Source: FDA, National Drug Code (US) Revision Year: 2022
Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid.
Arachidonic acid is released from membrane phospholipids by phospholipase A2. Corticosteroids are capable of producing a rise in intraocular pressure.
Loteprednol etabonate is structurally similar to other corticosteroids. However, the number 20 position ketone group is absent.
The anti-infective component in the combination (tobramycin) is included to provide action against susceptible organisms. In vitro studies have demonstrated that tobramycin is active against susceptible strains of the following microorganisms:
Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains.
Streptococci, including some of the Group A-beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumoniae. Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus mirabilis, Morganella morganii, most Proteus vulgaris strains, Haemophilus influenzae and H. aegyptius, Moraxella lacunata, Acinetobacter calcoaceticus and some Neisseria species.
In a controlled clinical study of ocular penetration, the levels of loteprednol etabonate in the aqueous humor were found to be comparable between LOTEMAX and ZYLET treatment groups.
Results from a bioavailability study in normal volunteers established that plasma levels of loteprednol etabonate and Δ1 cortienic acid etabonate (PJ 91), its primary, inactive metabolite, were below the limit of quantitation (1 ng/mL) at all sampling times.
The results were obtained following the ocular administration of one drop in each eye of 0.5% loteprednol etabonate ophthalmic suspension 8 times daily for 2 days or 4 times daily for 42 days. This study suggests that limited (<1 ng/mL) systemic absorption occurs with 0.5% loteprednol etabonate.
Long-term animal studies have not been conducted to evaluate the carcinogenic potential of loteprednol etabonate or tobramycin.
Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse lymphoma TK assay, a chromosome aberration test in human lymphocytes, or in an in vivo mouse micronucleus assay.
Oral treatment of female and male rats with 25 mg/kg/day of loteprednol etabonate (67 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 (13 times the RHOD). Subcutaneous administration of male and female rats with tobramycin did not affect mating behavior or cause impairment of fertility at 100 mg/kg/day (450 times the RHOD based on body surface area, assuming 100% absorption).
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