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 ophthalmic solution (ionic buffered solution) 0.004% can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly [see patient counseling information ( 17 )]. 5.2 eyelash changes travoprost ophthalmic solution (ionic buffered solution) 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 [see patient counseling information (17)]. 5.3 intraocular inflammation travoprost ophthalmic solution (ionic buffered solution) 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. travoprost ophthalmic solution (ionic buffered solution) 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 angle-closure, inflammatory or neovascular glaucoma travoprost ophthalmic solution (ionic buffered solution) has not been evaluated for the treatment of angle-closure, inflammatory or neovascular glaucoma. 5.6 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 [see patient counseling information ( 17 )]. 5.7 use with contact lenses contact lenses should be removed prior to instillation of travoprost ophthalmic solution (ionic buffered solution) and may be reinserted 15 minutes following its administration.

ion, pain, and pruritus. ocular adverse reactions reported at an incidence of 1% to 4% in clinical trials with travoprost ophthalmic solution or travoprost ophthalmic solution (ionic buffered solution) 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 or travoprost ophthalmic solution (ionic buffered solution) 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 travoprost ophthalmic solution (ionic buffered 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.

on, 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 post-implantation 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 mhrod, based on estimated plasma c max ). the noael for maternal toxicity was 0.72 mcg/kg (4 times the mhrod, 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 0.004% and any potential adverse effects on the breast-fed child from travoprost ophthalmic solution 0.004%. 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 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.

dministered 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 post-implantation 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 mhrod, based on estimated plasma c max ). the noael for maternal toxicity was 0.72 mcg/kg (4 times the mhrod, based on estimated plasma c max ).

nificant 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.

) 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.

max ). at 10 mcg/kg/day (60 times the mrhod, based on estimated plasma c max ), the mean number of corpora lutea was reduced, and the post-implantation losses were increased.

60 times the mrhod, based on estimated plasma c max ), the mean number of corpora lutea was reduced, and the post-implantation losses were increased.

uctures, fingers, or any other surface in order to avoid contamination of the solution by common bacteria known to cause ocular infections. serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see warnings and precautions (5.6)]. when to seek physician advice advise the patient that if they develop an intercurrent ocular condition (e.g., trauma or infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of travoprost ophthalmic solution (ionic buffered solution) [see warnings and precautions (5.3, 5.4, 5.5)]. use with contact lenses contact lenses should be removed prior to instillation of travoprost ophthalmic solution (ionic buffered solution) and may be reinserted 15 minutes following its administration [see warnings and precautions (5.7)]. use with other ophthalmic drugs if more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes between applications. rx only * timoptic is a registered trademark of merck & co., inc. manufactured by: apotex inc. toronto, ontario canada, m9l 1t9 manufactured for: apotex corp. weston, florida 33326 march 2021 marketed/packaged by: gsms, inc. camarillo, ca usa 93012