Levocabastine

Levocabastine is a potent, fast-acting and highly selective histamine H1-antagonist with a sustained duration of action.

After topical application to the eyes, it almost immediately and for several hours relieves the typical symptoms of allergic conjunctivitis (itching, redness, chemosis, eyelid swelling, tearing).

After topical application to the nose, it almost immediately and for several hours relieves the typical symptoms of allergic rhinitis (sneezing, itchy nose, rhinorrhoea).

After intranasal and ocular application, the absorption of levocabastine is incomplete with a systemic bioavailability ranging from 60 to 80% for the nasal spray and from 30 to 60% for the eye drops. However, as the amount of levocabastine applied intranasally and ocularly is small, the levocabastine plasma concentrations achieved are very low. Steady-state concentrations of levocabastine are attained within 7 to 10 days following multiple dosage and are predictable from single-dose pharmacokinetics.

Levocabastine undergoes minimal hepatic metabolism, i.e. ester glucuronidation, and is predominantly cleared by the kidneys. 70% of the parent drug is recovered unchanged in the urine, and 10% of the dose is excreted in the urine as the acylglucuronide of levocabastine. The remaining 20% is excreted unchanged in the faeces.

After single intravenous dosing, levocabastine is rapidly distributed over the tissues, and the terminal half-life is 33 h. The total steady-state volume of distribution is 82 L (1.14 L/kg) with a total plasma clearance of 30 mL/min.

Given the extremely low plasma concentrations after ocular application, a dose adjustment is unlikely to be required in patients with renal impairment receiving levocabastine eye drops. However, dose reduction should be considered in patients with renal disease during prolonged treatment with levocabastine nasal spray. As hepatic metabolism of levocabastine is negligible, dose adjustments in patients with impaired hepatic function should not be necessary.

The plasma protein binding of levocabastine is 55% with albumin being the main binding protein.

Special populations

Elderly: In the elderly, after multiple nasal administrations of 0.4mg levocabastine for 14 days, the terminal half-life of levocabastine was increased by 15% and the peak plasma level was increased by 26%.

Renal impairment: After a single oral dose of 0.5mg levocabastine in solution, the terminal half-life of levocabastine in moderate to severe renal impairment (Creatinine Clearance 10–50mL/min) increased from 36 hours to 95 hours. Overall exposure to levobabastine based on AUC was increased by 56%.

Non-clinical data based on conventional studies with acute doses (application by oral, intravenous, inhalation, and dermal) or with repeated doses (effective orally, intravenously, in the eye or skin) involving eye irritation, skin sensitization, cardiovascular oral pharmacology, oral reproduction, genotoxicity, and oral cancer studies did not reveal any drug-related hazard. Effects were only observed in cases of exposure in excess of the maximum recommended human dose, indicating the small clinical utility of these effects.

In mice, rats and rabbits, levocabastine, at systemic doses up to 1,250 times (on a mg/kg basis) the recommended maximum nasal dose, did not reveal any embryotoxic or teratogenic effects. In rodents, levocabastine at systemic doses greater than 2,500 times (on a mg/kg basis) of the recommended maximum nasal dose, teratogenicity and/or increased fetal absorption were observed.