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EYSUVIS (loteprednol etabonate ophthalmic suspension) 0.25%, for topical ophthalmic use BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE EYSUVIS is a corticosteroid indicated for the short-term (up to two weeks) treatment of the signs and symptoms of dry eye disease. CONTRAINDICATIONS EYSUVIS, as with other ophthalmic corticosteroids, is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. WARNINGS AND PRECAUTIONS Delayed Healing and Corneal Perforation—Topical corticosteroids have been known to delay healing and cause corneal and scleral thinning. Use of topical corticosteroids in the presence of thin corneal or scleral tissue may lead to perforation. The initial prescription and each renewal of the medication order should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy, and, where appropriate, fluorescein staining. Intraocular Pressure (IOP) Increase—Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, as well as defects in visual acuity and fields of vision. Corticosteroids should be used with caution in the presence of glaucoma. Renewal of the medication order should be made by a physician only after examination of the patient and evaluation of the IOP. Cataracts—Use of corticosteroids may result in posterior subcapsular cataract formation. Bacterial Infections—Use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions of the eye, corticosteroids may mask infection or enhance existing infection. Viral Infections—Use of corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular corticosteroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Fungal Infections—Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local corticosteroid application. Fungus invasion must be considered in any persistent corneal ulceration where a corticosteroid has been used or is in use. Fungal cultures should be taken when appropriate. Risk of Contamination—Do not to allow the dropper tip to touch any surface, as this may contaminate the suspension. Contact Lens Wear—The preservative in EYSUVIS may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of EYSUVIS and may be reinserted 15 minutes following administration. ADVERSE REACTIONS Adverse reactions associated with ophthalmic corticosteroids include elevated intraocular pressure, which may be associated with infrequent optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, delayed wound healing and secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera. 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 clinical trials with EYSUVIS was instillation site pain, which was reported in 5% of patients. USE IN SPECIFIC POPULATIONS Pregnancy—Risk Summary: There are no adequate and well controlled studies with loteprednol etabonate in pregnant women. Loteprednol etabonate produced teratogenicity at clinically relevant doses in the rabbit and rat when administered orally during pregnancy. Loteprednol etabonate produced malformations when administered orally to pregnant rabbits at doses 1.4 times the recommended human ophthalmic dose (RHOD) and to pregnant rats at doses 34 times the RHOD. In pregnant rats receiving oral doses of loteprednol etabonate during the period equivalent to the last trimester of pregnancy through lactation in humans, survival of offspring was reduced at doses 3.4 times the RHOD. Maternal toxicity was observed in rats at doses 347 times the RHOD, and a maternal no observed adverse effect level (NOAEL) was established at 34 times the RHOD. The background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. Data—Animal Data: Embryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral gavage on gestation days 6 to 18, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations at 0.1 mg/kg (1.4 times the recommended human ophthalmic dose (RHOD) based on body surface area, assuming 100% absorption). Spina bifida (including meningocele) was observed at 0.1 mg/kg, and exencephaly and craniofacial malformations were observed at 0.4 mg/kg (5.6 times the RHOD). At 3 mg/kg (41 times the RHOD), loteprednol etabonate was associated with increased incidences of abnormal left common carotid artery, limb flexures, umbilical hernia, scoliosis, and delayed ossification. Abortion and embryofetal lethality (resorption) occurred at 6 mg/kg (83 times the RHOD). A NOAEL for developmental toxicity was not established in this study. The NOAEL for maternal toxicity in rabbits was 3 mg/kg/day. Embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral gavage on gestation days 6 to 15, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations, including absent innominate artery at 5 mg/kg (34 times the RHOD); and cleft palate, agnathia, cardiovascular defects, umbilical hernia, decreased fetal body weight and decreased skeletal ossification at 50 mg/kg (347 times the RHOD). Embryofetal lethality (resorption) was observed at 100 mg/kg (695 times the RHOD). The NOAEL for developmental toxicity in rats was 0.5 mg/kg (3.4 times the RHOD). Loteprednol etabonate was maternally toxic (reduced body weight gain) at 50 mg/kg/day. The NOAEL for maternal toxicity was 5 mg/kg. A peri-/postnatal study was conducted in rats administered loteprednol etabonate by oral gavage from gestation day 15 (start of fetal period) to postnatal day 21 (the end of lactation period). At 0.5 mg/kg (3.4 times the clinical dose), reduced survival was observed in live-born offspring. Doses ≥ 5 mg/kg (34 times the RHOD) caused umbilical hernia/incomplete gastrointestinal tract. Doses ≥ 50 mg/kg (347 times the RHOD) produced maternal toxicity (reduced body weight gain, death), decreased number of live-born offspring, decreased birth weight, and delays in postnatal development. A developmental NOAEL was not established in this study. The NOAEL for maternal toxicity was 5 mg/kg. Lactation—There are no data on the presence of loteprednol etabonate in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered, along with the mother's clinical need for EYSUVIS and any potential adverse effects on the breastfed infant from EYSUVIS. Pediatric Use—Safety and effectiveness in pediatric patients have not been established. Geriatric Use—No overall differences in safety and effectiveness have been observed between elderly and younger adult patients. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility—Long-term animal studies have not been conducted to evaluate the carcinogenic potential of loteprednol etabonate. Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse lymphoma thymidine kinase (tk) assay, in a chromosome aberration test in human lymphocytes, or in vivo in the single dose mouse micronucleus assay. Treatment of male and female rats with 25 mg/kg/day of loteprednol etabonate (174 times the RHOD based on body surface area, assuming 100% absorption) prior to and during mating caused pre-implantation loss and decreased the number of live fetuses/live births. The NOAEL for fertility in rats was 5 mg/kg/day (34 times the RHOD). For a copy of the Full Prescribing Information, please visit www.EYSUVIS.com. Manufactured for: Kala Pharmaceuticals, Inc. Watertown, MA 02472 Part # 2026R02 Marks designated by TM or ® are owned by Kala Pharmaceuticals, Inc. Patented. www.kalarx.com/patents © 2020 Kala Pharmaceuticals, Inc. All rights reserved. October 2020 Kala ® US-EYS-2000115

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