Travoprost

1 INDICATIONS AND USAGE Travoprost ophthalmic solution 0.004% is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Travoprost ophthalmic solution is a prostaglandin analog indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension (1)

2 DOSAGE AND ADMINISTRATION The recommended dosage is one drop in the affected eye(s) once daily in the evening. 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 IOP- lowering effect. Reduction of the IOP starts approximately 2 hours after the first administration with maximum effect reached after 12 hours. Travoprost ophthalmic solution may be used concomitantly with other topical ophthalmic drug products to lower IOP. If more than one topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes apart. One drop in the affected eye(s) once daily in the evening

3 DOSAGE FORMS AND STRENGTHS Ophthalmic solution containing travoprost 0.04 mg/mL. Ophthalmic solution containing travoprost 0.04 mg/mL

4 CONTRAINDICATIONS None. None

6 ADVERSE REACTIONS Most common adverse reaction (30% to 50%) is conjunctival hyperemia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Somerset Therapeutics, LLC at 1-800-417-9175 or the FDA at 1-800-FDA-1088 or www.fda.gov/ medwatch. 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. The most common adverse reaction observed in controlled clinical trials with 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 ophthalmic solution 0.004%, 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. Non-ocular 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. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post approval use of travoprost ophthalmic solution 0.004% 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 ophthalmic solution, 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.

8 USE IN SPECIFIC POPULATIONS 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 (8.4) 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies 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, travoprost ophthalmic solution should be administered 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% to 4% and of miscarriage is 15% to 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 (GD) 6 to 18, to target the period of organogenesis. At 10 mcg/kg (60 times the maximum recommended human ocular dose [MRHOD], based on estimated plasma C max ), 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 (18 times the MRHOD, based on estimated plasma C max ). The maternal NOAEL was 10 mcg/kg. An embryo-fetal study was conducted in pregnant mice administered travoprost once daily by SC injection from GD 6 to 11, to target the period of organogenesis. At 1 mcg/kg (6 times the MRHOD, based on estimated plasma C max ), travoprost caused postimplantation loss and decreased fetal weight. The no observed adverse effect level (NOAEL) for malformations was 0.3 mcg/kg (2 times the MRHOD, based on estimated plasma C max ). The maternal NOAEL was 1 mcg/kg. Pre/postnatal studies were conducted in rats administered travoprost once daily by subcutaneous injection from GD 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 (0.7 times the MRHOD, based on estimated plasma C max ), adverse pregnancy outcomes (embryo-fetal lethality, abortion, and 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 (0.6 times the MRHOD, based on estimated plasma C max ). The NOAEL for maternal toxicity was 0.72 mcg/kg (4 times the MRHOD, based on estimated plasma C max ). 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 radio-labeled travoprost and/or its metabolites were excreted in milk following subcutaneous administration. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for travoprost ophthalmic solution and any potential adverse effects on the breast-fed child from travoprost ophthalmic solution. 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. 8.6 H …

11 DESCRIPTION Travoprost is a synthetic prostaglandin F analog. Its chemical name is [1 R - [1α( Z ),2β(1 E ,3 R *),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl) phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethylester. It has a molecular formula of C 26 H 35 F 3 O 6 and a molecular weight of 500.55 g/mol. The chemical structure of travoprost is: Travoprost is a colorless to slightly yellow viscous oil that is freely soluble in acetonitrile, toluene, ethyl acetate and methanol; practically insoluble in hexane and in water. Travoprost ophthalmic solution, USP is supplied as sterile, buffered aqueous solution of travoprost with a pH of approximately 5.7 and an osmolality of approximately 290 mOsmol/kg. Travoprost ophthalmic solution, USP contains Active: travoprost 0.04 mg/mL; Inactives: polyoxyl 40 hydrogenated castor oil, boric acid, propylene glycol, sorbitol, zinc chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH), and water for injection. Preserved in the bottle with an ionic buffered system (boric acid, propylene glycol, sorbitol, zinc chloride). Image

16 HOW SUPPLIED/STORAGE AND HANDLING Travoprost ophthalmic solution, USP is a sterile, isotonic, buffered, preserved, aqueous solution of travoprost (0.04 mg/mL). Travoprost ophthalmic solution, USP is supplied as a 2.5 mL solution in a 5 mL and a 5 mL solution in a 10 mL natural LDPE bottle plugged with a natural LDPE nozzle, capped with turquoise colored HDPE cap and tamper-evident seal. 2.5 mL fill NDC 70069-586-01 5 mL fill NDC 70069-587-01 Storage: Store at 2°C to 25°C (36°F to 77°F). After opening, travoprost ophthalmic solution, USP can be used until the expiration date on the bottle.