, to target the period of organogenesis. Loteprednol etabonate produced fetalmalformations, including absent innominate artery at 5 mg/kg (106 times the RHOD); and cleft palate, agnathia,cardiovascular defects, umbilical hernia, decreased fetal body weight and decreased skeletal ossification at 50mg/kg (1066 times the RHOD). Embryofetal lethality (resorption) was observed at 100 mg/kg (2133 times theRHOD). The NOAEL for developmental toxicity in rats was 0.5 mg/kg (10.6 times the RHOD). Loteprednoletabonate was maternally toxic (reduced body weight gain) at 50 mg/kg/day. The NOAEL for maternal toxicitywas 5 mg/kg.
A peri-/postnatal study was conducted in rats administered loteprednol etabonate by oral gavage from gestationday 15 (start of fetal period) to postnatal day 21 (the end of lactation period). At 0.5 mg/kg (10.6 times theclinical dose), reduced survival was observed in live-born offspring. Doses ≥ 5 mg/kg (106 times the RHOD)
caused umbilical hernia/incomplete gastrointestinal tract. Doses ≥ 50 mg/kg (1066 times the RHOD) producedmaternal toxicity (reduced body weight gain, death), decreased number of live-born offspring, decreased birthweight, and delays in postnatal development. A developmental NOAEL was not established in this study. TheNOAEL for maternal toxicity was 5 mg/kg.
8.2 Lactation
There are no data on the presence of loteprednol etabonate in human milk, the effects on the breastfed infant, orthe effects on milk production. The developmental and health benefits of breastfeeding should be considered,along with the mother’s clinical need for LOTEMAX® SM and any potential adverse effects on the breastfed
infant from LOTEMAX® SM.
8.4 Pediatric Use
Safety and effectiveness of LOTEMAX® SM in pediatric patients have not been established.
8.5 Geriatric Use
No overall differences in safety and effectiveness have been observed between elderly and younger patients.
11 DESCRIPTION
LOTEMAX® SM (loteprednol etabonate ophthalmic gel) 0.38% contains a sterile, topical corticosteroid forophthalmic use. Loteprednol etabonate is a white to off-white powder.
Loteprednol etabonate is represented by the following structural formula:
Chemical Name:
chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylateEach gram contains:
Active: loteprednol etabonate 3.8 mg (0.38%);Inactives: boric acid, edetate disodium dihydrate, glycerin, hypromellose, poloxamer, polycarbophil,propylene glycol, sodium chloride, water for injection, and sodium hydroxide to adjust to a pH of between 6and 7.
Preservative: benzalkonium chloride 0.003%
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Loteprednol etabonate is a corticosteroid. Corticosteroids have been shown to inhibit the inflammatory responseto a variety of inciting agents. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration,capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated withinflammation. While glucocorticoids are known to bind to and activate the glucocorticoid receptor, themolecular mechanisms involved in glucocorticoid/glucocorticoid receptor-dependent modulation ofinflammation are not clearly established. However, corticosteroids are thought to inhibit prostaglandin
production through several independent mechanisms.
12.3 Pharmacok |
