Travynor®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRAVINOR® (TRAVINOR)

Composition:

Active substance: travoprost;

1 ml of solution contains 0.040 mg (40 mcg) of travoprost;

Excipients: benzalkonium chloride, macrogol-15-hydroxystearate, trometamol, boric acid, disodium edetate, mannitol (E 421), 1 M solution of sodium hydroxide or 1 M solution of hydrochloric acid, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: colorless transparent aqueous solution.

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

Pharmacological properties.

Pharmacodynamics.

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

Clinical efficacy and safety. Clinical studies have shown that in patients with open-angle glaucoma or ocular hypertension receiving travoprost once daily in the evening, intraocular pressure was reduced by 8–9 mmHg (approximately 33%) from a baseline of 24–26 mmHg. Clinical data are also available on the combination of travoprost with 0.5% timolol and some data on combination with 0.2% brimonidine, both demonstrating an additive effect of travoprost when used with these anti-glaucoma agents. There are no clinical data on the concomitant use of travoprost 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 micrograms once daily).

Pediatrics. The efficacy of travoprost in children aged 2 months to 18 years was demonstrated in a 12-week, double-masked, clinical study comparing travoprost with timolol in 152 patients diagnosed with ocular hypertension or childhood glaucoma. Patients received either travoprost 0.004% once daily or timolol 0.5% (0.25% for patients under 3 years of age) twice daily. The primary efficacy endpoint was the change in intraocular pressure (IOP) from baseline at 12 weeks. Mean reductions in IOP were similar between the travoprost and timolol groups (see Table 1 below).

At 12 weeks, mean IOP reduction in the travoprost group was comparable to that in the timolol group in the age subgroups 3 to 12 years (n = 36) and 12 to 18 years (n = 26). In the age subgroup of 2 months to 3 years, mean IOP reduction at 12 weeks was 1.8 mmHg in the travoprost group and 7.3 mmHg in the timolol group. The IOP reduction in the timolol group was based on data from only 6 patients, compared to 9 patients in the travoprost group. Four patients in the travoprost group, compared to none in the timolol group, did not show a relevant reduction in mean IOP at 12 weeks. Data in children under 2 months of age are not available.

The IOP-lowering effect was observed after the second week of treatment and was consistently maintained throughout the 12-week study period across all age groups.

Table 1

Comparison of mean change in IOP from baseline (mmHg) at 12 weeks

Pharmacokinetics.

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

Distribution. After ocular administration of travoprost to 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 10–30 minutes after dosing. Thus, plasma levels of the compound rapidly decline within 1 hour after administration to levels below the quantification limit of 10 pg/mL. Due to 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. Metabolism is the major route of elimination for both travoprost and the active free acid. The systemic metabolic pathways are parallel 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 eliminated via the kidneys. The effect 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 less than 14 mL/min). Dose adjustment in these patients is not required.

Pediatrics. A pharmacokinetic study in children aged 2 months to 18 years after administration of travoprost demonstrated very low plasma concentrations of the free acid, ranging from less than 10 pg/mL to 54.5 pg/mL, i.e., below the quantification limit. In 4 previous systemic pharmacokinetic studies in adults, the plasma concentration of the free acid after administration of travoprost ranged from below the quantification limit to 52.0 pg/mL. While the majority of data showed plasma concentrations below the detection limit 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.

For lowering elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

For lowering elevated intraocular pressure in children aged 2 months to 18 years with ocular hypertension or pediatric glauoma.

Contraindications.

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

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 preparations containing thimerosal. No evidence of precipitation was observed.

Special precautions for use.

Change in eye color

Travynor® may gradually change eye color due to increased number of melanosomes (pigment granules) in melanocytes. Before initiating treatment, patients should be informed about the possibility of irreversible change in eye color. Treating one eye may lead to irreversible heterochromia. The long-term effects and consequences of prolonged influence on melanocytes are currently unknown. Iris color change occurs slowly and may go unnoticed for months or even years. Iris color change has primarily been observed in patients with mixed iris color, i.e. blue-brown, gray-brown, yellow-brown, and green-brown; however, 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. After discontinuation of treatment, no further increase in brown iris pigment has been observed.

Changes in eyelid skin and periorbital area

According to published data, 0.4% of patients experienced darkening of the eyelid skin and/or periorbital area associated with the use of travoprost.

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

Travynor® may gradually alter the structure of eyelashes of the treated eye(s); available data indicate that such changes occurred in approximately half of patients and included increased length, thickness, pigmentation, or number of eyelashes. The mechanism of eyelash structural changes and long-term consequences of this effect are currently unknown.

In studies conducted in monkeys, travoprost caused 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 Travynor® 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, and pigmentary or pseudoexfoliative glaucoma. Therefore, Travynor® should be prescribed with caution to patients with active ocular infections.

Patients with aphakia

During treatment with prostaglandin F2α analogs, macular edema has been reported.

Travynor® should be used 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 treatment of patients with risk factors for cystoid macular edema.

Iritis/uveitis

Travynor® should be prescribed with caution to patients with risk factors for iritis/uveitis.

Skin contact

Contact of Travynor® 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 planning to become pregnant should take care to avoid direct exposure to the contents of the bottle. In case of accidental contact with a significant amount of the solution, the affected area should be immediately and thoroughly washed.

Contact lenses

Patients should be advised to remove contact lenses before instilling Travynor® and to wait 15 minutes after instillation before reinserting contact lenses.

Children

Data on efficacy and safety of the medicinal product in patients aged 2 months to 3 years (9 patients) are limited (see section "Pharmacological properties"). Data in children under 2 months of age 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 use are lacking.

Use during pregnancy or breastfeeding.

Women of childbearing potential / contraception. Travynor® should not be used in women of childbearing potential who are not using contraceptive methods (see section "Pharmacological properties").

Pregnancy. Travoprost exerts harmful pharmacological effects on pregnant women and/or the fetus/newborn. Travynor® should not be used during pregnancy unless clearly necessary.

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

Fertility. There are no data on the effect of the medicinal product Travynor® on human fertility. Animal studies demonstrated that travoprost at a dose 250 times higher than the maximum recommended ophthalmic dose did not adversely affect fertility.

Ability to influence reaction speed when driving or operating machinery.

Travynor® has no effect or has a negligible effect on the ability to drive or operate machinery. However, as with any ophthalmic drops, transient blurred vision or other visual disturbances may affect the ability to drive or operate machinery. If blurred vision occurs after instillation, the patient 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 Travatan® ophthalmic solution should be administered 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, thereby decreasing the likelihood of systemic adverse effects.

If more than one ophthalmic agent for local use is being used, an interval of at least 5 minutes should be maintained between their administration (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 Travatan®, discontinue the other medication and begin treatment with Travatan® 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 such patients (see section "Pharmacological properties").

If the patient wears contact lenses, see section "Special precautions for use".

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

Children

Travatan® 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 (9 patients) are limited (see section "Pharmacological properties").

The safety and efficacy of Travatan® in children under 2 months of age have not been established. Data are lacking.

Overdose

There have been no reports of overdose. Local overdose is unlikely to result in or be associated with toxic effects. In case of local overdose of Travatan®, the eye(s) should be rinsed with warm water. In the event of accidental ingestion, symptomatic and supportive therapy should be administered.

Adverse reactions.

The most common adverse reactions observed during the use of Travatan® 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 Table 2.

The frequency of the adverse reactions listed below is classified as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data). Within each frequency group, adverse reactions are listed in order of decreasing severity. Data on adverse effects were obtained from clinical studies and from the post-marketing period of Travatan® use.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

After opening the bottle, the storage period should not exceed 4 weeks.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging.

2.5 mL in a polypropylene bottle with a dropper and a first-opening control, 1 bottle per carton.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT" (finished product manufactured from bulk supplied by Rafarm S.A., Greece).

Manufacturer's address and place of business.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua