PERICOB Powder for solution for injection Ref.[115212] Active ingredients: Parecoxib

Following IV or IM injection, parecoxib is rapidly converted to valdecoxib, the pharmacological moiety, by enzymatic hydrolysis in the liver.

Absorption

Exposure of valdecoxib following single doses of parecoxib injection, as measured by both the area under the plasma concentration vs. time curve (AUC) and peak concentration (C_max is approximately linear in the range of clinical doses. AUC and C_max following twice a day (BID) administration of valdecoxib is linear up to 50 mg IV and 20 mg IM. Steady state plasma concentrations of valdecoxib were reached within 4 days with BID dosing.

Following single IV and IM doses of parecoxib sodium 20 mg, C_max of valdecoxib is achieved at approximately 30 minutes and approximately 1 hour, respectively. Exposure to valdecoxib was similar in terms of AUC and C following IV and IM administration.

Distribution

The volume of distribution of valdecoxib after its IV administration is approximately 55 litres (greater than total body water). Plasma protein binding is approximately 98% over the concentration range achieved with the highest recommended dose, 80 mg/day. Valdecoxib, but not parecoxib, is extensively partitioned into erythrocytes.

Metabolism

Parecoxib is rapidly and almost completely converted to valdecoxib in vivo with a plasma half-life of approximately 22 minutes. Elimination of valdecoxib is by extensive hepatic metabolism involving multiple pathways, including cytochrome P450 CYP3A4 and CYP2C9 isoenzymes and GYP-independent glucuronidation of the sulfonamide moiety. A hydroxylated metabolite of valdecoxib (via the CYP pathway) has been identified in human plasma that is active as a COX-2 inhibitor. It represents approximately 10% of the concentration of valdecoxib; but because of this metabolite’s low concentration, it is not expected to contribute a significant clinical effect after administration of therapeutic doses of parecoxib sodium. The valdecoxib metabolite undergoes extensive metabolism, with less than 5% of the dose excreted in urine and faeces.

Elimination

Valdecoxib is eliminated via hepatic metabolism with less than 5% unchanged medicine recovered in the urine. No unchanged parecoxib is detected in urine and only trace amounts in the faeces. About 70% of the dose is excreted in the urine as inactive metabolites. Plasma clearance (CLJ for valdecoxib is about 6 l/hr. After IV or IM dosing of parecoxib sodium, the elimination half-life (t_½) of valdecoxib is about 8 hours.

Special populations

Elderly subjects

In healthy elderly subjects, the apparent oral clearance of valdecoxib was reduced, resulting in an approximately 40% higher plasma exposure of valdecoxib compared to healthy young subjects. When adjusted for body weight, steady state plasma exposure of valdecoxib was 16% higher in elderly females compared to elderly males.

Renal impairment

In patients with varying degrees of renal impairment administered 20 mg IV parecoxib injection as a single dose, parecoxib was rapidly cleared from plasma. Because renal elimination of valdecoxib is not important to its disposition, no changes in valdecoxib clearance were found even in patients with renal impairment. Dosages of more than 20 mg have not been studied in renal impairment. Therefore, on the basis of pharmacokinetics, dosing adjustment in patients with mild to moderate impaired renal function is not necessary.

Hepatic impairment

Moderate hepatic impairment did not result in a reduced rate or extent of parecoxib conversion to valdecoxib. In patients with moderate hepatic impairment (Child-Pugh scale 7-9), treatment should be initiated with half the usual recommended dose of parecoxib injection and the maximum daily dose should be reduced to 40 mg since valdecoxib exposures were more than doubled (130%) in these patients. Patients with severe hepatic impairment have not been studied and therefore the use of parecoxib injection in patients with severe hepatic impairment is not recommended.