touching the eyelids, surrounding areas, or other surfaces with the tip of the dropper bottle.

Children.

The efficacy and safety of travoprost in patients under 18 years of age have not been established; therefore, its use in this patient group is not recommended until appropriate data are available.

Overdose.

There have been no reports of any cases of overdose. Local overdose is unlikely to result in or be associated with a toxic effect. In case of local overdose with Agluprost, rinse the eye(s) with lukewarm water. In case of accidental ingestion, symptomatic and supportive therapy should be administered.

Adverse reactions.

In studies of travoprost as monotherapy (once daily) or as an adjunctive therapy with 0.5% timolol, no serious ocular or systemic adverse effects related to the use of this medicinal product were reported. The most frequently reported adverse effect associated with the use of travoprost as monotherapy was hyperemia (22%), including hyperemia of the eye, conjunctiva, or sclera. In 83.6% of patients who developed hyperemia, it was mild in severity. Almost all patients (98%) who experienced hyperemia did not discontinue treatment due to this adverse effect. Over time (with continued use of the drug for 6 to 12 months), hyperemia decreased. No post-marketing reports of serious ocular or systemic adverse effects related to once-daily use of travoprost have been received. Iris hyperpigmentation (29.5%) associated with the use of travoprost has also been reported (see section "Special precautions"). Conjunctival hyperemia considered related to travoprost use was reported in 10% of cases, with patients discontinuing the drug due to hyperemia in 2% of cases.

The adverse effects listed below were considered related to the use of travoprost (with benzalkonium chloride as a preservative) as monotherapy and classified according to the following frequency categories: very common (≥1/10), common (>1/100, <1/10), uncommon (>1/1000, ≤1/100), rare (>1/10,000, ≤1/1000), and very rare (≤1/10,000). Within each group, adverse effects are listed in order of decreasing severity.

During the post-marketing period of use of travoprost as monotherapy, the following adverse reactions not identified during clinical trials have also been reported.

Ophthalmic effects: macular oedema (see section "Dosage and Administration").

Systemic effects: bradycardia, tachycardia, exacerbation of bronchial asthma, dizziness, tinnitus, increase in PSA levels (prostate-specific antigen), abnormal hair growth.

Shelf life. 2 years.

Shelf life after first opening of the container – 4 weeks.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C. Keep out of reach of children.

Packaging.

2.5 ml solution in a bottle, 1 bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Alcon Parenterals (India) Limited, India / Ahlcon Parenterals (India) Limited, India.

Manufacturer's address and place of business.

SP-918, Phase-III, RIICO Industrial area, Bhiwadi, Dist. Alwar (Rajasthan), 301 019, India / SP-918, Phase-III, RIICO Industrial area, Bhiwadi, Dist. Alwar (Rajastan), 301 019, India.

Marketing Authorisation Holder. SCAN BIOTECH LTD, India / SCAN BIOTECH LTD, India.

Address of the Marketing Authorisation Holder.

E-4/300, Arera Colony Extension, 462016, Bhopal, (M.P.) India / E-4/300, Arera Colony Extension, 462016, Bhopal, (M.P.) India.