Lotemax Gel

DESCRIPTION

LOTEMAX (loteprednol etabonateophthalmicgel) 0.5% contains a sterile, topicalcorticosteroidfor ophthalmic use. Loteprednol etabonate is a white to off-white powder.

Loterprednol etabonate is represented by the following structural formula:

Chemical Name:chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate

Each gram contains:

ACTIVE: Loteprednol Etabonate 5 mg (0.5%);

依地酸INACTIVES:硼酸、二钠二水合物,glycerin, polycarbophil, propylene glycol, sodium chloride, tyloxapol, water for injection, and sodium hydroxide to adjust to a pH of between 6 and 7.

PRESERVATIVE: benzalkonium chloride 0.003%.

INDICATIONS

LOTEMAX^®is a corticosteroid indicated for the treatment of post-operative inflammation and pain following ocular surgery.

DOSAGE AND ADMINISTRATION

Invert closed bottle and shake once to fill tip before instilling drops.

Apply one to two drops of LOTEMAX into the conjunctival sac of the affected eye four times daily beginning the day after surgery and continuing throughout the first 2 weeks of the post-operative period.

HOW SUPPLIED

Dosage Forms And Strengths

LOTEMAX (loteprednol etabonate ophthalmic gel) is a sterile preserved ophthalmic gel containing 5 mg of loteprednol etabonate per gram of gel.

Storage And Handling

LOTEMAX^®(loteprednol etabonate ophthalmic gel) 0.5%is a sterile ophthalmic gel supplied in a white low density polyethylene plastic bottle with a white controlled drop tip and a pink polypropylene cap in the following size:

5 g in a 10 mL bottle (NDC24208-503-07)

Storage:Store upright at 15° to 25° C (59° to 77° F).

Manufactured by:Bausch & Lomb Incorporated Tampa, FL 33637 USA. Revised: Apr 2020

SIDE EFFECTS

Adverse reactions associated with ophthalmic steroids 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.

The most common adverse drug reactions reported in the clinical trials (2-5%) were anterior chamber inflammation, eye pain, and foreign body sensation.

DRUG INTERACTIONS

No Information Provided

警告

Included as part of the"PRECAUTIONS"Section

PRECAUTIONS

Intraocular Pressure (IOP) Increase

Prolonged use of corticosteroids, including LOTEMAX, may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. Steroids should be used with caution in the presence of glaucoma. If this product is used for 10 days or longer, intraocular pressure should be monitored.

Cataracts

Use of corticosteroids may result in posterior subcapsular cataract formation.

Delayed Healing

The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. The initial prescription and 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.

Bacterial Infections

Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions of the eye, steroids may mask infection or enhance existing infection.

Viral Infections

Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids 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 steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Fungal cultures should be taken when appropriate.

Contact Lens Wear

Patients should not wear contact lenses during their course of therapy with LOTEMAX.

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 genotoxicin vitroin theAmes test, the mouselymphomatk assay, or in a chromosome aberration test in human lymphocytes, orin vivoin the single dose mouse micronucleus assay.

Treatment of female and male rats with doses ≥ 25 mg/kg/day of loteprednol etabonate (152 times the RHOD based on body surface area, assuming 100% absorption) prior to and during mating caused preimplantation loss and decreased the number of live fetuses/live births. The NOAEL for fertility in rats was 5 mg/kg/day (30 times the RHOD).

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 ≥1.2 times the recommended human ophthalmic dose (RHOD) and to pregnant rats at doses ≥ 30 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 times the RHOD. Maternal toxicity was observed in rats at doses ≥ 304 times the RHOD, and a maternal no observedadverse effectlevel (NOAEL) was established at 30 times the RHOD.

The background risk of major birth defects andmiscarriagefor the indicated population is unknown. However, 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 doses ≥ 0.1 mg/kg (1.2 times the recommended human ophthalmic dose (RHOD) based on body surface area, assuming 100% absorption).Spina bifida(includingmeningocele) was observed at doses ≥ 0.1 mg/kg, and exencephaly and craniofacial malformations were observed at doses ≥ 0.4 mg/kg (4.9 times the RHOD). At 3 mg/kg (36 times the RHOD), loteprednol etabonate was associated with increased incidences of abnormal left commoncarotid artery, limb flexures, umbilicalhernia,scoliosis, and delayedossification.Abortionand embryofetal lethality (resorption) occurred at doses ≥ 6 mg/kg (73 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 doses ≥ 5 mg/kg (30 times the RHOD); andcleft palate, agnathia,cardiovascular缺陷,脐疝,减少胎儿的身体ight and decreased skeletal ossification at doses ≥ 50 mg/kg (304 times the RHOD). Embryofetal lethality (resorption) was observed at 100 mg/kg (608 times the RHOD). The NOAEL for developmental toxicity in rats was 0.5 mg/kg (3 times the RHOD). Loteprednol etabonate was maternally toxic (reduced body weight gain) at doses of ≥ 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 doses ≥ 0.5 mg/kg (3 times the clinical dose), reduced survival was observed in live-born offspring. Doses ≥ 5 mg/kg (30 times the RHOD) caused umbilical hernia/incompletegastrointestinal tract. Doses ≥ 50 mg/kg (304 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 LOTEMAX and any potential adverse effects on the breastfed infant from LOTEMAX.

Pediatric Use

The safety and effectiveness of LOTEMAX have been established in the pediatric population. Use of LOTEMAX in this population is supported by evidence from adequate and well-controlled trials of LOTEMAX in adults with additional data from a safety and efficacy trial in pediatric patients from birth to 11 years of age [seeClinical Studies].

Geriatric Use

No overall differences in safety and effectiveness have been observed between elderly and younger patients.

OVERDOSE

No Information Provided

CONTRAINDICATIONS

LOTEMAX is contraindicated in most viral diseases of thecorneaandconjunctivaincludingepithelialherpessimplexkeratitis(dendritickeratitis),vaccinia, andvaricella, in mycobacterial infection of the eye and fungal diseases ofocularstructures.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Corticosteroids inhibit theinflammatory responseto a variety of inciting agents and probably delay or slow healing. They inhibit the edema,fibrindeposition,capillarydilation, leukocyte migration, capillary proliferation,fibroblastproliferation, deposition ofcollagen, and scar formation associated with inflammation. While glucocorticoids are known to bind to and activate theglucocorticoidreceptor, the molecular mechanisms involved in glucocorticoid/glucocorticoid receptor-dependent modulation of inflammation are not clearly established. However, corticosteroids are thought to inhibitprostaglandinproduction through several independent mechanisms.

Pharmacokinetics

Loteprednol etabonate islipid可溶的nd can penetrate into cells. Loteprednol etabonate is synthesized through structural modifications of prednisolone-related compounds so that it will undergo a predictable transformation to an inactive metabolite. Based uponin vivoandin vitropreclinicalmetabolismstudies, loteprednol etabonate undergoes extensive metabolism to the inactive carboxylic acid metabolites, PJ-91 and PJ-90. The systemic exposure to loteprednol etabonate following ocular administration of LOTEMAX has not been studied in humans.

Clinical Studies

Adult Studies

In two randomized, multicenter,double-masked, parallel-group, vehicle-controlled studies in 813 subjects with post-operative inflammation, LOTEMAX was more effective compared to its vehicle in resolvinganterior chamberinflammation and pain followingcataract surgery. Primary endpoints were completeresolutionofanteriorchamber cells (cell count of 0) and no pain at post-operative day 8.

In these studies, LOTEMAX had a statistically significant higher incidence of subjects with complete clearing of anterior chamber cells (31% vs. 14-16%) and were pain-free at post-operative day 8 (73-76% vs. 42-46%).

Pediatric Study

The safety and effectiveness of LOTEMAX were evaluated in a pediatric study of patients from birth to less than 11 years of age (mean age of 3 years) undergoingcataractsurgery. Patients were randomized to receive either LOTEMAX (54 patients) or prednisolone acetate ophthalmic suspension 1% (53 patients) four times daily for 14 days. At Day 14, the percentages of patients with complete clearing of anterior chamber inflammation were 57% in the LOTEMAX group and 63% in the prednisolone group.

PATIENT INFORMATION

Administration

Invertclosed bottle and shake once to fill tip before instilling drops.

Risk Of Contamination

Advise patients not to allow the dropper tip to touch any surface, as this may contaminate the gel.

Contact Lens Wear

Advise patients not to wear contact lenses when using LOTEMAX.

Risk Of Secondary Infection

Advise the patient to consult a physician if pain develops, redness, itching or inflammation becomes aggravated.