Daveris

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DAVÉRIS (DAVERIS)

Composition:

Active substance: travoprost;

1 ml of solution contains 40 mcg of travoprost;

Excipients: boric acid; tromethamine; polyoxyl 40 hydrogenated castor oil; mannitol (E 421); edetate disodium; benzalkonium chloride; hydrochloric acid; sodium hydroxide; water for injections.

Pharmaceutical form. Eye drops, solution.

Basic physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group

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

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Travoprost, a prostaglandin F2α analog, is a full selective agonist of the prostaglandin FP receptor, with a high degree of 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 of travoprost, with maximum effect achieved by 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 using travoprost (with polyquaternium-1 as preservative) in patients with open-angle glaucoma or ocular hypertension, who received travoprost 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 on its use in combination with brimonidine 0.2% were obtained from clinical trials, which demonstrated an additive effect when used concomitantly with these anti-glaucoma agents. There are no clinical data on the concomitant use of travoprost with other ophthalmic hypotensive medicinal products.

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 pediatric patients aged 2 months to 18 years was demonstrated in a 12-week, double-masked, clinical study comparing travoprost 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).

At 12 weeks, mean reductions in IOP in the age groups 3 to 12 years (n=36) and 12 to 18 years (n=26) were similar between the travoprost and timolol groups. In the age group from 2 months to 3 years, the mean reduction in IOP 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 for infants 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

Non-clinical safety data

In ocular toxicity studies in monkeys, administration of travoprost at a dose of 0.45 mcg twice daily caused increased palpebral fissure. 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.

Toxicological studies on reproductive function were conducted in rats, mice, and rabbits using 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 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 belongs to ester prodrugs. 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 the free acid of travoprost in aqueous humor are reached within 1–2 hours after topical administration. Drug concentrations in aqueous humor decline 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. Maximum plasma concentrations of the free active acid of 25 pg/mL or less were observed 10–30 minutes after dosing. Thus, plasma levels of the substance 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 the 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.

Patients with hepatic and/or renal impairment

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 below 14 mL/min). Dose adjustment in these patients is not necessary.

Pediatric population

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 four previous systemic pharmacokinetic studies in adults, plasma concentrations of the free acid after administration of travoprost were below the quantification limit of 52.0 pg/mL. While the majority of 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 travoprost, 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 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 formulations containing thiomersal. 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 melanosome (pigment granules) in melanocytes. Patients should be informed about the possibility of irreversible change in eye color before starting treatment with this medicinal product. 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 unnoticed for 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 travoprost, no further increase in brown pigment in the iris has been observed.

Changes in eyelid and periorbital skin

In controlled clinical studies, 0.4% of patients experienced darkening of the eyelid and/or periorbital skin associated with the use of travoprost.

With 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 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, and only limited experience in eye diseases caused by thyroid dysfunction, open-angle glaucoma in pseudophakic patients, pigmentary or pseudoexfoliative glaucoma. The medicinal product should be used with caution in patients with active ocular infections.

Skin contact

Contact of the medicinal product 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 intending to become pregnant should take appropriate precautionary measures to avoid direct exposure to the contents of the bottle. In case of accidental spillage of a significant amount of the bottle's contents, the affected area should be immediately and thoroughly cleaned.

Patients with aphakia

Macular edema has been reported during the use of prostaglandin F2α analogs.

The medicinal product should be used with caution in patients with aphakia, pseudophakia, posterior lens capsule rupture, anterior chamber lenses, or in patients with known risk factors for developing cystoid macular edema.

Patients with known predisposing risk factors for iritis/uveitis

The medicinal product should be used with caution in such patients.

Patients using contact lenses

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

Children

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

Precautions related to excipients

The medicinal product contains benzalkonium chloride, which may be absorbed by soft contact lenses and may discolor them. Contact lenses should be removed before instillation of eye drops and reinserted only 15 minutes after instillation. Benzalkonium chloride may also cause ocular irritation.

The medicinal product also contains polyoxylated hydrogenated castor oil, which may cause skin reactions.

Use during pregnancy or breastfeeding

Women of childbearing potential / contraception

The medicinal product 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. The medicinal product 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. The medicinal product is not recommended during breastfeeding.

Fertility

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, did not have harmful effects 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 eye 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

The medicinal product is intended for topical administration (into the conjunctival sac).

Adults (including elderly patients)

Instill 1 drop of the solution 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 drugs administered into the eye, potentially decreasing the likelihood of systemic adverse reactions.

If more than one ophthalmic topical 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 1 drop in the affected eye(s) once daily.

If switching from another ophthalmic anti-glaucoma agent to Daveris, discontinue the other agent and begin Daveris the following day.

To prevent contamination of the dropper tip and the contents of the bottle, care must be taken not to touch the eyelids, adjacent areas, or other surfaces with the tip of the dropper bottle.

Patients with hepatic or 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 these patients (see section "Pharmacological properties").

Patients wearing contact lenses

See section "Special precautions for use".

Children

The medicinal product 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 travoprost 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 toxic effects.

In case of local overdose with the medicinal product, rinse the eye(s) with warm water.

In the event of accidental ingestion of the medicinal product, symptomatic and supportive therapy should be administered.

Adverse Reactions

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

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), and not known (frequency cannot be estimated from available data).

Within each frequency category, adverse effects are listed in order of decreasing severity.

The data on adverse effects were obtained from clinical trials and post-marketing experience with travoprost.

Immune system disorders:

• Uncommon: hypersensitivity, seasonal allergy.

Psychiatric disorders:

• Not known: depression, anxiety, insomnia.

Nervous system disorders:

• Uncommon: headache;
• Rare: dizziness, visual field defect, dysgeusia.

Eye disorders:

• Very common: ocular hyperemia;
• Common: increased iris pigmentation, eye pain, eye discomfort, dry eye, eye pruritus, eye irritation;
• Uncommon: 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 of eyelid margins, eyelash growth;
• Rare: 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;
• Not known: macular edema, periorbitopathy / deepening of the eyelid sulcus.

Ear and labyrinth disorders:

• Not known: vertigo, tinnitus.

Cardiac disorders:

• Uncommon: palpitations;
• Rare: arrhythmia, decreased heart rate;
• Not known: chest pain, bradycardia, tachycardia, arrhythmia.

Vascular disorders:

• Rare: decrease in diastolic blood pressure, increase in systolic blood pressure, hypotension, hypertension.

Respiratory, thoracic and mediastinal disorders:

• Uncommon: cough, nasal congestion, throat irritation;
• Rare: dyspnea, asthma, respiratory disorders, pharyngalgia, dysphonia, allergic rhinitis, dry nose;
• Not known: asthma exacerbation, epistaxis.

Gastrointestinal disorders:

• Rare: peptic ulcer exacerbation, gastrointestinal disorders, constipation, dry mouth;
• Not known: diarrhea, stomach pain, nausea, vomiting.

Skin and subcutaneous tissue disorders:

• Uncommon: skin hyperpigmentation (around the eye), skin discoloration, hair texture abnormalities, hypertrichosis;
• Rare: allergic dermatitis, contact dermatitis, erythema, rash, hair color changes, madarosis;
• Not known: pruritus, abnormal hair growth.

Musculoskeletal and connective tissue disorders:

• Rare: musculoskeletal pain, arthralgia.

Renal and urinary disorders:

• Not known: dysuria, urinary incontinence.

General disorders and administration site conditions:

• Rare: asthenia.

Investigations:

• Not known: increased PSA (prostate-specific antigen) levels.

Paediatric population

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 paediatric 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 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 of suspected adverse reactions after marketing authorization is important. It allows continued 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: https://aisf.dec.gov.ua.

Shelf life

3 years.

After opening the bottle, the medicinal product should be used within 28 days.

Storage conditions

Store at a temperature not exceeding 25 °C in a place inaccessible to children.

Packaging

2.5 ml in a dropper bottle; 1 dropper bottle per cardboard box.

Prescription status

Prescription only.

Manufacturer

UORLД MEDICIN ILAC SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorisation Holder

WORLD MEDICINE, LLC, Ukraine.