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Pharmacology: Pharmacodynamics: Following injection, parecoxib sodium is rapidly converted to valdecoxib: the in vivo pharmacology of parecoxib is therefore that of valdecoxib. The mechanism of action of valdecoxib is by inhibition of cyclooxygenase-2 (COX-2)-mediated prostaglandin synthesis. At therapeutic plasma concentrations in humans, valdecoxib does not inhibit cyclooxygenase-1 (COX-1). In animal models, valdecoxib is anti-inflammatory, analgesic, and antipyretic.
By inhibition of both peripheral and central COX-2, valdecoxib reduces the production of prostaglandins that are important mediators of pain and inflammation. Therefore, PARECOXB Injection is not expected to exhibit the potential for dependence, sedation or respiratory depression seen with opioid analgesic agents.
Pharmacokinetics: Following IV or IM injection, parecoxib is rapidly converted to valdecoxib, the pharmacologically active substance, by enzymatic hydrolysis in the liver.
Absorption: Following IV or IM injection, parecoxib sodium is rapidly and essentially completely converted to valdecoxib. Exposure [plasma concentration vs. time curve (AUC) and peak concentration (Cmax)] of valdecoxib following injection of parecoxib sodium is approximately linear in the dosage range of clinical doses. Steady state was reached within 4 days with BD dosing.
Following single IV and IM doses of parecoxib sodium 20 mg, Cmax of valdecoxib is achieved in approximately 30 minutes and approximately 1 hour, respectively.
Exposure to valdecoxib was similar in terms of AUC and Cmax following IV and IM administration. Exposure to parecoxib was similar after IV or IM administration in terms of AUC. Average Cmax of parecoxib after IM dosing was lower compared to bolus IV dosing, which is attributed to slower extravascular absorption after IM administration. These decreases were not considered clinically important since Cmax of valdecoxib is comparable after IM and IV parecoxib sodium administration.
Distribution: The volume of distribution of valdecoxib after its IV administration is approximately 55 L. Plasma protein binding is about 98% over the concentration range (0.21 - 2.38 mcg/mL) 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. The rate of conversion of parecoxib to valdecoxib is not affected in patients with mild to moderate hepatic impairment. Elimination of valdecoxib is by extensive hepatic metabolism involving multiple pathways. The cytochrome P-450 (CYP-450) dependent pathway involves predominantly 3A4 and 2C9 isozymes while the CYP-450 independent pathway leads to glucuronide conjugates of the sulfonamide moiety.
One active minor metabolite (a hydroxylated form via the CYP-450 pathway) of valdecoxib has been identified in human plasma at approximately 10% the concentration of valdecoxib. It also undergoes extensive metabolism, with <5% of the dose excreted in the urine and faeces. Because of its minor presence, this metabolite is not expected to contribute a significant clinical effect after administration of therapeutic doses of parecoxib sodium.
Excretion: Following conversion from parecoxib, valdecoxib is eliminated via hepatic metabolism with <5% of the dose excreted unchanged in the urine. No unchanged parecoxib is detected in urine and only a trace amount in faeces. About 70% of the dose is excreted in the urine as inactive metabolites. The elimination hatf-life (T1/2) of valdecoxib after IV or IM dosing of parecoxib sodium is about 8 hours. Plasma clearance (CLp) for valdecoxib is about 6 L/hr. In patients undergoing haemodialysis the CLp of valdecoxib was similar to the CLp found in healthy subjects.
Special Populations: Elderly (>65 years): Parecoxib sodium Injection has been administered to 335 elderly patients (65-96 years of age) in pharmacokinetic and therapeutic trials. 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.
Children and Adolescents: Parecoxib sodium Injection has not been investigated in paediatric patients under 18 years of age.
Race: Pharmacokinetic differences due to race have not been identified in clinical and pharmacokinetic studies conducted to date.
Renal Impairment: In patients with varying degrees of renal impairment administered 20 mg IV parecoxib, 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 severe renal impairment or in patients undergoing dialysis.
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 score 7-9), treatment should be initiated with half the usual recommended dose of parecoxib 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 in patients with severe hepatic impairment is not recommended.
