IZBA: Indications, Dosage, Precautions, Adverse Effects
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IZBA - Product Information

Manufacture: Alcon
Country: Canada
Condition: Intraocular Hypertension
Class: Ophthalmic glaucoma agents
Form: Eye drops (ophthalmic)
Ingredients: Travoprost (Travoprost), Polyquantemium-1, Boric acid, Hydrochloric acid and/or Sodium hydroxide (to adjust pH), Mannitol, Polyoxyethylene hydrogenated castor oil 40 (HCO-40), Propylene glycol, Purified water and Sodium chloride.

Summary Product Information

Route of Administration Dosage Form / Strength Clinically Relevant Nonmedicinal Ingredients
Ophthalmic (topical) Solution / 0.003% travoprost Polyquaternium-1 (POLYQUAD*) as preservative, boric acid, propylene glycol.

For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

IZBA* (travoprost ophthalmic solution) 0.003% w/v, is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Geriatrics (> 65 years of age)

No overall differences in safety and effectiveness have been observed between elderly and other adult patients.

Pediatrics (< 18 years of age)

The safety and efficacy of IZBA* has not been established in pediatric populations. Therefore, IZBA* is not recommended in these patients.

Contraindications

IZBA* should not be used in the following:

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
  • Patients who are pregnant or attempting pregnancy.

Warnings and Precautions

General

FOR OPHTHALMIC USE ONLY.

Patients should remove contact lenses prior to administration of IZBA*; lenses may be reinserted 15 minutes following administration.

Carcinogenesis and Mutagenesis

See Toxicology section for animal data.

Dependence/Tolerance

No evidence of drug abuse, withdrawal or rebound phenomena has been identified with the use of travoprost in clinical trials.

Driving and Using Machinery

The instillation of IZBA* may cause temporary blurred vision and other visual disturbances, which may affect the ability to drive or use machines. If blurred vision occurs after instillation, the patient should be advised to wait until vision clears before driving or using machinery.

Ophthalmologic

IZBA* may gradually change eye colour, increasing the amount of brown pigmentation in the iris by increasing the number of melanosomes (pigment granules) in melanocytes. The long term effects on the melanocytes and any consequences of potential injury to the melanocytes and/or deposition of pigment granules to other areas of the eye are currently unknown. Typically the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become more brownish. The change in iris colour occurs slowly and may not be noticeable for months to years. In clinical trials, iris pigmentation was detected as early as 3 months. This change in eye colour has predominantly been seen in patients with mixed coloured irises i.e., blue-brown, gray-brown, yellow-brown and green-brown; however, it has also been observed in patients with brown eyes. These changes may be permanent. Patients should be informed of the possibility of iris colour change.

Patients who receive treatment in only one eye may experience increased brown pigmentation of the iris, periorbital and/or eyelid tissue, and eyelashes in the treated eye. They may also experience disparity between the eyes in length, thickness, and/or number of eyelashes. These changes in pigmentation and lash growth may be permanent.

Periorbital and/or eyelid skin darkening has been reported in association with the use of travoprost ophthalmic solution (0.004%).

IZBA* may gradually change eyelashes in the treated eye; these changes include increased length, thickness, pigmentation, and/or number of lashes. During long-term clinical trials, eyelash photographs taken periodically during the studies, revealed an overall incidence of eyelash changes of 61%. The overall incidence of patient complaints regarding these changes was 0.8%. Changes in eyelashes may be noticed as early as one and a half months after initiation of treatment. The mechanism of eyelash changes and their long term consequence are currently unknown.

There is no experience with IZBA* in inflammatory ocular conditions, or in neovascular or angle-closure glaucoma.

IZBA* should be used with caution in patients with active intraocular inflammation (iritis/uveitis), as well as patients with predisposing risk factors for uveitis.

Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin F analogues. These reports have mainly occurred in aphakic patients, pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. IZBA* should be used with caution in these patients.

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the epithelial surface.

Renal/Hepatic

Travoprost ophthalmic solution, 0.004%, has been studied in patients with mild to severe hepatic impairment (Childs-Pugh Classification A-C) and also in patients with mild to severe renal impairment (creatinine clearance from as low as 14 mL/min/1.737m2 to 77 mL/min/1.73m2. No clinically relevant changes in hematology, blood chemistry, urinalysis laboratory data or plasma concentrations of free acid were observed in patients with impaired (mild, moderate, or severe) hepatic or renal function. No dosage adjustment is necessary in patients with hepatic or renal impairment.

Sexual Function/Reproduction

There are no data on the effects of IZBA* on human fertility.

Special Populations

Pregnant Women

No adequate and well-controlled studies have been performed in pregnant women. Travoprost, like all FP agonists, may interfere with the maintenance of pregnancy and should not be used by women during pregnancy or by women attempting to become pregnant.

Travoprost was teratogenic in rats. Travoprost administered intravenously to pregnant rats from gestation days 6-17 at a dose of 10 μg/kg/day, induced a slight increase in the incidence of skeletal malformations such as fused sternebrae, domed head and hydrocephaly. No effect was observed at 3 μg/kg/day (75 times the maximum recommended human dose of 0.04 μg/kg/day). The no effect level or fetal external, visceral or skeletal malformation was observed after 1.0 μg/kg/day subcutaneous administration during gestation days 6-16 to pregnant mice, though post-implantation loss was increased at that dose, but not at 0.3 μg/kg/day.

Since prostaglandins are biologically active and 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 case of accidental contact with the contents of the bottle, thoroughly cleanse the exposed area with soap and water immediately.

Nursing Women

A study in lactating rats demonstrated that radiolabeled travoprost and/or its metabolites were excreted in milk. It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when IZBA* is administered to a nursing woman.

Pediatrics (< 18 years of age)

The safety and efficacy of IZBA* has not been established in pediatric populations. Therefore, IZBA* is not recommended in these patients.

Geriatrics (> 65 years of age)

No overall differences in safety and effectiveness have been observed between elderly and other adult patients.

Adverse Reactions

Adverse Drug Reaction Overview

IZBA* (travoprost 0.003%; POLYQUAD* preserved) is a benzalkonium chloride-free (BAK-free) formulation containing a 25% lower concentration of travoprost relative to Travatan* (travoprost 0.004%; BAK-preserved) and Travatan*Z (travoprost 0.004%; sofZia-preserved).

In a single clinical study, 442 patients were exposed to IZBA* once daily (QD) versus 421 patients exposed to Travatan* once daily (QD) for up to 3 months.

The majority of adverse events (AE) reported for either treatment group during the pivotal study were for local ocular effects with a known casual association with the use of travoprost and topical ocular prostaglandin analogs (PGAs) in general. As expected, lower exposure to travoprost resulted in a slightly lower incidence of adverse drug reactions (ADR) reported in patients dosing with IZBA* versus Travatan*. The most common ADR reported in the study was hyperemia of the eye (ADRs for ocular and conjunctival combined). The severity of hyperemia was similar between the 2 treatments groups as approximately 90% of the reports in each group were assessed as mild.

No Serious Adverse Event (SAE) assessed as related to the use of IZBA* was reported in the study. The majority of SAEs reported were resolved during the course of the study, the use of study drug was not interrupted, and the patients completed the clinical study without further incidence of the SAE.

Overall, the safety profile of IZBA* was similar to that of Travatan* (travoprost 0.004%; BAK-preserved) in clinical trial C-11-034. IZBA* was associated with numerically less hyperemia than Travatan* treatment over the course of the 3 month trial.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 1 summarizes adverse events assessed by the examining physician as related to the use of test article (ADR) at an incidence of ≥ 1% reported in patients with exposure to IZBA* (POLYQUAD* preserved), relative to Travatan* (travoprost 0.004%; BAK-preserved), in clinical trial C-11-034.

Table 1: Clinical Trial Adverse Drug Reactions ≥ 1% Reported with the use of IZBA* and Corresponding Incidences Observed with Travatan* (Study C-11-034)>
  IZBA*
(Travoprost 0.003%; POLYQUAD* preserved)
n = 442
Travatan*
(Travoprost 0.004%; BAK-preserved)
n = 421
N % N %
Eye disorders        
Ocular hyperaemia 27 6.1 32 7.6
Conjunctival hyperaemia 25 5.7 29 6.9
Eye pruritus 12 2.7 8 1.9
Eye irritation 9 2.0 5 1.2
Dry eye 6 1.4 5 1.2

IZBA* = Travoprost 30 μg/mL eye drops, solution preserved with POLYQUAD*

Travatan* = Travoprost 40 μg/mL eye drops, solution preserved with benzalkonium chloride (BAK)

Less Common Clinical Trial Adverse Drug Reactions (< 1%)

The list below summarizes ADRs reported at an incidence of < 1% in clinical trial C-11-034. Adverse drug reactions are presented in alphabetical order within the System Organ Classification (SOC).

Eye disorders: anterior chamber cell, anterior chamber inflammation, blepharitis, conjunctivitis, conjunctivitis allergic, dark circles under eyes, erythema of eyelid, eye discharge, eyelid margin crusting, eyelid oedema, eye pain, eyelid pain, eyelid pruritus, eyelash thickening, foreign body sensation in eyes, growth of eyelashes, iritis, photophobia, punctate keratitis, vision blurred, visual impairment

Investigations: corneal staining

Nervous system disorders: dizziness, headache, somnolence

Skin and subcutaneous tissue disorders: pruritus, rash, skin discolouration

Post-Market Adverse Drug Reactions

Additional adverse drug reactions (ADRs) reported during the post-market use of travoprost ophthalmic solution, 0.004% via post-marketing surveillance and other clinical trials are summarized below.

Table 2 summarizes ADRs reported in other clinical trials involving travoprost ophthalmic solution, 0.004%. The duration of these studies ranged from 3 months (including 12 weeks) to 5 years with a total of 4081 patients.

Table 2: Adverse Drug Reactions reported in other Clinical Trials involving Travoprost Ophthalmic Solution, 0.004%
System Organ Classification Preferred Term*
Immune system disorders Uncommon: hypersensitivity
Nervous system disorders Rare: dysgeusia
Eye disorders Common: iris hyperpigmentation, ocular discomfort.
Uncommon: cataract, corneal erosion, eyelids pruritus, keratitis, lacrimation increased, periorbital oedema, visual acuity reduced
Rare: anterior chamber pigmentation, asthenopia, conjunctival follicles, conjunctival oedema, eczema eyelids, eye allergy, eyelash discolouration, eye inflammation, eyelid irritation, hypoaesthesia eye, iridocyclitis, uveitis
Cardiac disorders Rare: heart rate decreased, palpitations
Vascular disorders Rare: hypertension
Respiratory, thoracic and mediastinal disorders Rare: asthma, cough, dyspnoea, nasal discomfort, nasal dryness, oropharyngeal pain
Gastrointestinal disorders Rare: constipation, dry mouth
Skin and subcutaneous tissue Uncommon : skin hyperpigmentation disorders
Rare: hair colour changes , hypertrichosis, madarosis
General disorders and administration site conditions Rare asthenia

*Within each frequency-grouping, ADRs are presented in alphabetical order.

Additional ADRs identified from post-marketing surveillance of travoprost ophthalmic solution, 0.004% are listed below in alphabetical order. The frequencies of these events cannot be determined from the available data:

Abdominal pain, anxiety, arthralgia, chest pain, depression, diarrhea, dysuria, erythema, hypotension, macular oedema, musculoskeletal pain, nausea, prostatic specific antigen increased, sunken eyes, tinnitus, urinary incontinence.

Drug Interactions

Overview

Drug interaction studies with cytochrome P450 substrates have not been conducted with AL-5848 (travoprost active acid metabolite). The very low systemic exposure to AL-5848 after topical ocular administration of travoprost would not likely influence the P450 enzyme-mediated metabolism of other concomitant agents. Concomitant administration of potent inhibitors of cytochrome P450 enzymes would not impact the low systemic exposure of AL-5848 after topical ocular administration since travoprost is metabolized extensively by routes other than the cytochrome P450 pathways.

Drug-Drug Interactions

Drug-drug interactions with other concomitantly administered drugs are not likely to be clinically relevant. As reported, plasma levels following topical ocular administration of Travoprost 0.004% are very low (approximately 70% below the assay LOQ of 10 pg/mL) and those that were measurable declined rapidly (t1/2 approximately 45 minutes).

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

Interactions with functions of daily living have not been established.

Dosage and Administration

Recommended Dose and Dosage Adjustment

The recommended dosage for IZBA* is one drop in the affected eye(s) once daily. Optimal effect is observed with evening dosing. IZBA* should not be administered more than once daily since it has been shown that more frequent administration of prostaglandin analogs may decrease the intraocular pressure lowering effect.

Reduction of intraocular pressure starts approximately 2 hours after administration and the maximum effect is reached after 12 hours.

Missed Dose

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

Administration

For ophthalmic use only.

Travoprost may be used concomitantly with other topical ophthalmic products including beta-blockers (i.e., timolol) and brinzolamide to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.

Overdosage

There have been no reported cases of overdose for IZBA* during the clinical development program.

A topical overdose of IZBA* may be flushed from the eye(s) with lukewarm water. Treatment of a suspected oral ingestion is symptomatic and supportive.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

A single-dose intravenous study in rats was conducted to elucidate maximal acute hazard. The dose employed was 250,000 times the proposed daily clinical exposure and over 5000-times the possible exposure from the entire contents of one product container. No treatment-related pharmacotoxic signs were present in the animals receiving travoprost.

Action and Clinical Pharmacology

Mechanism of Action

Travoprost, an isopropyl ester prodrug, is rapidly hydrolyzed by esterases in the cornea to the biologically active free acid. Travoprost free acid is highly selective, potent agonist for the FP prostanoid receptor. FP receptor agonists are thought to reduce intraocular pressure (IOP) by increasing the outflow of aqueous humor, primarily by increased uveoscleral outflow.

IZBA*, when applied topically to the eye, reduces elevated as well as normal intraocular pressure, whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage. The Advanced Glaucoma Intervention Study (AGIS) established elevated intraocular pressure as a positive risk factor for glaucomatous visual field loss. Eyes with intraocular pressures below 18 mmHg at all visits were found to have little to no visual field loss during the six-year monitoring period.

Pharmacodynamics

Since IZBA* is a topical product intended for a local effect within the eye, plasma drug concentrations cannot be related to pharmacodynamics (IOP-lowering).

Pharmacokinetics

There have been no studies conducted to evaluate the pharmacokinetics of travoprost ophthalmic solution, 0.003% in humans. The absorption, distribution, metabolism, excretion and toxicokinetics of AL-6221 have been studied in travoprost ophthalmic solution 0.004% BAK-preserved and BAK-free formulations. Clinical pharmacokinetic studies in normal subjects, Japanese normal subjects, renally-impaired and hepatically-impaired subjects with travoprost ophthalmic solution 0.004% showed extremely low systemic exposure with most plasma samples containing travoprost free acid concentrations below the 0.010 ng/mL limit of quantitation. For those samples containing quantifiable drug levels, concentrations ranged from 0.010 to 0.052 ng/mL. In the few subjects having sufficient quantifiable data for half-life determination, the elimination half-life was approximately 45 minutes. There was insufficient quantifiable data for calculation of AUC, clearance or volume of distribution. Data in animals indicates that travoprost exhibits linear pharmacokinetics. Since IZBA* contains a 25% lower dose than the 0.004% solution used in clinical pharmacokinetic studies, systemic exposure would be even lower than that observed previously indicating that the systemic pharmacokinetics travoprost and its active free acid metabolite are not a cause of concern for the safety of IZBA*.

Absorption

Travoprost is absorbed through the cornea. Studies in rabbits have shown peak concentrations in aqueous humor were reached one to two hours following topical administration. In humans, peak plasma concentrations of travoprost free acid were low (25 pg/mL) or less) and occurred within 30 minutes following topical ocular administration of one drop of 0.004% travoprost ophthalmic solution.

Distribution

Travoprost free acid is moderately distributed into body tissues with a volume of distribution of 2.6 L/kg in rats. Radioactivity levels in rat tissues following a single subcutaneous dose of 14C-travoprost dropped rapidly during the first 3 hours and by 24 hours were below or near detection limits (<0.2 – 6 ng equiv./g). Binding of travoprost free acid to plasma proteins is moderate at 90% and linear over a 10,000-fold concentration range (0.10 – 100 ng/mL).

Metabolism

Metabolism was studied in rats, dogs and monkeys. Systemically, travoprost free acid is rapidly and extensively metabolized in the kidney, liver and lung to inactive metabolites. Bio-transformations include beta-oxidation of the α(carboxylic acid) chain to give the 1,2-dinor and 1,2,3,4-tetranor analogs, oxidation of the 15-hydroxyl moiety, as well as reduction of the 13, 14 double bond.

Excretion

In rats, 95% of a subcutaneous radiolabeled dose was eliminated within 24 hours. Approximately 75% of the dose was eliminated in the feces with the remainder excreted in urine.

Special Populations and Conditions

Pediatrics

The efficacy and safety of IZBA* in pediatric patients have not been established, and use is not recommended in these patients until further data become available.

Geriatrics

There were no differences seen between elderly patients and younger patients with travoprost ophthalmic solution, 0.003%. Additionally, no differences were seen in the efficacy and safety of travoprost ophthalmic solution, 0.003% compared to travoprost ophthalmic solution, 0.004% BAK formulation in elderly patients.

Gender

No meaningful differences in AL-5848 pharmacokinetics were observed between male and female subjects indicating no gender differences in the pharmacokinetics of travoprost free acid (AL-5848).

Hepatic Insufficiency

After administration of travoprost ophthalmic solution, 0.004% (BAK-preserved) formulation, once daily for 7 days, the systemic exposure of AL-5848 is minimal and levels cannot be correlated with the severity of hepatic impairment. No dose adjustment of travoprost 0.004% BAK formulation is necessary in patients with different degrees (mild to severe) of hepatic impairment. Based on these results, no dose adjustment of IZBA* is necessary.

Race

A single-centre, open-label, randomized, 3 parallel-group, multiple-dose safety pharmacokinetic study in healthy male Japanese subjects was conducted to characterize the steady-state plasma pharmacokinetics of travoprost and AL-5848. Thirty-eight subjects (19 – 64 years of age) received topical ocular administration of either travoprost 0.004 (with or without digital punctal occlusion) or travoprost 0.0015% without digital punctal occlusion once-daily in the morning for 7 days (one drop in each eye). The results demonstrated that the systemic exposure of travoprost and AL-5848 was minimal in healthy male Japanese volunteers after repeated topical ocular administration of travoprost 0.004% or travoprost 0.0015%. Punctal occlusion did not influence the systemic availability of AL-5848.

Renal Insufficiency

Plasma concentrations of travoprost and its active metabolite (AL-5848) observed were similar to those reported in healthy subjects and in patients with varying degrees of hepatic impairment. The majority of post-dose plasma samples were below the assay LOQ (<10 pg/mL). No dose adjustment of travoprost 0.004% BAK formulation was necessary in patients with different degrees (from mild to severe) of renal impairment. Based on these results, no dose adjustment of IZBA* is necessary.

Storage and Stability

Store at 2° to 25°C.

Special Handling Instructions

This medicinal product does not require any special storage conditions.

Dosage Forms, Composition and Packaging

IZBA* is a sterile, isotonic, buffered, preserved, aqueous solution containing 30 μg/mL travoprost supplied in a plastic bottle.

IZBA* is supplied as a 2.5 mL solution in a 4 mL plastic bottle and a 5 mL solution in a 7.5 mL plastic bottle. The dispenser bottles are fitted with a dropper tip and closure, and are presented in a foil pouch or with a polyvinyl chloride (PVC) shrink band around the neck and closure as a security-feature.

Each mL of solution contains:

ACTIVE: travoprost (0.03 mg/mL)
PRESERVATIVE: Polyquantemium-1 (POLYQUAD*) (0.01 mg/mL)
INACTIVES: boric acid, hydrochloric acid and/or sodium hydroxide (to adjust pH), mannitol, polyoxyethylene hydrogenated castor oil 40 (HCO-40), propylene glycol, purified water and sodium chloride.