Travonext

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

Composition:

Active substance: travoprost;

1 ml of solution contains travoprost 40 mcg;

Excipients: benzalkonium chloride, macrogol-15-hydroxystearate, tromethamine, boric acid, edetate disodium (Trilon B), mannitol (E 421), sodium hydroxide or hydrochloric acid 1N, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colorless aqueous solution, practically free from particles.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Travoprost, a prostaglandin F2α analog, is a full selective agonist of prostaglandin FP receptors, with high affinity for these 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 achieved by 12 hours. A significant reduction in intraocular pressure following a single dose may persist for more than 24 hours.

Clinical efficacy and safety

Data on the use of travoprost in combination with 0.5% timolol and limited data on its use in combination with 0.2% brimonidine were obtained from clinical studies, which demonstrated an additive effect of travoprost when used concomitantly with these anti-glaucoma agents. There are no clinical data on its concomitant use with other ophthalmic hypotensive medications.

Secondary pharmacology

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

Children

Based on clinical trial data comparing travoprost with timolol in patients diagnosed with ocular hypertension or pediatric glaucoma, the efficacy of travoprost has been demonstrated in children aged 2 months to 18 years.

Preclinical 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.

Toxicity studies on reproductive function were conducted in rats, mice, and rabbits via systemic administration. The results relate to FP receptor agonist activity in the mother, associated with early embryonic lethality, post-implantation fetal loss, and fetal toxicity. In pregnant rats, systemic administration of travoprost at doses 200 times higher than the therapeutic dose during organogenesis caused an increased incidence of developmental abnormalities. Low levels of radioactivity were detected in the amniotic fluid and fetal tissues of pregnant rats administered 3H-travoprost. Studies on reproductive performance and fetal development 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 1.2–6 times higher than the therapeutic dose (up to 25 pg/mL).

Pharmacokinetics.

Absorption

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 free acid in aqueous humor within 1–2 hours after topical administration of Travoprost. Drug concentrations in the aqueous humor decrease with an elimination half-life of approximately 1.5 hours.

Distribution

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

Biotransformation

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

Elimination

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 <14 mL/min). Dose adjustment in these patients is not required.

Children

Pharmacokinetic data from a study involving children aged 2 months to 18 years showed very low plasma concentrations of the free acid of travoprost, ranging from <10 pg/mL to 54.5 pg/mL, i.e., below the lower limit of quantification. Data from 4 previous pharmacokinetic studies in adults showed plasma concentrations of the free acid after travoprost administration ranging from below the lower limit of quantification to 52.0 pg/mL. Although most data demonstrated plasma concentrations below the limit of quantification throughout the studies, making statistical comparisons of systemic exposure across all age groups impossible, the overall trend indicates that after topical administration of travoprost, plasma levels of the free acid are very low in all age groups evaluated.

Clinical characteristics.

Indications.

Reduction of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Reduction of elevated intraocular pressure in children aged 2 months to 18 years with ocular hypertension or pediatric 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.

Studies on interaction with other medicinal products have not been conducted.

Specific in vitro interaction studies were performed using travoprost and medicinal products containing thimerosal. No evidence of precipitation was observed.

Special precautions for use.

Change in eye color

The medicinal product Travonext may gradually change eye color due to an increase in the number of melanosomes (pigment granules) in melanocytes. Prior to initiating treatment, patients should be informed about the possibility of irreversible change in eye color. Treatment of one eye may lead to irreversible heterochromia. The long-term effects and consequences of prolonged influence on melanocytes are currently unknown. The change in iris color occurs slowly and may go unnoticed for months or even years. Changes in eye color have been primarily observed in patients with mixed iris color, i.e., blue-brown, gray-brown, yellow-brown, and green-brown, although this phenomenon has also been observed in patients with brown eyes. Typically, brown pigmentation spreads concentrically from around the pupil toward the periphery of the iris of the affected eye, although the entire iris or parts thereof may become more intensely brown. No further increase in brown iris pigment has been observed after discontinuation of treatment.

Changes in eyelid and periorbital skin

In controlled clinical studies, 0.4% of patients experienced darkening of the eyelid and/or periorbital skin associated with the use of travoprost.

With the use of prostaglandin analogs, changes in the periorbital area and eyelid skin have been observed, including deepening of the eyelid sulcus.

The medicinal product Travonext may gradually alter the structure of eyelashes of the eye(s) into which it is administered. In clinical trials, such changes were observed in approximately half of the patients and included increased length, thickness, pigmentation, and/or number of eyelashes. The mechanism of eyelash structural changes and long-term consequences of this effect are currently unknown.

As demonstrated in studies conducted in monkeys, 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, and only limited experience in eye diseases caused by thyroid dysfunction, open-angle glaucoma in pseudophakic patients, pigmentary or pseudoexfoliative glaucoma. Therefore, the medicinal product Travonext should be used with caution in patients with active ocular infection.

Patients with aphakia

During treatment with prostaglandin F2α analogs, cases of macular edema have been reported.

It is recommended to use the medicinal product Travonext with caution in patients with aphakia, pseudophakia, or rupture of the posterior lens capsule, or with anterior chamber lenses, or for treatment of patients with known risk factors for cystoid macular edema.

Iritis/uveitis

The medicinal product Travonext should be used with caution in patients with known risk factors for iritis/uveitis.

Skin contact

Contact of the medicinal product Travonext with the skin should be avoided, as transdermal absorption of travoprost has been demonstrated in rabbit studies.

Prostaglandins and their analogs are biologically active substances that can be absorbed through the skin. Therefore, pregnant women or women intending to become pregnant should take appropriate precautionary measures to avoid direct exposure to the contents of the bottle. In case of accidental contact with a significant amount of the bottle contents, the affected area should be thoroughly washed immediately.

Contact lenses

Patients should be informed about the necessity to remove contact lenses before instilling the medicinal product Travonext and to wait 15 minutes after instillation before reinserting contact lenses.

Excipients

The medicinal product Travonext contains the preservative benzalkonium chloride, which may cause eye irritation and discoloration of soft contact lenses. Reports have been received that benzalkonium chloride may cause punctate keratopathy and/or toxic ulcerative keratopathy. Careful monitoring is required in patients using Travonext frequently or over prolonged periods.

Children

Data on the efficacy and safety of travoprost in patients aged 2 months to 3 years are limited. For children under 2 months of age, data are lacking.

For children under 3 years of age with primary congenital glaucoma, surgical interventions (e.g., trabeculotomy/goniotomy) remain the first-line treatment.

Long-term safety data in pediatric patients are lacking.

Use during pregnancy or breastfeeding.

Women of reproductive age/contraception

The medicinal product Travonext should not be used in women of reproductive age who are not using contraceptive methods (see section "Pharmacological properties").

Pregnancy

Travoprost exerts harmful pharmacological effects on pregnant women and/or the fetus/newborn infant; therefore, it should not be used during pregnancy unless clearly necessary.

Period of 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 breast milk; therefore, the use of the medicinal product Travonext during breastfeeding is not recommended.

Reproductive function

There are no data on the effect of the medicinal product Travonext on human reproductive function. Animal studies have demonstrated that travoprost at a dose 250 times higher than the maximum recommended ophthalmic dose did not have harmful effects on reproductive function.

Ability to influence reaction speed when driving or operating machinery.

The medicinal product Travonext does not affect or has a negligible effect on the ability to drive vehicles or operate machinery. However, as with any ophthalmic drops, temporary blurred vision or other visual disturbances may affect the ability to drive or operate machinery. If blurred vision occurs 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 Travonext into the conjunctival sac (sacs) of the affected eye(s) once daily. Optimal effect is achieved when the dose is administered in the evening.

After instillation, it is recommended to press the nasolacrimal duct or gently close the eyelids. This reduces systemic absorption of drugs administered into the eye, which may decrease the likelihood of systemic adverse effects.

If more than one ophthalmic agent for local use is being administered, an interval of at least 5 minutes should be maintained between applications (see section "Interaction with other medicinal products and other forms of interaction").

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

When switching from another ophthalmic anti-glaucoma agent to Travonext, the previous medicinal product should be discontinued and treatment with Travonext should be initiated the following day.

Use in hepatic and renal impairment

The use of Travonext 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 (see section "Pharmacological properties").

For patients wearing contact lenses, see section "Special precautions for use".

Patients should be advised to tear open the upper protective packaging of the dropper bottle immediately before first use. To prevent contamination of the dropper tip and the contents of the bottle, care should be taken not to touch the eyelids, adjacent areas, or other surfaces with the tip of the dropper bottle.

Children

Travonext may be used in children aged 2 months to 18 years according to the same dosing regimen as in adults. However, data in the age group from 2 months to 3 years are limited.

Safety and efficacy of Travonext in children under 2 months of age have not been established. Data are lacking.

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 Travonext, the eye(s) should be rinsed with warm water. In case of accidental ingestion, symptomatic and supportive therapy should be administered.

Adverse Reactions

Summary of safety data

The most commonly observed adverse reactions during clinical studies with travoprost were ocular hyperemia and increased pigmentation of the iris, occurring in approximately 20% and 6% of patients, respectively.

The list of adverse reactions is presented in tabular form.

The adverse reactions listed below are classified as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), or frequency not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are listed in order of decreasing severity. Data on adverse reactions were obtained from clinical trials and from post-marketing experience with travoprost.

Children

Based on a 3-month Phase 3 study and a 7-day pharmacokinetic study involving 102 children treated with travoprost, the type and characteristics of reported adverse reactions were similar to those observed in adult patients. Short-term safety profiles in various pediatric subgroups were also similar to those in adults (see section "Pharmacological properties"). The most frequently reported adverse reactions in children were ocular hyperemia (16.9%) and eyelash growth (6.5%). In a comparable 3-month study in adult patients, these adverse reactions occurred at frequencies of 11.4% and 0.0%, respectively.

Additional adverse reactions reported in children participating in the 3-month study (n=77) included eyelid erythema, keratitis, increased lacrimation, and photophobia, each reported as single cases with an incidence rate of 1.3%, compared to 0.0% observed in adult patients in a comparable study (n=185).

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. The shelf life of the unopened container is 2 years.

After first opening, use within 4 weeks.

Storage conditions. Store in the original packaging. The medicinal product does not require special storage conditions. Keep out of reach and sight of children.

Packaging. 2.5 mL in a white plastic dropper bottle closed with a screw cap and protective ring; 1 dropper bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer.

RAFARM SA/RAFARM SA.

Manufacturer's address and location of operations.

Thesi Pousi-Xatzi Agiou Louka, Paiania (Attica), ZIP code 19002, PO Box 37, Greece.