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THERAPEUTIC CLASS: ARCOXIA (etoricoxib) is a member of a class of arthritis/analgesia medications called Coxibs. ARCOXIA is a highly selective inhibitor of cyclooxygenase-2 (COX-2).
Pharmacology: Pharmacodynamics: Mechanism of Action: Etoricoxib is an oral, selective cyclooxygenase-2 (COX-2) inhibitor within the clinical dose range.
Across clinical pharmacology studies, ARCOXIA produced dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily. Etoricoxib did not inhibit gastric prostaglandin synthesis and had no effect on platelet function.
Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by pro-inflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function, and central nervous system functions (fever induction, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in man but its relevance to ulcer healing has not been established.
Pharmacokinetics: Absorption: Orally administered etoricoxib is well absorbed. The absolute bioavailability is approximately 100%. Following 120-mg once-daily dosing to steady state, the peak plasma concentration (geometric mean Cmax = 3.6 mcg/mL) was observed at approximately 1 hour (Tmax) after administration to fasted adults. The geometric mean area under the curve (AUC0-24hr) was 37.8 mcg·hr/mL. The pharmacokinetics of etoricoxib are linear across the clinical dose range.
Dosing with food (a high-fat meal) had no effect on the extent of absorption of etoricoxib after administration of a 120-mg dose. The rate of absorption was affected, resulting in a 36% decrease in Cmax and an increase in Tmax by 2 hours. These data are not considered clinically significant. In clinical trials, etoricoxib was administered without regard to food intake.
Distribution: Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of 0.05 to 5 mcg/mL. The volume of distribution at steady state (Vdss) is approximately 120 L in humans.
Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.
Metabolism: Etoricoxib is extensively metabolized with <1% of a dose recovered in urine as the parent drug. The major route of metabolism to form the 6'-hydroxymethyl derivative is catalyzed by CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles in vivo have not been studied.
Five metabolites have been identified in man. The principal metabolite is the 6'-carboxylic acid derivative of etoricoxib formed by further oxidation of the 6'-hydroxymethyl derivative. These principal metabolites either demonstrate no measurable activity or are only weakly active as COX-2 inhibitors. None of these metabolites inhibit COX-1.
Elimination: Following administration of a single 25-mg radiolabeled intravenous dose of etoricoxib to healthy subjects, 70% of radioactivity was recovered in urine and 20% in feces, mostly as metabolites. Less than 2% was recovered as unchanged drug.
Elimination of etoricoxib occurs almost exclusively through metabolism followed by renal excretion. Steady state concentrations of etoricoxib are reached within seven days of once daily administration of 120 mg, with an accumulation ratio of approximately 2, corresponding to a half-life of approximately 22 hours. The plasma clearance after a 25-mg intravenous dose is estimated to be approximately 50 mL/min.
Characteristics in Patients: Elderly: Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young. (See DOSAGE & ADMINISTRATION.)
Gender: The pharmacokinetics of etoricoxib are similar between men and women. (See DOSAGE & ADMINISTRATION.)
Hepatic Insufficiency: Patients with mild hepatic insufficiency (Child-Pugh score 5-6) administered etoricoxib 60 mg once daily had an approximately 16% higher mean AUC as compared to healthy subjects given the same regimen. Patients with moderate hepatic insufficiency (Child-Pugh score 7-9) administered etoricoxib 60 mg every other day had similar mean AUC to the healthy subjects given etoricoxib 60 mg once daily; etoricoxib 30 mg once daily has not been studied in this population. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score ≥10). (See Hepatic Insufficiency under DOSAGE & ADMINISTRATION.)
Renal Insufficiency: The pharmacokinetics of a single dose of etoricoxib 120 mg in patients with moderate-to-severe renal insufficiency and patients with end-stage renal disease on hemodialysis were not significantly different from those in healthy subjects. Hemodialysis contributed negligibly to elimination (dialysis clearance approximately 50 mL/min).
Pediatric Patients: The pharmacokinetics of etoricoxib in pediatric patients (<12 years old) have not been studied.
In a pharmacokinetic study (N=16) conducted in adolescents (aged 12 to 17) the pharmacokinetics in adolescents weighing 40 to 60 kg given etoricoxib 60 mg once daily and adolescents >60 kg given etoricoxib 90 mg once daily were similar to the pharmacokinetics in adults given etoricoxib 90 mg once daily. Safety and effectiveness of etoricoxib in pediatric patients have not been established.
