Travapress rompharm

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRAVAPRESS ROMPHARM (TRAVAPRESS ROMPHARM)

Composition:

Active substance: travoprost;

1 ml of solution contains 0.04 mg of travoprost;

Excipients: polyquad, boric acid, sodium chloride, mannite (E 421), polyethylene glycol glyceryl hydroxystearate, propylene glycol, sodium hydroxide 1 M or hydrochloric acid 1 M, purified water.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colorless 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 potent and selective full 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 the uveoscleral pathway. 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.

Clinical efficacy and safety

Clinical studies using travoprost (with polyquad as a preservative) in patients with open-angle glaucoma or ocular hypertension, administered once daily in the evening, demonstrated a reduction in intraocular pressure of 8–9 mmHg (approximately 33%) from a baseline of 24–26 mmHg. Data on the use of travoprost in combination with timolol 0.5% and limited data with brimonidine 0.2% were obtained from clinical trials, which showed an additive effect of travoprost when used concomitantly 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 in rabbits after 7 days of topical ocular administration (1.4 mcg once daily).

Travoprost with polyquad as a preservative caused minimal toxic effect on the ocular surface in human corneal cell cultures and after topical ocular administration in rabbits, compared to ophthalmic solutions containing benzalkonium chloride as a preservative.

Children

The efficacy of Travapresc Rompharm in children aged from 2 months to 18 years was demonstrated in a 12-week, double-masked clinical trial of travoprost compared to timolol in 152 patients diagnosed with ocular hypertension or childhood 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 in the travoprost and timolol groups. In the age group from 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. In 4 patients in the travoprost group, compared to 0 in the timolol group, there was no relevant reduction in mean IOP at 12 weeks. Data in children under 2 months of age are lacking.

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 eyelid opening. 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.

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 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 was observed 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 that peak concentrations of 20 ng/mL of free acid in the aqueous humor are achieved 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 instillation of travoprost 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 levels of the drug rapidly declined 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 F2a, 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 via the kidneys. The effect of travoprost has been studied in patients with impaired liver function (from mild to severe) as well as in patients with impaired kidney function (from mild to severe) (creatinine clearance below 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, the plasma concentration of the free acid after travoprost administration ranged from below the quantification limit to 52.0 pg/mL. While most data showed plasma concentrations below the detection limit throughout all studies, making statistical comparisons of systemic exposure across all age groups impossible, the overall trend indicates that after topical administration of Travapresc Rompharm, 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 glau游戏副本

Special precautions for use.

Change in eye color

Travoprost may gradually change eye color by increasing the number of melanosomes (pigment granules) in melanocytes. Patients should be informed prior to starting treatment 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 pigmentation changes occur slowly and may go unnoticed for months or even years. Changes in iris color have 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 treated eye, although the entire iris or parts of it 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

In controlled clinical trials, darkening of the eyelid skin and/or periorbital area was reported in 0.4% of patients using travoprost.

With 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 (in the eye(s) treated); 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 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. Experience is limited in eye diseases associated with 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

Macular edema has been reported during treatment with prostaglandin F2a analogs.

Travoprost should be used with caution in patients with aphakia, pseudophakia, or a ruptured posterior lens capsule, or with anterior chamber lenses, as well as in patients with known 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 solution 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 may be absorbed through the skin. Therefore, pregnant women or women planning to become pregnant should take appropriate precautions to avoid direct exposure to travoprost solution. In case of accidental contact with a significant amount of the solution, the affected area should be thoroughly washed immediately.

Soft contact lenses

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

Excipients

Travapresc Rompharm contains propylene glycol, which may cause skin irritation.

Travapresc Rompharm contains macrogol glycerol hydroxystearate, which may cause skin reactions.

Children

Data on 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 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 pass 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 showed that travoprost, at a dose 250 times higher than the maximum recommended ophthalmic dose, had no harmful effect on reproductive function.

Ability to affect reaction speed when driving or operating machinery.

Travoprost has no or negligible influence 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.

Dosage and Administration

For ophthalmic use.

Use in adults, including elderly patients

One drop of Travapres Rompharm 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 on the nasolacrimal duct or gently close the eyelids. This reduces systemic absorption of ophthalmic medications, thereby decreasing the likelihood of systemic adverse effects.

If more than one topical ophthalmic agent is being used, the interval between their administration should be at least 5 minutes (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 Travapres Rompharm, the previous medication should be discontinued and Travapres Rompharm initiated the following day.

Use in hepatic and renal impairment

The use of travoprost has been studied in patients with hepatic impairment (mild to severe) and 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 protective overwrap of the dropper bottle immediately before the first use. 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.

Children

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

Safety and efficacy of Travapres Rompharm 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, the eye(s) should be irrigated with warm water. In case of accidental ingestion, symptomatic and supportive therapy should be administered.

Adverse reactions

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

The table below lists adverse reactions classified by frequency: 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 grouping, adverse reactions are listed in order of decreasing severity. Data on adverse effects were obtained from clinical trials and post-marketing experience with travoprost.

Table 2

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 commonly observed 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 single cases with an incidence rate 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 marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should 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.

3 years.

Do not use after the expiry date stated on the packaging.

The shelf life of the medicinal product after first opening of the container is 28 days.

Storage conditions.

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

Packaging.

2.5 mL in a polyethylene bottle with a dropper cap; 1 bottle per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

C.T. Rompharm Company S.R.L.

(S.C. Rompharm Company S.R.L.)

Manufacturer's address and location of operations.

Eroilor str., No 1A, Otopeni city, 075100, county Ilfov, Romania