tment should be informed of the possibility of increased pigmentation. beyond 5 years the effects of increased pigmentation are not known [ see clinical studies (14.2) ]. 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 latanoprost ophthalmic solution can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. 5.2 eyelash changes latanoprost ophthalmic solution may gradually change eyelashes and vellus hair in the treated eye; these changes include increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected growth of eyelashes. eyelash changes are usually reversible upon discontinuation of treatment. 5.3 intraocular inflammation latanoprost ophthalmic solution should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular inflammation because inflammation may be exacerbated. 5.4 macular edema macular edema, including cystoid macular edema, has been reported during treatment with latanoprost ophthalmic solution. latanoprost ophthalmic 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 herpetic keratitis reactivation of herpes simplex keratitis has been reported during treatment with latanoprost ophthalmic solution. latanoprost ophthalmic solution should be used with caution in patients with a history of herpetic keratitis. latanoprost ophthalmic solution should be avoided in cases of active herpes simplex keratitis because inflammation may be exacerbated. 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. 5.7 contact lens use latanoprost ophthalmic solution contains benzalkonium chloride, which may be absorbed by contact lenses. contact lenses should be removed prior to the administration of latanoprost ophthalmic solution, and may be reinserted 15 minutes after administration.

ministered at least five (5) minutes apart. contact lenses should be removed prior to the administration of latanoprost ophthalmic solution, and may be reinserted 15 minutes after administration. one drop in the affected eye(s) once daily in the evening. ( 2 )

erience because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. latanoprost ophthalmic solution was studied in three multicenter, randomized, controlled clinical trials. patients received 50 mcg/ml latanoprost ophthalmic solution once daily or 5 mg/ml active-comparator (timolol) twice daily. the patient population studied had a mean age of 65±10 years. seven percent of patients withdrew before the 6-month endpoint. table 1: ocular adverse reactions and ocular signs/symptoms reported by 5–15% of patients receiving latanoprost symptom/finding adverse reactions (incidence (%)) latanoprost (n=460) timolol (n=369) foreign body sensation 13 8 punctate keratitis 10 9 stinging 9 12 conjunctival hyperemia 8 3 blurred vision 8 8 itching 8 8 burning 7 8 increased pigmentation of the iris 7 0 less than 1% of the patients treated with latanoprost ophthalmic solution required discontinuation of therapy because of intolerance to conjunctival hyperemia. table 2: adverse reactions that were reported in 1–5% of patients receiving latanoprost adverse reactions (incidence (%)) latanoprost (n=460) timolol (n=369) ocular events/signs and symptoms excessive tearing 4 6 eyelid discomfort/pain 4 2 dry eye 3 3 eye pain 3 3 eyelid margin crusting 3 3 erythema of the eyelid 3 2 photophobia 2 1 eyelid edema 1 3 blepharitis 1 3 systemic events upper respiratory tract infection/nasopharyngitis/influenza 3 3 myalgia/arthralgia/back pain 1 0.5 rash/allergic skin reaction 1 0.3 6.2 postmarketing experience the following reactions have been identified during postmarketing use of latanoprost ophthalmic solution in clinical practice. because they are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. the reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to latanoprost ophthalmic solution, or a combination of these factors, include: nervous system disorders : dizziness; headache; toxic epidermal necrolysis eye disorders : eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation, and number of eyelashes); keratitis; corneal edema and erosions; intraocular inflammation (iritis/uveitis); macular edema, including cystoid macular edema; trichiasis; periorbital and lid changes resulting in deepening of the eyelid sulcus; iris cyst; eyelid skin darkening; localized skin reaction on the eyelids; conjunctivitis; pseudopemphigoid of the ocular conjunctiva respiratory, thoracic and mediastinal disorders : asthma and exacerbation of asthma; dyspnea skin and subcutaneous tissue disorders : pruritus infections and infestations : herpes keratitis cardiac disorders : angina; palpitations; angina unstable general disorders and administration site conditions : chest pain

velopmental toxicity. post-implantation loss due to late resorption was shown at doses ≥0.2 mcg/kg/day (equivalent to 1.3 times the maximum recommended human ophthalmic dose [rhod], on a mg/m 2 basis, assuming 100% absorption). spina bifida and abortion occurred at 5 mcg/kg/day (equivalent to 32 times the maximum rhod). total litter loss due to early resorption was observed at doses ≥50 mcg/kg/day (324 times the maximum rhod). transient signs of maternal toxicity were observed after iv dosing (increased breathing, muscle tremors, slight motor incoordination) at 300 mcg/kg/day (1,946 times the maximum rhod). no maternal toxicity was observed at doses up to 50 mcg/kg/day. embryofetal studies were conducted in pregnant rats administered latanoprost daily by iv injection on gestation days 6 through 15, to target the period of organogenesis. a noael for rat developmental toxicity was not established. cleft palate was observed at 1 mcg/kg (equivalent to 3.2 times the maximum rhod, on a mg/m 2 basis, assuming 100% absorption). brain porencephalic cyst(s) were observed ≥50 mcg/kg (162 times the maximum rhod). skeletal anomalies were observed at 250 mcg/kg (811 times the maximum rhod). no maternal toxicity was detectable at 250 mcg/kg/day. prenatal and postnatal development was assessed in rats. pregnant rats were administered latanoprost daily by iv injection from gestation day 15, through delivery, until weaning (lactation day 21). no adverse effects on rat offspring were observed at doses up to 10 mcg/kg/day (32 times the maximum rhod, on a mg/m 2 basis, assuming 100% absorption). at 100 mcg/kg/day (324 times the maximum rhod), maternal deaths and pup mortality occurred. 8.2 lactation risk summary 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 latanoprost ophthalmic solution is administered to a nursing woman. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for latanoprost ophthalmic solution and any potential adverse effects on the breastfed child from latanoprost ophthalmic solution. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use no overall differences in safety or effectiveness have been observed between elderly and younger patients.

lantation loss due to late resorption was shown at doses ≥0.2 mcg/kg/day (equivalent to 1.3 times the maximum recommended human ophthalmic dose [rhod], on a mg/m 2 basis, assuming 100% absorption). spina bifida and abortion occurred at 5 mcg/kg/day (equivalent to 32 times the maximum rhod). total litter loss due to early resorption was observed at doses ≥50 mcg/kg/day (324 times the maximum rhod). transient signs of maternal toxicity were observed after iv dosing (increased breathing, muscle tremors, slight motor incoordination) at 300 mcg/kg/day (1,946 times the maximum rhod). no maternal toxicity was observed at doses up to 50 mcg/kg/day. embryofetal studies were conducted in pregnant rats administered latanoprost daily by iv injection on gestation days 6 through 15, to target the period of organogenesis. a noael for rat developmental toxicity was not established. cleft palate was observed at 1 mcg/kg (equivalent to 3.2 times the maximum rhod, on a mg/m 2 basis, assuming 100% absorption). brain porencephalic cyst(s) were observed ≥50 mcg/kg (162 times the maximum rhod). skeletal anomalies were observed at 250 mcg/kg (811 times the maximum rhod). no maternal toxicity was detectable at 250 mcg/kg/day. prenatal and postnatal development was assessed in rats. pregnant rats were administered latanoprost daily by iv injection from gestation day 15, through delivery, until weaning (lactation day 21). no adverse effects on rat offspring were observed at doses up to 10 mcg/kg/day (32 times the maximum rhod, on a mg/m 2 basis, assuming 100% absorption). at 100 mcg/kg/day (324 times the maximum rhod), maternal deaths and pup mortality occurred.

first hour after local administration. studies in man indicate that the peak concentration in the aqueous humor is reached about two hours after topical administration. elimination metabolism latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the biologically active acid. the active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation. excretion the elimination of the acid of latanoprost from human plasma is rapid (t ½ = 17 min) after both iv and topical administration. systemic clearance is approximately 7 ml/min/kg. following hepatic β-oxidation, the metabolites are mainly eliminated via the kidneys. approximately 88% and 98% of the administered dose are recovered in the urine after topical and iv dosing, respectively.

rance is approximately 7 ml/min/kg. following hepatic β-oxidation, the metabolites are mainly eliminated via the kidneys. approximately 88% and 98% of the administered dose are recovered in the urine after topical and iv dosing, respectively.

atients continued to show signs of increasing iris pigmentation throughout the 5 years of the study. observation of increased iris pigmentation did not affect the incidence, nature, or severity of adverse events (other than increased iris pigmentation) recorded in the study. iop reduction was similar regardless of the development of increased iris pigmentation during the study.

nfections. serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [s ee warnings and precautions (5.6) ]. when to seek physician advice advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection) or 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 the multiple-dose container. contact lens use advise patients that latanoprost ophthalmic solution contains benzalkonium chloride, which may be absorbed by contact lenses. contact lenses should be removed prior to administration of the solution. lenses may be reinserted 15 minutes following administration of latanoprost ophthalmic solution. use with other ophthalmic drugs advise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. if a dose is missed advise patients that if one dose is missed, treatment should continue with the next dose as normal. distributed by: bausch & lomb americas inc. bridgewater, nj 08807 usa © 2022 bausch & lomb incorporated or its affiliates 9144712 (folded) 9144812 (flat)