Travoprost-farmeks

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRAVOPROST-FARMEKS

Composition:

Active substance: travoprost; 1 ml of solution contains 0.04 mg of travoprost;

Excipients: polyoxyl 40 hydrogenated castor oil, boric acid, benzalkonium chloride, mannitol (E 421), sodium chloride, propylene glycol, sodium hydroxide and/or hydrochloric acid concentrated (for pH adjustment), water for injections.

Pharmaceutical form. Eye drops.

Main physicochemical properties: clear solution ranging from colorless to slightly yellow.

Pharmacotherapeutic group.

Ophthalmological agents. Anti-glaucoma drugs and miotics. Prostaglandin analogues. ATC code S01E E04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Travoprost, a prostaglandin F2α analogue, is a full selective agonist of prostaglandin FP receptors with high affinity for FP-receptors. It reduces intraocular pressure by increasing the outflow of aqueous humor through the trabecular meshwork and the uveoscleral pathway. Reduction of intraocular pressure in humans begins approximately 2 hours after administration, 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 studies of travoprost in patients with open-angle glaucoma or ocular hypertension, who were treated once daily in the evening, demonstrated a reduction in intraocular pressure of 8–9 mmHg (approximately 33 %) from a baseline of 24–26 mmHg. Clinical data have been obtained on the use of travoprost in combination with 0.5 % timolol and limited data on its use in combination with 0.2 % brimonidine, both of which demonstrated an additive effect of travoprost when used concomitantly with these antiglaucoma 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).

Children

The efficacy of travoprost ophthalmic solution in children aged 2 months to 18 years was demonstrated in a 12-week, double-masked, clinical trial comparing travoprost with timolol in 152 patients diagnosed with ocular hypertension 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 12 weeks. Mean reductions in IOP were similar between the travoprost and timolol groups (see Table 1).

In age groups from 3 to 12 years (n = 36) and from 12 to 18 years (n = 26), mean IOP reduction at 12 weeks was similar between the travoprost and timolol groups. At 12 weeks, mean IOP reduction in the age group from 2 months to 3 years 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. In 4 patients in the travoprost group, compared to 0 patients in the timolol group, there was no 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

Safety Preclinical Data

In ocular toxicity studies in monkeys, administration of travoprost at a dose of 0.45 mcg twice daily caused increased palpebral fissure. 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 via systemic administration. The results relate to the activity of the FP-receptor agonist in the uterus, 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 measured 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 rate was observed 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 ester prodrug. It is absorbed through the cornea, where the isopropyl ester is hydrolyzed to the active free acid. Studies in rabbits showed that peak concentrations of 20 ng/mL of free acid in intraocular fluid are reached within 1–2 hours after topical administration of travoprost. Drug concentrations in intraocular fluid decline with an elimination half-life of approximately 1.5 hours.

Distribution

After instillation of travoprost ophthalmic solution in 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. Plasma concentrations 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 primary route of elimination for both travoprost and its 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. 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.

Children

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, plasma concentrations of the free acid after travoprost administration were either below the quantification limit or did not exceed 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 concentrations 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.

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

Travoprost may gradually change eye color by increasing the amount of melanin (pigment granules) in melanocytes. Prior to initiating treatment, patients should be informed about the possibility of irreversible eye color change. 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 be unnoticeable for several months or even years. The change in eye color 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 of it 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

In controlled clinical trials, 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, including deepening of the eyelid sulcus, have been observed.

Travoprost may gradually alter 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.

As demonstrated in studies conducted in monkeys, travoprost causes slight widening 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 diseases caused by thyroid dysfunction, open-angle glaucoma in pseudophakic patients, and pigmentary or pseudoexfoliative glaucoma. Therefore, travoprost should be used with caution in patients with active ocular infections.

Patients with aphakia

Cases of macular edema have been reported during treatment with prostaglandin F2α 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 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 rabbit studies.

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

Contact lenses

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

Excipients

Travoprost-Farmeks contains propylene glycol, which may cause skin irritation.

Travoprost-Farmeks contains hydrogenated polyoxyl 40 ricinoleate, which may cause skin reactions.

Travoprost-Farmeks contains benzalkonium chloride, which may cause irritation. Contact between the medicinal product and soft contact lenses should also be avoided (remove contact lenses before using the product and reinsert them 15 minutes after instillation) — benzalkonium chloride may decolorize soft contact lenses.

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 available 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 in pediatric patients are lacking.

Use during pregnancy or breastfeeding.

Women of reproductive age / contraception

Travoprost-Farmeks should not be used in women of reproductive age who are not using contraceptive methods (see section "Pharmacological properties").

Pregnancy

Travoprost has harmful pharmacological effects on pregnant women and/or the fetus/newborn. Travoprost-Farmeks 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 Travoprost-Farmeks during breastfeeding is not recommended.

Reproductive function

There are no data on the effects 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.

Travoprost-Farmeks has no or 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, the patient should wait until vision clears before driving or operating machinery.

Method of Administration and Dosage

For ophthalmic use.

Treatment of adults, including elderly patients

One drop of Travoprost-Farmeks into the conjunctival sac (sacs) of the affected eye(s) once daily. The 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 administered, the interval between applications should be at least 5 minutes (see section "Interaction with other medicinal products and other forms of interactions").

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

When switching from another ophthalmic anti-glaucoma agent to Travoprost-Farmeks, the other medication should be discontinued and treatment with Travoprost-Farmeks started the following day.

Use in patients with hepatic or renal impairment

The effect of Travoprost-Farmeks 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").

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

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

Children

Travoprost-Farmeks 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").

Safety and efficacy of Travoprost-Farmeks 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 of Travoprost-Farmeks, the eye(s) should be rinsed with warm water. In case of accidental ingestion of the medicinal product, symptomatic and supportive therapy should be administered.

Adverse reactions

The most frequently observed adverse reactions during clinical trials with travoprost ophthalmic solution were ocular hyperemia and increased iris pigmentation, occurring in approximately 20% and 6% of patients, respectively.

The list of adverse reactions is presented in Table 2.

Adverse reactions are classified according to the following frequency categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), 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 the post-marketing experience with travoprost ophthalmic solution.

Table 2

Children

Based on a 3-month Phase III 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. Safety profiles with short-term use in various pediatric subgroups were also similar to those in 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 similar 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 participating in the 3-month study (n = 77) included eyelid erythema, keratitis, increased lacrimation, and photophobia, each reported as isolated 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

It is important to report suspected adverse reactions after a medicinal product has received marketing authorization. This allows for ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report such adverse reactions according to national legislation.

Shelf life. 2 years.

Storage period after first opening of the bottle — 4 weeks.

Storage conditions.

Store in the original packaging at a temperature of 2 °C to 8 °C.

After first opening, store the bottle at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

2.5 mL in a clear colorless glass bottle of hydrolytic class I, stoppered with a rubber plug and sealed with an aluminum cap with a plastic overcap.

One bottle with a polymer dropper cap, placed in an individual package, in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

TOV "FARMEKS GROUP".

Manufacturer's address and place of business.

100, Shevchenka Street, Boryspil, Kyiv Oblast, Ukraine, 08301.