Travoprost Bipharma

Travoprost Bipharma Z^® (travoprost ophthalmic solution) 0.004% is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

The recommended dosage is one drop in the affected eye(s) once daily in the evening. Travoprost Bipharma Z^® (travoprost ophthalmic solution) 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 the intraocular pressure starts approximately 2 hours after the first administration with maximum effect reached after 12 hours.

Travoprost Bipharma Z^® may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure (IOP). If more than one topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes apart.

None.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

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 Travoprost Bipharma Z^® (travoprost ophthalmic solution) 0.004% can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly.

Eyelash Changes

Travoprost Bipharma Z^® 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.

Intraocular Inflammation

Travoprost Bipharma Z^® should be used with caution in patients with active intraocular inflammation (e.g., uveitis) because the inflammation may be exacerbated.

Macular Edema

Macular edema, including cystoid macular edema, has been reported during treatment with travoprost ophthalmic solution. Travoprost Bipharma Z^® 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.

Angle-Closure, Inflammatory Or Neovascular Glaucoma

Travoprost Bipharma Z^® has not been evaluated for the treatment of angle-closure, inflammatory or neovascular glaucoma.

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.

Use With Contact Lenses

Contact lenses should be removed prior to instillation of Travoprost Bipharma Z^® and may be reinserted 15 minutes following its administration.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Two-year carcinogenicity studies in mice and rats at subcutaneous 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 over 400 times the human exposure at the maximum recommended human ocular dose (MRHOD) of 0.04 mcg/kg, based on plasma active drug levels.

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.

Travoprost did not affect mating or fertility indices in male or female rats at subcutaneous doses up to 10 mcg/kg/day (250 times the MRHOD of 0.04 mcg/kg/day on a mcg/kg basis). At 10 mcg/kg/day, the mean number of corpora lutea was reduced, and the post-implantation losses were increased. These effects were not observed at 3 mcg/kg/day (75 times the MRHOD).

Use In Specific Populations

Pregnancy

Pregnancy Category C

Teratogenic effects

Travoprost was teratogenic in rats, at an intravenous dose up to 10 mcg/kg/day [250 times the maximal recommended human ocular dose (MRHOD)], evidenced by an increase in the incidence of skeletal malformations as well as external and visceral malformations, such as fused sternebrae, domed head and hydrocephaly. Travoprost was not teratogenic in rats at intravenous doses up to 3 mcg/kg/day (75 times the MRHOD), or in mice at subcutaneous doses up to 1 mcg/kg/day (25 times the MRHOD). Travoprost produced an increase in post-implantation losses and a decrease in fetal viability in rats at intravenous doses greater than 3 mcg/kg/day (75 times the MRHOD) and in mice at subcutaneous doses greater than 0.3 mcg/kg/day (7.5 times the MRHOD).

In the offspring of female rats that received travoprost subcutaneously from Day 7 of pregnancy to lactation Day 21 at doses of = 0.12 mcg/kg/day (3 times the MRHOD), the incidence of postnatal mortality was increased, and neonatal body weight gain was decreased. Neonatal development was also affected, evidenced by delayed eye opening, pinna detachment and preputial separation, and by decreased motor activity.

There are no adequate and well-controlled studies of Travoprost Bipharma Z^® (travoprost ophthalmic solution) 0.004% administration in pregnant women. Because animal reproductive studies are not always predictive of human response, Travoprost Bipharma Z^® should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

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 Travoprost Bipharma Z^® is administered to a nursing woman.

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.

Geriatric Use

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

Hepatic And Renal Impairment

Travoprost ophthalmic solution 0.004% has been studied in patients with hepatic impairment and also in patients with renal impairment. No clinically relevant changes in hematology, blood chemistry, or urinalysis laboratory data were observed in these patients.

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.

The most common adverse reaction observed in controlled clinical trials with Travoprost Bipharma^® (travoprost ophthalmic solution) 0.004% and Travoprost Bipharma Z^® (travoprost ophthalmic solution) 0.004% was ocular hyperemia which was reported in 30% to 50% of patients. Up to 3% of patients discontinued therapy due to conjunctival hyperemia. Ocular adverse reactions reported at an incidence of 5% to 10% in these clinical trials included decreased visual acuity, eye discomfort, foreign body sensation, pain and pruritus.

Ocular adverse reactions reported at an incidence of 1% to 4% in clinical trials with Travoprost Bipharma^® or Travoprost Bipharma Z^® 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.

Postmarketing Experience

Additional adverse reactions have been identified during post approval use of Travoprost Bipharma^® or Travoprost Bipharma Z^® in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to Travoprost Bipharma^® or Travoprost Bipharma Z^®, or a combination of these factors, include: arrhythmia, vomiting, epistaxis, tachycardia, and insomnia.

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

No Information Provided

Travoprost is absorbed through the cornea and is hydrolyzed to the active free acid. Data from 4 multiple dose pharmacokinetic studies (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.