Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2011 Publisher: Alcon Laboratories (UK) Ltd Pentagon Park Boundary Way Hemel Hempstead Herts HP2 7UD United Kingdom
Pharmacotherapeutic group: decongestants and antiallergics; other antiallergics
ATC code: S01GX06
Emedastine is a potent selective and topically effective histamine H1 antagonist (Ki = 1.3 nM). In vitro examinations of emedastine’s affinity for histamine receptors (H1, H2, and H3) demonstrate 10,000-fold selectivity for the H1 receptor, Ki's = 1.3 nM, 49,064 nM and 12, 430 nM, respectively. In vivo topical ocular administration of emedastine produces a concentration-dependent inhibition of histamine-stimulated conjunctival vascular permeability. Studies with emedastine have not shown effects on adrenergic, dopaminergic, and serotonin receptors.
Emedastine is absorbed systemically, as are other topically administered drug substances. In a study involving ten normal volunteers dosed bilaterally twice daily for 15 days with EMADINE 0.5 mg/ml eye drops solution, plasma concentrations of the parent compound were generally below the quantitation limit of the assay (0.3 ng/ml). Samples in which emedastine was quantifiable ranged from 0.30 to 0.49 ng/ml.
The human oral bioavailability of emedastine is approximately 50% and maximum plasma concentrations were achieved within one-two hours after dosing.
Emedastine is principally metabolised by the liver. The elimination half-life of topical emedastine is ten hours. Approximately 44% of an oral dose is recovered in the urine over 24 hours, with only 3.6% of the dose excreted as parent drug substance. Two primary metabolites, 5-and 6-hydroxyemedastine, are excreted in the urine as both free and conjugated forms. The 5′-oxo analogues of 5-and 6-hydroxyemedastine and the N-oxide are also formed as minor metabolites.
Emedastine difumarate demonstrated low acute toxicity in a number of species by various routes of administration. No clinically significant local or systemic effects were observed in long-term topical ocular studies in rabbits.
Corneal limbal mononuclear cell infiltrates were noted in ¼ male monkeys treated with 0.5 mg/ml and in 4/4 males and ¼ females treated with1.0 mg/ml. Scleral mononuclear cell infiltrates were present in ¼ males and ¼ females treated with 0.5 mg/ml and in 2/4 males and ¼ females treated with1.0 mg/ml. Mean peak plasma levels were approximately 1 ng/ml and 2 ng/ml for the 0.5 and 1.0 mg/ml treatments respectively.
Emedastine was found to increase the QT interval in dogs; the NOEL corresponds to levels 23-fold higher than those found in patients (7 ng/ml as compared with 0.3 ng/ml, i.e., the limit of detection for emedastine).
Emedastine difumarate was not found to be carcinogenic in studies in mice and rats. Emedastine difumarate was not genotoxic in a standard battery of in vitro and in vivo genotoxicity assays.
In a teratology study in rats, foetotoxic but not teratogenic effects were observed at the highest dose evaluated (140 mg/kg/day); no effects were observed at a lower level (40 mg/kg/day) which corresponds to an exposure well in excess of that produced by the therapeutic recommended dose. No reproductive toxicity was observed in a study in rabbits.
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