5.1 Pigmentation

Travoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid), and eyelashes. Pigmentation is expected to increase as long as travoprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of travoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The long term effects of increased pigmentation are not known.
Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with IZBA can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly.

5.2 Eyelash Changes

IZBA may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, thickness, and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment.

5.3 Intraocular Inflammation

IZBA should be used with caution in patients with active intraocular inflammation (e.g., uveitis) because the inflammation may be exacerbated.

5.4 Macular Edema

Macular edema, including cystoid macular edema, has been reported during treatment with travoprost ophthalmic solution. IZBA should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.

5.5 Bacterial Keratitis

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 ocular epithelial surface.

5.6 Use With Contact Lenses

Contact lenses should be removed prior to instillation of IZBA and may be reinserted 15 minutes following its administration.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Different methodologies were used to collect adverse reactions during the development of travoprost. The most common adverse reaction observed in controlled clinical studies with travoprost 0.004% was ocular hyperemia. Ocular hyperemia was reported in 30% to 50% of patients by physician rating the severity of patient’s post treatment ocular hyperemia compared to standardized reference photographs and/or patients who discontinued therapy due to ocular hyperemia.

In a 3 month clinical trial involving 442 patients exposed to IZBA and 422 control patients exposed to travoprost ophthalmic solution, 0.004%, the most common adverse drug reaction was ocular hyperemia. This was reported in 12% of patients treated with IZBA based on clinical observations and/or patient complaints. One patient (0.2%) discontinued treatment with IZBA due to ocular hyperemia. Rates observed in the control patients were comparable.

Ocular adverse reactions reported in clinical studies with travoprost ophthalmic solutions, including IZBA at an incidence of 5% to 10% included decreased visual acuity, eye discomfort, foreign body sensation, pain, and pruritus. Ocular adverse reactions reported at an incidence of 1% to 4% included abnormal vision, blepharitis, blurred vision, cataract, conjunctivitis, corneal staining, dry eye, iris discoloration, keratitis, lid margin crusting, ocular inflammation, photophobia, subconjunctival hemorrhage, and tearing.

Nonocular adverse reactions reported at an incidence of 1% to 5% in these clinical studies were allergy, angina pectoris, anxiety, arthritis, back pain, bradycardia, bronchitis, chest pain, cold/flu syndrome, depression, dyspepsia, gastrointestinal disorder, headache, hypercholesterolemia, hypertension, hypotension, infection, pain, prostate disorder, sinusitis, urinary incontinence, and urinary tract infections.

In postmarketing use with prostaglandin analogs, periorbital and lid changes, including deepening of the eyelid sulcus have been observed.

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies of IZBA administration in pregnant women to inform a drug associated risk.

In animal reproduction studies, subcutaneous (SC) administration of travoprost to pregnant mice and rats throughout the period of organogenesis produced embryo-fetal lethality, spontaneous abortion, and premature delivery at potentially clinically relevant doses.

Advise pregnant women of a potential risk to a fetus. Because animal reproductive studies are not always predictive of human response, IZBA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data

Animal Data

An embryo-fetal study was conducted in pregnant rats administered travoprost once daily by SC injection from gestation Day 6 to 17 to target the period of organogenesis. At 10 mcg/kg [81 times the maximum recommended human ocular dose (MRHOD), based on plasma Cmax)], travoprost was teratogenic in rats, evidenced by an increase in the incidence of skeletal malformations as well as external and visceral malformations, including fused sternebrae, domed head, and hydrocephaly. Travoprost caused post-implantation loss at 10 mcg/kg. The no observed adverse effect level (NOAEL) for post-implantation loss was 3 mcg/kg (24 times the MRHOD, based on estimated plasma Cmax). The maternal NOAEL was 10 mcg/kg.

An embryo-fetal study was conducted in pregnant mice administered travoprost once daily by SC injection from gestation Day 6 to 11, to target the period of organogenesis. At 1 mcg/kg (8.1 times the MRHOD, based on plasma Cmax), travoprost caused post-implantation loss and decreased fetal weight. The NOAEL for embryo-fetal toxicity was 0.3 mcg/kg (2.4 times the MRHOD, based on estimated plasma Cmax). The maternal NOAEL was 1 mcg/kg.

Pre/postnatal studies were conducted in rats administered travoprost once daily by SC injection from gestation Day 7 (early embryonic period) to postnatal Day 21 (end of lactation period). At doses of greater than or equal to 0.12 mcg/kg/day (0.97 times the MRHOD, based on estimated plasma Cmax), adverse pregnancy outcomes (embryo-fetal lethality, abortion, early delivery), low birth weight, and developmental delays were observed. The NOAEL for adverse pregnancy outcomes, low birth weight, and developmental delay was 0.1 mcg/kg (0.81 times the MRHOD, based on estimated plasma Cmax). The NOAEL for maternal toxicity was 0.72 mcg/kg (5.8 times the MRHOD, based on estimated plasma Cmax).

8.2 Lactation

Risk Summary

There are no data on the effects of travoprost on the breastfed child or milk production. It is not known if travoprost is present in human milk following ophthalmic administration. A study in lactating rats demonstrated that radiolabeled travoprost and/or its metabolites were transferred into milk following SC administration.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for use IZBA and any potential adverse effects on the breast-fed child from use of IZBA.

8.4 Pediatric Use

Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long term chronic use.

8.5 Geriatric Use

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

12.1 Mechanism of Action

Travoprost free acid, a prostaglandin analog is a selective FP prostanoid receptor agonist which is believed to reduce IOP by increasing uveoscleral outflow. The exact mechanism of action is unknown at this time.

12.3 Pharmacokinetics

Travoprost is absorbed through the cornea and is hydrolyzed to the active free acid. Data from four multiple dose pharmacokinetic studies using travoprost ophthalmic solution, 0.004% (totaling 107 subjects) have shown that plasma concentrations of the free acid are below 0.01 ng/mL (the quantitation limit of the assay) in two-thirds of the subjects. In those individuals with quantifiable plasma concentrations (N = 38), the mean plasma Cmax was 0.018 ± 0.007 ng/mL (ranged, 0.01 to 0.052 ng/mL) and was reached within 30 minutes. From these studies, travoprost is estimated to have a plasma half-life of 45 minutes. There was no difference in plasma concentrations between Days 1 and 7, indicating steady-state was reached early and that there was no significant accumulation.

Travoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to its biologically active free acid. Systemically, travoprost free acid is metabolized to inactive metabolites via beta-oxidation of the α(carboxylic acid) chain to give the 1,2-dinor and 1,2,3,4-tetranor analogs, via oxidation of the 15-hydroxyl moiety, as well as via reduction of the 13,14 double bond.

The elimination of travoprost free acid from plasma was rapid and levels were generally below the limit of quantification within one hour after dosing. The terminal elimination half-life of travoprost free acid was estimated from fourteen subjects and ranged from 17 minutes to 86 minutes with the mean half-life of 45 minutes. Less than 2% of the topical ocular dose of travoprost was excreted in the urine within 4 hours as the travoprost free acid.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies in mice and rats at SC doses of 10, 30, or 100 mcg/kg/day did not show any evidence of carcinogenic potential. However, at 100 mcg/kg/day, male rats were only treated for 82 weeks, and the maximum tolerated dose (MTD) was not reached in the mouse study. The high dose (100 mcg/kg) corresponds to exposure levels more than 400 times (mouse) and more than 700 times (rat) the human exposure at the MRHOD, based on estimated plasma Cmax for active travoprost free acid.

Mutagenesis

Travoprost was not mutagenic in the Ames test, mouse micronucleus test or rat chromosome aberration assay. A slight increase in the mutant frequency was observed in one of two mouse lymphoma assays in the presence of rat S-9 activation enzymes.

Impairment of Fertility

Travoprost did not affect mating or fertility indices in male or female rats at SC doses up to 3 mcg/kg/day (24 times the MRHOD, based on estimated plasma Cmax). At 10 mcg/kg/day (81 times the MRHOD, based on estimated plasma Cmax), the mean number of corpora lutea was reduced, and the post-implantation losses were increased.