Travatan

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRAVATAN® (TRAVATAN®)

Composition:

Active substance: travoprost; 1 ml of solution contains 40 mcg of travoprost;

Excipients: Poliquad, polyoxyl 35 castor oil, hydrogenated, boric acid, mannitol (E 421), sodium chloride, propylene glycol, sodium hydroxide and/or hydrochloric acid concentrated (for pH adjustment), purified water.

Pharmaceutical form. Eye drops.

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

Pharmacotherapeutic group.

Medicinal products used in ophthalmology. Anti-glaucoma agents 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 receptors, with high affinity for these receptors. It reduces intraocular pressure by increasing the outflow of aqueous humor through the trabecular meshwork and the uveoscleral pathway. Reduction in intraocular pressure in humans 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 persist for more than 24 hours.

Clinical efficacy and safety

Clinical studies using Travatan® (with polyquad as 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 baseline values of 24–26 mmHg. Data on the use of Travatan® in combination with 0.5% timolol and limited data with 0.2% brimonidine were obtained from clinical trials, which demonstrated an additive effect of Travatan® when used concomitantly with these anti-glaucoma agents. There are no clinical data on concomitant use 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).

Travatan® with polyquad as preservative demonstrated minimal toxic effects on the ocular surface in human corneal cell cultures and after topical ocular administration in rabbits, compared to ophthalmic drops containing benzalkonium chloride as preservative.

Children

The efficacy of Travatan® in pediatric patients 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 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 with travoprost at 12 weeks was comparable to that with timolol. At 12 weeks, mean IOP reduction in the 2-months-to-3-years age group 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 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 Pharmacology Data

In ocular toxicity studies in monkeys, administration of travoprost at a dose of 0.45 mcg twice daily caused an increase in palpebral fissure. Local application of travoprost at concentrations up to 0.012% twice daily to the right eye of monkeys 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 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 detected in amniotic fluid and fetal tissues of pregnant rats administered 3H-travoprost. Reproductive function and fetal development studies revealed an increased risk of fetal loss 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 intraocular fluid are achieved within 1–2 hours after topical administration of Travatan®. Drug concentrations in intraocular fluid decline with an elimination half-life of approximately 1.5 hours.

Distribution

After ocular instillation of Travatan® 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 compound 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 major route of elimination for both travoprost and its active free acid. The 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 Travatan® 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.

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 4 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 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 following topical administration of Travatan®, 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.

Interaction with other medicinal products and other forms of interaction.

Studies on interactions with other medicinal products have not been conducted.

Specific in vitro interaction studies were conducted using Travatan® and formulations containing thimerosal. No evidence of precipitation was observed.

Special precautions for use.

Change in eye color

Travatan® may gradually change eye color by increasing the number of melanosomes (pigment granules) in melanocytes. Patients should be informed about the possibility of irreversible eye color change before starting treatment. Treating 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 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 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 pigment 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 Travatan®.

With the use of prostaglandin analogs, changes in the periorbital area and eyelid skin, including deepening of the eyelid groove, have been observed.

Travatan® may gradually alter the structure of the 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, Travatan® causes slight enlargement 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 Travatan® in inflammatory eye diseases, neovascular glaucoma, angle-closure glaucoma, narrow-angle or congenital glaucoma, and only limited experience in eye conditions associated with thyroid dysfunction, open-angle glaucoma in pseudophakic patients, or pigmentary or pseudoexfoliative glaucoma. Therefore, Travatan® should be used with caution in patients with active ocular infections.

Patients with aphakia

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

Travatan® should be prescribed with caution to patients with aphakia, pseudophakia, a ruptured posterior lens capsule, or anterior chamber lenses, or for treating patients with known risk factors for cystoid macular edema.

Iritis/uveitis

Travatan® should be used with caution in patients with known predisposing risk factors for iritis/uveitis.

Skin contact

Contact of Travatan® 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 planning 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 the bottle's contents, the affected area should be immediately and thoroughly cleaned.

Contact lenses

Patients should be informed about the necessity to remove contact lenses before instilling Travatan® and to wait 15 minutes after instillation before reinserting contact lenses.

Excipients

Travatan® contains propylene glycol, which may cause skin irritation.

Travatan® contains polyoxyl 40 hydrogenated castor oil, which may cause 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

Travatan® 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. Travatan® 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 Travatan® during breastfeeding is not recommended.

Reproductive function

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

Ability to influence reaction speed when driving or operating machinery.

Travatan® has no or negligible influence on the ability to drive vehicles or operate machinery. However, as with the use of 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.

Method of Administration and Dosage

For ophthalmic use.

Use in adults, including elderly patients

One drop of Travatan® in the conjunctival sac (sacs) of the affected eye (eyes) once daily. Maximum effect is achieved when the dose is administered in the evening.

After instillation, it is recommended to press the nasolacrimal duct closed or gently close the eyelids. This reduces systemic absorption of ophthalmic medications, potentially decreasing the likelihood of systemic adverse effects.

If more than one topical ophthalmic agent is being used, an interval of at least 5 minutes should be maintained between applications (see section "Interaction with other medicinal products and other forms of interaction").

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

When switching from another ophthalmic anti-glaucoma agent to Travatan®, the previous medication should be discontinued and treatment with Travatan® initiated the following day.

Use in hepatic and renal impairment

The use of Travatan® 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").

For patients wearing contact lenses, see section "Special precautions for use".

Patients should be advised to open the protective overwrap of the dropper bottle immediately before first use. To prevent 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

Travatan® can 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").

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

Adverse reactions.

Brief overview of safety data.

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

The list of adverse reactions is presented in Table 2 below.

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), or frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing severity. Data on adverse reactions were obtained from clinical trials and from the post-marketing period of Travatan® use.

Table 2

Children

Based on a 3-month Phase 3 study and a 7-day pharmacokinetic study involving 102 children treated with Travatan®, the type and characteristics of reported adverse reactions were similar to those observed in adult patients. Short-term safety profiles in different pediatric subgroups were also similar to those in adults (see section "Pharmacological properties"). The most frequently 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 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 been authorized. This enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report such adverse reactions in accordance with applicable legislation.

Shelf life. 2 years.

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

Storage conditions.

No special storage conditions are required for this medicinal product.

Packaging.

2.5 ml in an oval dropper bottle made of polypropylene or low-density polyethylene with a polypropylene cap. Each bottle is packed in a secondary packaging and placed in a cardboard box containing 1 or 3 bottles. Not all pack sizes may be marketed.

Prescription category. Prescription only.

Manufacturer.

Novartis Manufacturing NV / Novartis Manufacturing NV.

Manufacturer's address and location of operations.

Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium / Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium.