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Emadine 0.05% w/v, Eye drops, Solution (2011)

Active ingredients: Emadine

Pharmacodynamic properties

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.

Pharmacokinetic properties

Absorption

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.

Metabolism

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.

Preclinical safety data

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.