Pharmacologic Category: COX-2 Selective Inhibitor.
Pharmacology: Pharmacodynamics: Parecoxib (Dynastat) is a prodrug of valdecoxib. Valdecoxib is an NSAID that exhibits antiinflammatory, analgesic and antipyretic properties in animal models. The mechanism of action is believed to be due to inhibition of prostaglandin synthesis primarily through inhibition of COX-2. At therapeutic plasma concentrations in humans valdecoxib does not inhibit cyclooxygenase-1 (COX-1).
Clinical Studies: Parecoxib has been studied in a broad range of major and minor surgeries. The efficacy of parecoxib (Dynastat) was established in studies of dental, gynecologic (hysterectomy), orthopedic (knee and hip replacement), and coronary artery bypass graft surgical pain (see Contraindications). The first perceptible analgesic effect occurred in 7 to 13 minutes, with clinically meaningful analgesia demonstrated in 23 to 39 minutes and a peak effect within 2 hours following administration of single doses of 40 mg IV or IM parecoxib (Dynastat). The magnitude of analgesic effect of the 40 mg dose was comparable with that of ketorolac 60 mg IM or ketorolac 30 mg IV. After a single dose, the duration of analgesia was dose and clinical pain model dependent, and ranged from 6 to greater than 12 hours.
Use Beyond 3 Days: Most trials were designed for dosing up to 3 days. Data from 3 of 28 randomized placebo controlled trials, where the protocols allowed treatment of parecoxib for >3 days was pooled and analyzed, 358 patients received parecoxib for >3 days and 318 patients received placebo for >3 days. Both groups had similar demographics. The mean (SD) duration of treatment was 4.1 (0.4) days for parecoxib and 4.2 (0.5) days for placebo, the range was 4 to 7 days for parecoxib and 4 to 9 days for placebo. The occurrence of AE in patients receiving parecoxib for 4 to 7 days (median duration 4 days) was low after treatment Day 3 and similar to placebo.
Opioid-sparing Effects: Parecoxib (Dynastat), at recommended doses, significantly reduced opioid consumption and patient-reported opioid-related adverse effects (fatigue, drowsiness, confusion, inability to concentrate, dizziness, nausea, constipation, difficult urination, itching, retching/vomiting), while providing improved pain relief compared to opioids alone.
In a placebo-controlled, orthopedic and general surgery study (n = 1050), patients received parecoxib (Dynastat) at an initial parenteral dose of 40 mg IV followed by 20 mg twice daily for a minimum of 72 hours in addition to receiving standard care including supplemental patient controlled opioids (IV morphine sulfate). The reduction in opioid use with parecoxib (Dynastat) treatment on Days 2 and 3 was 7.2 mg and 2.8 mg (37% and 28% respectively).
This reduction in opioid use was accompanied by significant reductions in patient-reported opioid symptom distress, as well as improved pain relief compared to opioids alone. Additional studies in other surgical settings provided similar observations.
Platelets: In clinical trials studying young (18-55 years) and elderly (65-83 years) adult subjects, single and multiple doses up to 7 days of parecoxib (Dynastat) 20 mg and 40 mg twice daily, had no effect on platelet aggregation or bleeding time. By comparison, ketorolac 15 mg and 30 mg as a single dose, or after 5 days treatment, significantly reduced platelet aggregation and significantly increased bleeding time. Parecoxib (Dynastat) (40 mg twice daily) did not have a clinically significant effect on aspirin-mediated inhibition of platelet function, and did not alter the pharmacodynamic effects of heparin on aPTT or platelets, compared to placebo.
Gastrointestinal Studies: In short-term studies (7 days), the incidence of endoscopically observed gastroduodenal ulcers or erosions in healthy young and elderly (65 years) subjects administered parecoxib (Dynastat) (5%-21%), although higher than placebo (5%-12%), was statistically significantly lower than the incidence observed with NSAIDs (66%-90%).
CABG post-operative Safety Studies: In addition to routine adverse event reporting, pre-specified event categories, adjudicated by an independent expert committee, were examined in two placebo-controlled safety studies in which patients received parecoxib sodium (Dynastat) for at least 3 days and then were transitioned to oral valdecoxib for a total duration of 10 to 14 days. All patients received standard of care analgesia during treatment.
Patients received low-dose acetylsalicylic acid prior to randomization and throughout the two CABG surgery studies.
The first CABG surgery study evaluated patients treated with IV parecoxib sodium (Dynastat) 40 mg twice daily for a minimum of 3 days, followed by treatment with valdecoxib 40 mg twice daily (parecoxib sodium/valdecoxib group) (n=311) or placebo/placebo (n=151) in a 14-day, double-blind placebo-controlled study. Nine pre-specified adverse event categories were evaluated (cardiovascular thromboembolic events, pericarditis, new onset or exacerbation of congestive heart failure, renal failure/dysfunction, upper GI ulcer complications, major non-GI bleeds, infections, non-infectious pulmonary complications, and death). There was a significantly (p <0.05) greater incidence of cardiovascular/thromboembolic events (myocardial infarction, ischemia, cerebrovascular accident, deep vein thrombosis and pulmonary embolism) detected in the parecoxib/valdecoxib treatment group compared to the placebo/placebo treatment group for the IV dosing period (2.2% and 0.0% respectively) and over the entire study period (4.8% and 1.3% respectively). Surgical wound complications (most involving the sternal wound) were observed at an increased rate with parecoxib/valdecoxib treatment.
In the second CABG surgery study, four pre-specified event categories were evaluated (cardiovascular/thromboembolic; renal dysfunction/renal failure; upper GI ulcer/bleeding; surgical wound complication). Patients were randomized within 24-hours post-CABG surgery to: parecoxib (Dynastat) initial dose of 40 mg IV, then 20 mg IV every 12 hours for a minimum of 3 days followed by valdecoxib PO (20 mg every 12 hours) (n=544) for the remainder of a 10-day treatment period; placebo IV followed by valdecoxib PO (n=544); or placebo IV followed by placebo PO (n=548). A significantly (p=0.033) greater incidence of events in the cardiovascular/thromboembolic category was detected in the parecoxib/valdecoxib treatment group (2.0%) compared to the placebo/placebo treatment group (0.5%). Placebo/valdecoxib treatment was also associated with a higher incidence of CV thromboembolic events versus placebo treatment, but this difference did not reach statistical significance. Three of the six cardiovascular thromboembolic events in the placebo/valdecoxib treatment group occurred during the placebo treatment period; these patients did not receive valdecoxib. Pre-specified events that occurred with the highest incidence in all three treatment groups involved the category of surgical wound complications, including deep surgical infections and sternal wound healing events.
There were no significant differences between active treatments and placebo for any of the other pre-specified event categories (renal dysfunction/failure, upper GI ulcer complications or surgical wound complications).
Parecoxib (Dynastat) has not been studied in cardiovascular revascularization procedures other than CABG.
In an analysis of 17 controlled trials in non-cardiac major surgery, where the majority of patients were treated for 2 days, patients receiving parecoxib (Dynastat) did not experience an increased risk of cardiovascular adverse events compared to placebo. This included patients with none, one or two cardiovascular risk factors. This analysis has about 77% power to detect a doubling in the background rate of cardiovascular adverse events in patients treated with parecoxib (Dynastat).
General Surgery: In a large (N=1050) major orthopedic/general surgery trial, patients received an initial dose of parecoxib (Dynastat) 40 mg IV, then 20 mg IV every 12 hours for a minimum of 3 days followed by valdecoxib PO (20 mg every 12 hours) (n=525) for the remainder of a 10-day treatment period, or placebo IV followed by placebo PO (n=525). There were no significant differences in the overall safety profile, including the four pre-specified event categories described above for the second CABG surgery study, for parecoxib sodium/valdecoxib compared to placebo treatment in these post-surgical patients.
Pharmacokinetics: Following IV or IM injection, parecoxib (Dynastat) is rapidly converted to valdecoxib, the pharmacologically active substance, by enzymatic hydrolysis in the liver.
Absorption: Exposure of valdecoxib following single doses of parecoxib (Dynastat), as measured by both the area under the plasma concentration vs. time curve (AUC) and peak concentration (Cmax), is approximately linear in the range of clinical doses. AUC and Cmax following twice daily administration is linear up to 50 mg IV and 20 mg IM. Steady state plasma concentrations of valdecoxib were reached within 4 days with twice daily dosing.
Following single IV and IM doses of parecoxib sodium (Dynastat) 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 (Dynastat) was similar after IV or IM administration in terms of AUC. Average Cmax of parecoxib (Dynastat) 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 (Dynastat) administration.
Distribution: The volume of distribution of valdecoxib after its IV administration is approximately 55 liters. Plasma protein binding is approximately 98% over the concentration range achieved with the highest recommended dose, 80 mg/day. Valdecoxib, but not parecoxib (Dynastat), is extensively partitioned into erythrocytes.
Metabolism: Parecoxib (Dynastat) is rapidly and almost completely converted to valdecoxib and propionic acid 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 (CYP) 3A4 and CYP2C9 isoenzymes and glucuronidation (about 20%) 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; 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 (Dynastat).
Elimination: Valdecoxib is eliminated via hepatic metabolism with less than 5% unchanged valdecoxib recovered in the urine. No unchanged parecoxib (Dynastat) is detected in urine and only trace amounts in the feces. About 70% of the dose is excreted in the urine as inactive metabolites. Plasma clearance (CLp) for valdecoxib is about 6 l/hour. After IV or IM dosing of parecoxib sodium (Dynastat), the elimination half-life (t1/2) of valdecoxib is about 8 hours.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazards for human based on conventional studies of safety pharmacology or repeated dose toxicity at 2-fold the maximum human exposure to parecoxib (Dynastat). However, in the repeated dose toxicity studies in dogs and rats, the systemic exposures to valdecoxib (the active metabolite of parecoxib (Dynastat)) were approximately 0.8-fold the systemic exposure in elderly human subjects at the maximum recommended therapeutic dose of 80 mg daily. Higher doses were associated with aggravation and delayed healing of skin infections, an effect probably associated with COX-2 inhibitors.
In reproduction toxicity tests, the incidence of post-implantation losses, resorptions and fetal body weight retardation occurred at doses not producing maternal toxicity in the rabbit studies. No effects of parecoxib (Dynastat) on male or female fertilities were found in rats.
The effects of parecoxib (Dynastat) have not been evaluated in late pregnancy or in the pre and post-natal period.
Parecoxib (Dynastat) administered intravenously to lactating rats as a single dose showed concentrations of parecoxib (Dynastat), valdecoxib and a valdecoxib active metabolite in mild similar to that of maternal plasma.
The carcinogenic potential of parecoxib (Dynastat) has not been evaluated.