Travoprost-farmaten

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRAVOPROST-PHARMATHEN (TRAVOPROST-PHARMATHEN)

Composition:

Active substance: travoprost;

1 ml of solution contains 40 mcg of travoprost;

Excipients: benzalkonium chloride, macrogol glycerol hydroxystearate 40, tromethamine, disodium edetate, boric acid, mannitol (E 421), sodium hydroxide, water for injections.

Dosage form. Eye drops.

Main physicochemical characteristics: clear, colorless aqueous solution.

Pharmacotherapeutic group. Antiglaucoma preparations and miotics. Prostaglandin analogues.

ATC code S01E E04.

Pharmacological Properties

Pharmacodynamics

Travoprost, a prostaglandin F2α analog, is a potent and selective agonist of the prostaglandin FP receptor. 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 around 12 hours. A significant reduction in intraocular pressure following a single dose may persist for more than 24 hours.

Data on the use of travoprost in combination with 0.5% timolol solution, and limited data on its use with 0.2% brimonidine solution, indicate an additive effect when travoprost is used concomitantly with these antiglaucoma agents. There are no clinical data on the concomitant use of travoprost with other ophthalmic hypotensive medicinal products.

Children

The efficacy of travoprost ophthalmic solution in children aged 2 months to 18 years was demonstrated in a 12-week, double-blind 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% (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.

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 comparable between 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. 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 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.

Pharmacokinetics

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 maximum concentration of the free acid (20 ng/mL) in the aqueous humor is reached within 1–2 hours after topical administration of travoprost. The concentration of travoprost in the aqueous humor declines with a half-life of approximately 1.5 hours.

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

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, involving reduction of the 13–14 double bond, oxidation of the 15-hydroxyl group, and β-oxidative cleavage of the upper side chain.

The free acid of travoprost and its metabolites are primarily excreted via the kidneys. Ophthalmic travoprost has been studied in patients with hepatic impairment (mild to severe) and in patients with renal impairment (mild to severe, including those with creatinine clearance below 14 mL/min). Dose adjustment is not required in these patient populations.

Children

A pharmacokinetic study in children aged 2 months to 18 years following travoprost administration showed very low plasma concentrations of the free acid, ranging from < 10 pg/mL to 54.5 pg/mL, mostly below the lower limit of quantification. In four previous systemic pharmacokinetic studies in adults, plasma concentrations of the free acid after travoprost administration ranged from below the lower limit of quantification to 52.0 pg/mL. Overall, plasma concentrations of travoprost were below the limit of detection throughout all studies, precluding statistical comparison of systemic exposure across age groups. After topical administration of travoprost ophthalmic solution, plasma levels of the free acid were 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 interaction with other medicinal products have not been conducted.

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

Special precautions for use

Travoprost may gradually change eye color by increasing the amount of melanosome (pigment granules) in melanocytes. Patients should be informed prior to initiating treatment that irreversible changes in eye color may occur. 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 not be noticeable for several months or even years. Color changes have been observed most frequently 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 around the pupil spreads concentrically 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.

In controlled clinical trials, 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.

Travoprost may gradually alter the structure of eyelashes in the treated eye. During clinical studies, such changes were observed in approximately half of patients 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.

In animal studies, travoprost caused slight enlargement of the palpebral fissure. However, this effect was not observed during clinical trials and is considered species-specific.

There is no experience with the use of travoprost in inflammatory eye diseases, neovascular glaucoma, closed-angle glaucoma, narrow-angle glaucoma, or congenital glaucoma. Experience is also limited in ocular conditions caused by thyroid dysfunction, open-angle glaucoma in pseudophakic patients, and in pigmentary or pseudoexfoliative glaucoma. Therefore, travoprost should be used with caution in patients with active intraocular inflammation.

Cases of macular edema have been reported during treatment with prostaglandin F2α analogs. Travoprost should be used with caution in patients with aphakia, pseudophakia with posterior capsule rupture, or anterior chamber lenses, as well as in those at risk of developing cystoid macular edema.

Travoprost should be used with caution in patients with known risk factors predisposing to iritis/uveitis.

Contact of the drug 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 contact of the drug with the skin. In case of accidental exposure of a significant amount of the solution to the skin, the affected area should be thoroughly washed immediately.

Patients should be instructed to remove contact lenses before applying the drug and to reinsert them no sooner than 15 minutes after instillation.

It has been reported that benzalkonium chloride, a preservative widely used in ophthalmic preparations, may cause punctate epithelial keratopathy and/or toxic ulcerative keratopathy. Since Travoprost-Farmaten contains benzalkonium chloride, careful monitoring of treatment is required with frequent or prolonged use.

Travoprost-Farmaten contains benzalkonium chloride, which may cause eye irritation and discoloration of soft contact lenses. Contact between the drug and soft contact lenses should be avoided.

Travoprost-Farmaten contains macrogol glycerol hydroxystearate 40, 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"). 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 reproductive age/contraception

Travoprost should not be used in women of reproductive age who are not using contraceptive methods.

Pregnancy

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

Breastfeeding

It is unknown whether travoprost from eye drops passes into breast milk. Animal studies have shown that travoprost and its metabolites can pass into breast milk; therefore, the use of the drug 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 influence reaction speed when driving or operating machinery

The drug has no or negligible effect on the ability to drive or operate machinery. However, as with any eye 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.

Dosage and Administration.

For ophthalmic use.

Use in adults, including elderly patients

Instill 1 drop of the medication 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 on the nasolacrimal duct or gently close the eyelids. This reduces systemic absorption and consequently decreases the likelihood of systemic adverse reactions.

If multiple topical ophthalmic medications are used simultaneously, at least a 5-minute interval should be maintained between administrations.

If a dose is missed, treatment should continue with the next scheduled dose. The dose must not exceed 1 drop of the medication in the affected eye(s) once daily.

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

Use in hepatic and renal impairment

The use of travoprost eye drops has been studied in patients with hepatic impairment (mild to severe), as well as in patients with renal impairment (mild to severe, with creatinine clearance below 14 mL/min). Dose adjustment is not required in these patients.

If the patient wears contact lenses, see section "Special Instructions".

Immediately before first use, remove the protective cap from the dropper bottle. To prevent contamination of the dropper tip and the eye drop solution, care should be taken not to touch the tip to the eyelids, surrounding areas, or any other surfaces.

Children.

Travoprost eye drops 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 eye drops 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 and is unlikely to result in toxic effects. In case of local overdose with travoprost, the eye(s) should be rinsed with warm water. In case of accidental ingestion, symptomatic and supportive therapy should be administered.

Adverse Reactions

The most frequently observed adverse reactions in clinical trials of travoprost ophthalmic solution were ocular hyperemia and increased iris pigmentation.

Adverse reactions reported with the use of travoprost ophthalmic solution are listed below by system organ class.

Immune system disorders: hypersensitivity, seasonal allergy.

Psychiatric disorders: depression, anxiety, insomnia.

Nervous system disorders: headache, dizziness, visual field defects, dysgeusia.

Ophthalmic disorders: ocular hyperemia, increased iris pigmentation, eye pain, ocular discomfort, dry eye, eye pruritus, eye irritation, corneal erosion, uveitis, iritis, anterior chamber inflammation, keratitis, punctate keratitis, photophobia, eye discharge, blepharitis, eyelid erythema, periorbital edema, eyelid pruritus, decreased visual acuity, blurred vision, increased lacrimation, conjunctivitis, ectropion, cataract, scaling along eyelid margins, eyelash growth, iridocyclitis, herpes simplex, eye inflammation, photopsia, eyelid eczema, conjunctival edema, halos around lights, conjunctival follicles, ocular hypoaesthesia, trichiasis, meibomitis, pigmentation of anterior chamber, mydriasis, asthenopia, increased eyelash pigmentation, eyelash thickening, macular edema, periorbitopathy/deepening of the eyelid sulcus.

Ear and labyrinth disorders: vertigo, tinnitus.

Cardiac disorders: palpitations, irregular heartbeat, decreased heart rate, chest pain, bradycardia, tachycardia, arrhythmia.

Vascular disorders: decreased diastolic blood pressure, increased systolic blood pressure, hypotension, hypertension.

Respiratory, thoracic and mediastinal disorders: cough, nasal congestion, throat irritation, dyspnea, asthma, respiratory disorders, sore throat, dysphonia, allergic rhinitis, dry nose, asthma exacerbation, epistaxis.

Gastrointestinal disorders: peptic ulcer exacerbation, gastrointestinal disorders, constipation, dry mouth, diarrhea, stomach pain, nausea, vomiting.

Skin and subcutaneous tissue disorders: skin hyperpigmentation (around the eye), skin discoloration, hair texture abnormalities, hypertrichosis, allergic dermatitis, contact dermatitis, erythema, rash, hair color changes, madarosis, pruritus, abnormal hair growth.

Musculoskeletal and connective tissue disorders: musculoskeletal pain, arthralgia.

Renal and urinary disorders: dysuria, urinary incontinence.

General disorders and administration site conditions: asthenia.

Investigations: increased PSA (prostate-specific antigen) levels.

Children

Clinical studies of travoprost ophthalmic solution in pediatric patients have shown that the type and characteristics of reported adverse reactions were similar to those observed in adults. Safety profiles with short-term use in various pediatric subgroups were also similar to those in adults. The most common adverse reactions in children were ocular hyperemia and eyelash growth. In addition, eyelid erythema, keratitis, increased lacrimation, and photophobia were observed in children.

Shelf life.

3 years.

Do not use after the expiry date stated on the packaging. Use within 4 weeks of first opening the bottle.

Storage conditions.

No special storage conditions are required.

Before first use, store the bottle in its outer packaging to protect from moisture.

Keep out of reach of children.

Packaging.

2.5 mL of ophthalmic solution in dropper bottles closed with caps with tamper-evident seal, packed in a multilayer pouch. One dropper bottle in a multilayer pouch in a cardboard box.

Prescription status. Prescription only.

Manufacturers.

Pharmathen S.A.;
Balkanpharma-Razgrad AD

Manufacturers' addresses.

Dervenakion 6, Pallini Attiki 15351, Greece;
68 Aprilsko vastanie Blvd., Razgrad 7200, Bulgaria.