Izba

Travoprost.

1 ml of solution contains 30 micrograms of travoprost.
Preservative: 1 ml of solution contains 10 micrograms of polyquaternium-1.
Excipients with known effect: 1 ml of solution contains 7.5 mg propylene glycol and 2 mg polyoxyethylene hydrogenated castor oil 40 (HCO-40) (see Precautions).
Excipients/Inactive Ingredients: Polyquaternium-1, polyoxyethylene hydrogenated castor oil 40 (HCO-40), boric acid (E284), mannitol (E421), sodium chloride, propylene glycol (E1520), sodium hydroxide and / or hydrochloric acid (to adjust pH), purified water.

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, prostaglandin analogues. ATC code: S01EE04.
Pharmacology: Pharmacodynamics: Mechanism of action: Travoprost, a prostaglandin F2 analogue, is a highly selective full agonist which has a high affinity for the prostaglandin FP receptor, and reduces the intraocular pressure by increasing the outflow of aqueous humour via trabecular meshwork and uveoscleral pathways. Reduction of the intraocular pressure in man starts about 2 hours after administration and maximum effect is reached after 12 hours. Significant lowering of intraocular pressure can be maintained for periods exceeding 24 hours with a single dose.
Clinical efficacy and safety: In a clinical trial, patients with open-angle glaucoma or ocular hypertension treated with IZBA eye drops dosed once-daily in the evening, demonstrated intraocular pressure lowering equivalent to Travoprost 40 μg/ml eye drops, solution at all on-therapy visits and time points (95 % CI within ±1.0 mmHg). The mean reduction from baseline in IOP ranged from 7.1 to 8.2 mmHg as summarised in Table 1. The mean percent reductions in IOP from baseline to each study visit and assessment time point ranged from 28.4 % to 30.7 %. (See Table 1.)

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An improved safety profile has been observed for IZBA eye drops when compared to the marketed Travoprost 40 μg/ml eye drops, solution (benzalkonium chloride preserved or polyquaternium-1 preserved). The most common adverse reaction associated with both IZBA eye drops and Travoprost 40 μg/ml eye drops, solution is hyperaemia. Hyperaemia (ocular or conjunctival) was observed in 11.8 % of patients (N = 442) exposed to IZBA eye drops compared with 14.5 % observed for patients exposed to Travoprost 40 μg/ml eye drops, solution, benzalkonium chloride preserved.
Secondary pharmacology: Travoprost significantly increased optic nerve head blood flow in rabbits following 7 days of topical ocular administration (1.4 micrograms, once-daily).
Travoprost 40 μg/ml eye drops, solution preserved with polyquaternium-1 induced minimal ocular surface toxicity, compared to eye drops preserved with benzalkonium chloride, on cultured human corneal cells and following topical ocular administration in rabbits.
Pharmacokinetics: Absorption: Travoprost is an ester prodrug. It is absorbed through the cornea where the isopropyl ester is hydrolysed to the active free acid. Studies in rabbits have shown peak concentrations of 20 ng/g of the free acid in aqueous humour one to two hours after topical dosing of Travoprost 40 μg/ml eye drops, solution. Aqueous humour concentrations declined with a half-life of approximately 1.5 hours.
Distribution: Following topical ocular administration of Travoprost 40 μg/ml eye drops, solution to healthy volunteers, low systemic exposure to active free acid was demonstrated. Peak active free acid plasma concentrations of 25 pg/ml or less were observed between 10 and 30 minutes post-dose. Thereafter, plasma levels declined rapidly to below the 10 pg/ml assay quantitation limit before 1 hour post-administration. Due to the low plasma concentrations and rapid elimination following topical dosing, the elimination half-life of active free acid in man could not be determined.
Biotransformation: Metabolism is the major route of elimination of both travoprost and the active free acid. The systemic metabolic pathways parallel those of endogenous prostaglandin F2 which are characterised by reduction of the double bond in position C13-C14, oxidation of the 15-hydroxyl and -oxidative cleavages of the upper side chain.
Elimination: Travoprost free acid and its metabolites are mainly excreted by the kidneys. Travoprost 40 μg/ml eye drops, solution has been studied in patients with mild to severe hepatic impairment and in patients with mild to severe renal impairment (creatinine clearance as low as 14 ml/min). No dosage adjustment is necessary in these patients.
Toxicology: Preclinical safety data: In ocular toxicity studies in monkeys, administration of travoprost at a dose of 0.45 microgram, twice a day, was shown to induce increased palpebral fissure. Topical ocular administration of travoprost to monkeys at concentrations of up to 0.012 % to the right eye, twice daily for one year resulted in no systemic toxicity.
Increased palpebral fissure observed in monkeys were not seen in rabbits or in the clinical trials with travoprost products and is considered to be species specific.
Reproduction toxicity studies have been undertaken in rat, mice and rabbit by systemic route. Findings are related to FP receptor agonist activity in uterus with early embryolethality, post-implantation loss, foetotoxicity. In pregnant rat, systemic administration of travoprost at doses more than 200 times the clinical dose during the period of organogenesis resulted in an increased incidence of malformations. Low levels of radioactivity were measured in amniotic fluid and foetal tissues of pregnant rats administered 3H-travoprost. Reproduction and development studies have demonstrated a potent effect on foetal loss with a high rate observed in rats and mice (180 pg/ml and 30 pg/ml plasma, respectively) at exposures 1.2 to 6 times the clinical exposure (up to 25 pg/ml).
Data to evaluate a potential effect on the environment are currently limited.

IZBA eye drops contains travoprost, a prostaglandin analogue.
IZBA eye drops is indicated for the decrease of elevated intraocular pressure in adult patients with ocular hypertension or open-angle glaucoma (see Pharmacology: Pharmacodynamics under Actions).

Posology: Use in adults, including elderly patients: The dose is 1 drop of IZBA eye drops in the conjunctival sac of the affected eye(s) once daily. Optimal effect is obtained if the dose is administered in the evening.
If a dose is missed, treatment should be continued with the next dose as planned. The dose should not exceed 1 drop in the affected eye(s) daily.
When substituting another ophthalmic antiglaucoma medicinal product with IZBA eye drops, the other medicinal product should be discontinued and IZBA eye drops should be started the following day.
Use in patients with hepatic or renal impairment: Travoprost 30 μg/ml has not been studied in patients with hepatic or renal impairment. However, travoprost 40 μg/ml has been studied in patients with mild to severe hepatic impairment and in patients with mild to severe renal impairment (creatinine clearance as low as 14 ml/min). No dosage adjustment is necessary in these patients (see Pharmacology: Pharmacokinetics under Actions).
Therefore, no need for dose adjustment at the lower concentration of active ingredient is anticipated.
Use in children and adolescents: The safety and efficacy of IZBA eye drops in children and adolescents below the age of 18 years has not been established.
No data are available.
Method of administration: For ocular use.
For patients who wear contact lenses, patients must be instructed to remove contact lenses prior to application of IZBA eye drops and wait at least 15 minutes after instillation of the dose before reinsertion. The patient should remove the protective overwrap immediately prior to initial use.
To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle. Keep the bottle tightly closed when not in use.
Nasolacrimal occlusion or gently closing the eyelid after administration is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic adverse reactions.
If more than one topical ophthalmic medicinal product is being used, the medicinal products must be administered at least 5 minutes apart. Eye ointments should be administered last.

A topical overdose of IZBA eye drops may be flushed from the eye(s) with lukewarm water.
A topical overdose is not likely to occur or to be associated with toxicity. Treatment of a suspected oral ingestion is symptomatic and supportive.

Hypersensitivity to the active substance or to any of the excipients listed under Description.

Eye colour change: Travoprost may gradually change the eye colour by increasing the number of melanosomes (pigment granules) in melanocytes. Before treatment is instituted, patients must be informed of the possibility of a permanent change in eye colour. Unilateral treatment can result in permanent heterochromia. The long term effects on the melanocytes and any consequences thereof are currently unknown. The change in iris colour occurs slowly and may not be noticeable for months to years. The change in eye colour has predominantly been seen in patients with mixed coloured irides, i.e., blue-brown, grey-brown, yellow-brown and green-brown; however, it has also been observed in patients with brown eyes. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may be become more brownish. After discontinuation of therapy, no further increase in brown iris pigment has been observed.
Periorbital and eye lid changes: In controlled clinical trials, periorbital and/or eyelid skin darkening in association with the use of travoprost has been reported in 0.2 % of patients.
Periorbital and lid changes including deepening of the eyelid sulcus have been observed with prostaglandin analogues.
Travoprost may gradually change eyelashes in the treated eye(s); these changes were observed in about half of the patients in clinical trials and include: increased length, thickness, pigmentation, and/or number of lashes. The mechanism of eyelash changes and their long term consequences are currently unknown.
There is no experience of travoprost in inflammatory ocular conditions; nor in neovascular, angle-closure, narrow-angle or congenital glaucoma and only limited experience in thyroid eye disease, in open-angle glaucoma of pseudophakic patients and in pigmentary or pseudoexfoliative glaucoma.
Aphakic patients: Caution is recommended when using travoprost in aphakic patients, pseudophakic patients with a torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema.
Iritis/uveitis: In patients with known predisposing risk factors for iritis/uveitis, travoprost can be used with caution.
Contact with the skin: Skin contact with travoprost must be avoided as transdermal absorption of travoprost has been demonstrated in rabbits.
Prostaglandins and prostaglandin analogues are biologically active materials that may be absorbed through the skin. Women who are pregnant or attempting to become pregnant should exercise appropriate precautions to avoid direct exposure to the contents of the bottle. In the unlikely event of coming in contact with a substantial portion of the contents of the bottle, thoroughly cleanse the exposed area immediately.
Excipients: IZBA eye drops contains propylene glycol which may cause skin irritation.
IZBA eye drops contains polyoxyethylene hydrogenated castor oil 40 which may cause skin reactions.
Effects on ability to drive and use machines: IZBA eye drops has no or negligible influence on the ability to drive and use machines.
Temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machines.

Women of child-bearing potential/contraception: IZBA eye drops must not be used in women of child bearing age/potential unless adequate contraceptive measures are in place (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Pregnancy: Travoprost has harmful pharmacological effects on pregnancy and/or the foetus/new-born child. IZBA eye drops should not be used during pregnancy unless clearly necessary.
Breast-feeding: It is unknown whether travoprost from eye drops is excreted in human breast milk. Animal studies have shown excretion of travoprost and metabolites in breast milk.
The use of IZBA eye drops by breast-feeding mothers is not recommended.
Fertility: There are no data on the effects of travoprost on human fertility. Animal studies showed no effect of travoprost on fertility at doses more than 250 times the maximum recommended human ocular dose.

Summary of the safety profile: In a clinical trial of 3 months duration (N = 442) involving IZBA eye drops as monotherapy, the most common adverse reaction observed was hyperaemia of the eye (ocular or conjunctival) reported in approximately 12 % of the patients.
Tabulated list of adverse reactions: The following adverse reactions were assessed to be related with IZBA eye drops monotherapy and are classified according to the following convention: very common ( ≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000).
Within each frequency grouping in Table 2, adverse reactions are presented in decreasing order of seriousness. (See Table 2.)

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The following adverse reactions were assessed to be related with Travoprost 40 μg/ml eye drops, solution (either preserved with benzalkonium chloride or polyquaternium-1) and are classified according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping in Table 3, adverse reactions are presented in decreasing order of seriousness. (See Table 3.)

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No interaction studies have been performed.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Do not store above 30 °C.
Discard 4 weeks after first opening.

Antiglaucoma Preparations

S01EE04 - travoprost ; Belongs to the class of prostaglandin analogues. Used in the treatment of glaucoma.

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