Travatan eye drops 40 mcg/ml bottle 2.5 ml

Instructions for use Travatan eye drops 40 mcg/ml bottle 2.5 ml

Composition

active ingredient: travoprost; 1 ml of solution contains 40 mcg of travoprost;

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

Dosage form

Eye drops.

Main physicochemical properties: clear solution from colorless to pale yellow.

Pharmacotherapeutic group

Means for use in ophthalmology. Antiglaucoma drugs and miotics. Prostaglandin analogues. ATX code S01E E04.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Travoprost, a prostaglandin F2a analogue, is a full, selective agonist with high affinity for prostaglandin FP receptors, and reduces intraocular pressure by increasing the outflow of aqueous humor through the trabecular meshwork and uveoscleral pathways. The onset of intraocular pressure reduction in humans begins approximately 2 hours after administration, with a maximum effect occurring 12 hours later. The significant reduction in intraocular pressure following a single dose can be maintained for more than 24 hours.

Clinical efficacy and safety

Clinical studies with Travatan® (preserved with polyquad) 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 Travatan® in combination with timolol 0.5% and limited data on the use in combination with brimonidine 0.2% were obtained in clinical studies that demonstrated an additive effect of Travatan® when used with these antiglaucoma drugs. There are no clinical data on its concomitant use with other ophthalmic hypotensive drugs.

Secondary pharmacology

Travoprost significantly increased blood flow to the optic disc in rabbits after 7 days of topical ocular administration (1.4 micrograms once daily).

Travatan® with the preservative polyquad resulted in minimal ocular surface toxicity in human corneal cell cultures and after topical ocular administration to rabbits compared to eye drops containing benzalkonium chloride as a preservative.

Children

The efficacy of Travatan® in children aged 2 months to 18 years was demonstrated in a 12-week, double-blind clinical trial of travoprost versus timolol in 152 patients with known ocular hypertension or pediatric glaucoma. Patients received either travoprost 0.004% once daily or timolol 0.5% (or 0.25% for patients <3 years of age) twice daily. The primary efficacy endpoint was the change in intraocular pressure (IOP) from baseline at 12 weeks of the study. The mean IOP reductions in the travoprost and timolol groups were similar (see Table 1).

In the age groups 3 to 12 years (n=36) and 12 to 18 years (n=26), the mean IOP reduction in the travoprost group at 12 weeks was similar to the mean IOP reduction in the timolol group. At 12 weeks, the mean IOP reduction in the 2 months to 3 years travoprost group was 1.8 mmHg and 7.3 mmHg in the timolol group. In the timolol group, the IOP reduction was based on data from only 6 patients compared to 9 patients in the travoprost group. There was no relevant mean IOP reduction at 12 weeks in 4 patients in the travoprost group versus 0 patients in the timolol group. 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 in all age groups.

Table 1

Comparison of change in mean IOP from baseline (mmHg) after 12 weeks

Preclinical safety data

Reproductive toxicity studies were conducted in rats, mice and rabbits by systemic administration. The results relate to FP receptor agonist activity 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 the therapeutic dose during the period of organogenesis caused an increase in the number of malformations. Low levels of radioactivity were measured in the amniotic fluid and fetal tissues of pregnant female rats administered 3H-travoprost. In reproductive and fetal development studies, an increased risk of fetal loss was observed with a high incidence in female rats and mice (180 pg/ml and 30 pg/ml in plasma, respectively) at doses 1.2-6 times 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 have shown that peak concentrations of 20 ng/mL of the free acid in the intraocular fluid are reached 1-2 hours after topical administration of Travatan®. Intraocular fluid drug concentrations decline with a half-life of approximately 1.5 hours.

Distribution

Following ocular administration of Travatan® to healthy volunteers, low systemic exposure to the active free acid was observed. Peak plasma concentrations of the free active acid were observed at 25 pg/mL or less 10 to 30 minutes after dosing. Plasma levels then rapidly declined within 1 hour after dosing to below the limit of quantification of 10 pg/mL. Due to the 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 parallel those of endogenous prostaglandin F2a, which are characterized by reduction of the 13-14 double bond, oxidation of the 15-hydroxyl, and b-oxidative cleavage of the upper side chain.

Breeding

Travoprost free acid and its metabolites are primarily excreted by the kidneys. Travatan® has been studied in patients with mild to severe hepatic impairment and in patients with mild to severe renal impairment (creatinine clearance <14 ml/min). No dose adjustment is necessary in these patients.

Children

A pharmacokinetic study in children aged 2 months to 18 years after administration of travoprost showed very low plasma free acid concentrations ranging from less than 10 pg/mL to 54.5 pg/mL, i.e. below the limit of quantification. In 4 previous systemic pharmacokinetic studies in adults, plasma free acid concentrations after administration of travoprost ranged from below the limit of quantification to 52.0 pg/mL. While the majority of the data showed plasma concentrations below the limit of quantification throughout all studies, thus making statistical comparisons of systemic exposure across age groups impossible, the general trend is that after topical administration of Travatan®, plasma free acid concentrations are very low in all age groups evaluated.

Indication

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.

Contraindication

Hypersensitivity to the active substance or to other components of the drug.

Interaction with other medicinal products and other types of interactions

No studies on interactions with other drugs have been conducted.

In vitro specific interaction studies have been performed with Travatan® and thiomersal-containing products. No evidence of precipitation was observed.

Application features

Eye color change

Skin changes of the eyelids and periorbital area

In controlled clinical trials, 0.4% of patients were reported to have darkening of the eyelid skin and/or periorbital area in association with the use of Travatan®.

Changes in the periorbital area and eyelid skin, including deepening of the palpebral sulcus, have been observed with the use of prostaglandin analogues.

Travatan® may gradually change the structure of the eyelashes of the eye(s) to which it is applied; in clinical trials, such changes were observed in approximately half of the patients and included increases in length, thickness, pigmentation and/or number of eyelashes. The mechanism of the change in eyelash structure and the long-term consequences of this action are currently unknown.

Travatan® has been shown to cause slight dilation of the palpebral fissure in monkeys. However, this effect was not observed in clinical studies and is considered to be 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 there is only limited experience with eye diseases caused by thyroid dysfunction, open-angle glaucoma in pseudophakic patients, pigmentary or pseudoexfoliative glaucoma. Therefore, Travatan® should be administered with caution to patients with active ocular infections.

Patients with aphakia

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

It is recommended that Travatan® be prescribed with caution in patients with aphakia, pseudophakia, and with a torn posterior lens capsule or anterior chamber lenses, or for the treatment of patients with known risk factors for the development of cystoid macular edema.

Iritis/uveitis

Travatan® should be prescribed with caution in patients with known predisposing risk factors for the development of 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 analogues are biologically active substances that can be absorbed through the skin. Therefore, pregnant women or women who intend to become pregnant should take appropriate precautions to avoid direct exposure to the contents of the vial. In the event of accidental contact with a significant amount of the contents of the vial, the affected area should be thoroughly cleaned immediately.

Contact lenses

Patients should be advised to remove contact lenses before instilling Travatan® and to wait 15 minutes after instillation before inserting contact lenses.

Excipients

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

Travatan® contains polyethoxylated hydrogenated castor oil 40, 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 of treatment.

There are no long-term safety studies in children.

Use during pregnancy or breastfeeding

Women of reproductive age/contraception

Travatan® should not be used in women of reproductive age not using contraceptives (see section “Pharmacological properties”).

Pregnancy

Travoprost has harmful pharmacological effects on pregnant women and/or the fetus/newborn child. Travatan® should not be used during pregnancy unless clearly necessary.

Breast-feeding

It is not known whether travoprost from eye drops passes into breast milk. Animal studies have shown that travoprost and its metabolites are able to pass 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 shown that travoprost at a dose of 250 times the maximum recommended dose for ophthalmic use did not have a harmful effect on reproductive function.

Ability to influence reaction speed when driving vehicles or other mechanisms

Travatan® has no or negligible influence on the ability to drive or use machines, however, as with any eye drop, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs during instillation, the patient should wait until the vision clears before driving or using machines.

Method of administration and doses

For ophthalmic use.

Instill 1 drop of Travatan® into the conjunctival sac(s) 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 pinch the nasolacrimal duct or slightly close the eyelids. This reduces the systemic absorption of drugs administered into the eye, which may reduce the likelihood of systemic side effects.

If more than one topical ophthalmic product is used, the interval between their applications should be at least 5 minutes (see section “Interaction with other medicinal products and other types of interactions”).

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

If another ophthalmic antiglaucoma agent is being substituted for Travatan®, the other agent should be discontinued and Travatan® should be initiated the following day.

Use in liver and kidney dysfunction

Travatan® has been studied in patients with mild to severe hepatic impairment and in patients with mild to severe renal impairment (creatinine clearance below 14 ml/min). No dose adjustment is necessary in these patients (see section 5.1).

For patients who wear contact lenses, see the section "Special instructions for use".

The patient should be advised to tear off the 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 dropper tip.

Children.

Travatan® can be used in children aged 2 months to 18 years at the same dosage regimen as adults. However, data in the age group 2 months to 3 years (9 patients) are limited (see section 5.1).

The safety and efficacy of Travatan® in children under 2 months of age have not been established. Data are not available.

Children

Travatan® can be used in children aged 2 months to 18 years at the same dosage regimen as adults. However, data in the age group 2 months to 3 years (9 patients) are limited (see section 5.1).

The safety and efficacy of Travatan® in children under 2 months of age have not been established. Data are not available.

Overdose

There have been no reports of any cases of overdose. Local overdose is unlikely to cause or be associated with toxic effects. In case of local overdose with Travatan®, the eye(s) should be flushed with warm water. In case of accidental ingestion, symptomatic and supportive therapy should be administered.

Side effects

A brief overview of safety data.

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

The list of adverse reactions is presented in Table 2.

The following adverse reactions are classified as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (< 1/10,000) or not known (frequency cannot be estimated from the available data). Within each grouping, adverse reactions are presented in order of decreasing seriousness. Adverse reactions have been reported in clinical trials and during post-marketing use of Travatan®.

Table 2

Children

In a 3-month Phase 3 study and a 7-day pharmacokinetic study in 102 pediatric patients treated with Travatan®, the type and nature of adverse reactions reported were similar to those seen in adult patients. The short-term safety profiles in the various pediatric subgroups were also similar to those seen in adults (see section 5.1). The most common adverse reactions reported in pediatric patients were ocular hyperemia (16.9%) and eyelash growth (6.5%). In a similar 3-month study in adult patients, these adverse reactions occurred at a frequency 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, lacrimation increased, and photophobia and were reported as isolated events 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 authorised. This allows for continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report such adverse reactions as required by law.

Expiration date

2 years.

Shelf life after first opening the bottle is 4 weeks.

Storage conditions

There are no special storage conditions for the drug.

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 an intermediate packaging and placed in a cardboard box containing 1 or 3 bottles. Not all pack sizes may be marketed.

Vacation category

According to the recipe.

Producer

Alcon Couvreur/Alcon Couvreur

Address

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