Flunarizine

Class IV selective calcium entry blocker, which reduces arterial and arteriolar smooth muscle spasm.

The drug is well absorbed reaching peak plasma concentrations within 2-4 hours, and reaching steady state at 5-6 weeks.

Absorption

Flunarizine is well absorbed (>80%) from the gastrointestinal tract, reaching peak plasma concentrations within 2 to 4 hours after oral dosing. Under conditions of reduced gastric acidity (higher gastric pH), bioavailability may be moderately lower.

Distribution

Flunarizine is >99% bound to plasma proteins. It has a large volume of distribution of approximately 78 L/kg in healthy subjects and approximately 207 L/kg in epileptic patients indicating extensive distribution into extravascular tissue. The drug quickly crosses the blood brain barrier; concentrations in the brain are approximately 10 times higher than those in plasma.

Metabolism

Flunarizine is metabolised in the liver into at least 15 metabolites. The primary metabolic pathway is CYP2D6.

Elimination

Flunarizine is primarily eliminated as parent drug and metabolites through the faeces via bile. Within 24 to 48 hours after administration, approximately 3% to 5% of the administered dose of flunarizine is eliminated in the faeces as parent drug and metabolites and <1% is excreted as unchanged drug in urine. Its terminal elimination half-life is highly variable, ranging from 5 to 15 hours in most individual subjects after a single dose. Some subjects show measurable plasma concentrations of flunarizine (>0.5 ng/mL) for a prolonged time period (up to 30 days), possibly due to redistribution of the drug from other tissues.

Plasma concentrations of flunarizine reach steady state after approximately 8 weeks of once-daily multiple dosing and are about 3-fold higher than those observed after a single dose. Steady state flunarizine concentrations are proportional over a dose range of 5 mg to 30 mg.

Preclinical effects of a CNS nature (e.g. sedation, salivation, ataxia) were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.