Travolin

INSTRUCTIONS for medical use of the medicinal product TRAVOLIN (TRAVOLIN)

Composition:

active substance: travoprost;

1 ml of solution contains 40 mcg of travoprost;

excipients: polyoxylated hydrogenated castor oil; boric acid; tromethamine; mannitol (E 421); disodium edetate dihydrate; benzalkonium chloride; hydrochloric acid; sodium hydroxide; water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear solution, colorless to pale yellow, free from visible 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 analogue, is a potent 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 of the drug, with maximum effect reached at 12 hours. A significant reduction in intraocular pressure following a single dose may last for more than 24 hours.

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).

Pediatric population

The efficacy of the drug 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 elevated intraocular pressure or pediatric glaucoma. Patients received either travoprost 0.004% once daily or timolol 0.5% (or 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 week 12. Mean reductions in IOP were similar between the travoprost and timolol groups (see Table 1).

At week 12, mean reductions in IOP were similar between the travoprost and timolol groups in the age subgroups of 3 to 12 years (n=36) and 12 to 18 years (n=26). In the age subgroup of 2 months to 3 years, mean reduction in IOP at week 12 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 achieve a relevant reduction in mean IOP at week 12. Data for 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 week 12

Safety Pharmacology Data

In ocular toxicity studies in monkeys, administration of travoprost at a dose of 0.45 mcg twice daily caused increased eyelid opening. Local application 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.

Reproductive toxicity studies were conducted in rats, mice, and rabbits using systemic administration. The results relate to the FP-receptor agonist activity in the uterus, 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 caused an increased incidence of developmental abnormalities. Low levels of radioactivity were detected in amniotic fluid and fetal tissues of pregnant rats administered 3H-travoprost. In reproductive and fetal development studies, an increased risk of fetal loss with a high incidence was observed 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 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 intraocular fluid within 1 to 2 hours after topical administration. Drug concentrations in intraocular fluid decline with an elimination half-life of approximately 1.5 hours.

Distribution

After ocular instillation in healthy volunteers, low systemic exposure to the active free acid was observed. Peak plasma concentrations of the active free acid were reached within 10–30 minutes after dosing and were at or below 25 pg/mL. Plasma levels of the drug declined rapidly 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. 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.

Excretion

The free acid of travoprost and its metabolites are primarily excreted by the kidneys. Dose adjustment is not required in patients with mild to severe hepatic impairment or in patients with mild to severe renal impairment (including those with creatinine clearance below 14 mL/min).

Children

A pharmacokinetic study in children aged 2 months to 18 years after administration of travoprost showed 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 four previous systemic pharmacokinetic studies in adults, plasma concentrations of the free acid after travoprost administration ranged from below the quantification limit to 52.0 pg/mL. While most data demonstrated 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 following topical administration, plasma levels of the free acid are very low in all age groups evaluated.

Clinical characteristics.

Indications.

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

To reduce 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 interactions with other medicinal products have not been conducted.

A specific in vitro interaction study using travoprost and formulations containing thimerosal showed no evidence of precipitation.

Special precautions for use.

Change in eye color

Travoprost may gradually change eye color by increasing 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 result in 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 several months or even years. This effect is predominantly observed in patients with mixed iris color (e.g., blue-brown, gray-brown, green-brown, or yellow-brown), although this phenomenon has also been observed in patients with brown eyes. Typically, brown pigmentation starts around the pupil and spreads concentrically toward the periphery of the iris of the affected eye; however, 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.

Changes in eyelid and periorbital skin

Darkening of the eyelid and/or periorbital skin has been reported in 0.4% of patients treated with travoprost.

Periorbital and eyelid skin changes, including deepening of the eyelid sulcus, have been observed with prostaglandin analogs.

Travoprost may gradually alter the structure of eyelashes in the treated eye (increased length, thickness, pigmentation, and/or number of eyelashes). The mechanism of eyelash changes and the long-term consequences of this effect are currently unknown.

In studies conducted in monkeys, the drug travoprost (ophthalmic solution) caused slight enlargement of the palpebral fissure. However, this effect has not been 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. Experience with use in eye diseases caused by thyroid dysfunction, open-angle glaucoma in pseudophakic patients, pigmentary or pseudoexfoliative glaucoma is limited. Therefore, Travoprost should be used with caution in patients with active ocular infections.

Patients with aphakia

Macular edema has been reported during treatment with F2α prostaglandin analogs.

Travoprost should be used with caution in patients with aphakia, pseudophakia, or a ruptured posterior lens capsule, or with anterior chamber intraocular lenses, as well as in patients with risk factors for cystoid macular edema.

Iritis/Uveitis

Travoprost should be used with caution in patients with active ocular infections and in those with known risk factors for iritis/uveitis.

Skin contact

Contact of Travoprost with the skin should be avoided, as transdermal absorption of travoprost has been demonstrated in animal studies.

Prostaglandins and their analogs are biologically active substances that may be absorbed through the skin. Therefore, pregnant women or women who intend 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 solution, the affected area should be immediately and thoroughly rinsed.

Contact lenses

Contact with soft contact lenses should be avoided. Contact lenses should be removed before instillation of the medication and reinserted no sooner than 15 minutes after instillation. Travoprost contains the preservative benzalkonium chloride, which may discolor soft contact lenses.

Excipients

Travoprost contains the preservative benzalkonium chloride, which may cause eye irritation. The product contains polyoxyl 40 hydrogenated castor oil, which may lead to skin reactions.

Children

Data on the efficacy and safety of the drug in patients aged 2 months to 3 years (9 patients) are limited (see section "Pharmacological properties"). There are no data for children under 2 months of age.

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 for use in children are lacking.

Use during pregnancy or breastfeeding.

Women of childbearing potential/contraception

Travoprost 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. Travoprost 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 penetrate into breast milk; therefore, the use of Travoprost during breastfeeding is not recommended.

Reproductive function

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

Ability to affect reaction speed when driving or operating machinery.

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.

Dosage and Administration

For ophthalmic use only.

Use in adults, including elderly patients

One drop of Travolin into the conjunctival sac 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 ophthalmic medications, which may decrease the likelihood of systemic adverse effects.

If more than one ophthalmic topical agent is being used, the interval between their administration 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 Travolin, discontinue the other medication and begin Travolin the following day.

Use in hepatic and renal impairment

No dose adjustment is necessary.

For patients who wear contact lenses, see section "Special Instructions".

To prevent contamination of the dropper tip and solution, care should be taken not to touch the eyelids, surrounding areas, or other surfaces with the tip of the dropper bottle.

Pediatric population

Travolin may be used in children aged 2 months to 18 years at the same dosage regimen as in adults. However, data in the age group from 2 months to 3 years (9 patients) are limited (see section "Pharmacological Properties").

Due to lack of data, the safety and efficacy of Travolin in children under 2 months of age have not been established.

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 with Travolin, rinse the eye(s) with warm water. In the event of accidental ingestion, symptomatic and supportive therapy should be administered.

Adverse reactions.

Brief overview of safety data.

The most common adverse reactions are ocular hyperemia and increased pigmentation of the iris, observed in approximately 20% and 6% of patients, respectively.

The list of adverse reactions is presented in Table 2.

The adverse reactions listed below are 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 grouping, adverse reactions are listed in order of decreasing severity.

Table 2.

Children

Based on a 3-month Phase 3 study and a 7-day pharmacokinetic study involving 102 children treated with travoprost (ophthalmic solution), 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 adults (see section "Pharmacological properties"). The most commonly 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 of 1.3%, compared to 0.0% in adult patients in a similar study (n=185).

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions in accordance with current legislation.

Shelf life.

2 years.

Storage period after first opening of the container: 4 weeks.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC.

Keep out of reach of children.

Packaging.

2.5 ml in a low-density polyethylene dropper bottle with a white polypropylene cap. One dropper bottle placed in a secondary packaging, which is contained in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

INDOCO REMEDIES LIMITED

INDOCO REMEDIES LIMITED

Manufacturer's address and location of operations.

PLANT II, L-32, 33, 34 VERNA INDUSTRIAL AREA, VERNA, IN-403 722, INDIA

PLANT II, L-32, 33, 34 VERNA INDUSTRIAL AREA, VERNA, IN-403 722, INDIA

Marketing Authorisation Holder.

M.BIOTECH LIMITED

M.BIOTECH LIMITED

Address of the Marketing Authorisation Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom