Dynastat

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, Coxibs, ATC code: M01AH04 Parecoxib is a prodrug of valdecoxib.​‍​​​​​‍​‍‍‍‍​‍‍ Valdecoxib is a selective COX‑2 inhibitor within the clinical dose range. 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. The difference in antiplatelet activity between some COX‑1 inhibiting NSAIDs and COX‑2 selective inhibitors may be of clinical significance in patients at risk of thrombo-embolic reactions. COX‑2 selective inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane. The clinical relevance of these observations has not been established. Parecoxib has been used in a range of major and minor surgeries. The efficacy of this medicine was established in studies of dental, gynaecologic (hysterectomy), orthopaedic (knee and hip replacement), and coronary artery bypass graft surgical pain. The first perceptible analgesic effect occurred in 7‑13 minutes, with clinically meaningful analgesia demonstrated in 23-39 minutes and a peak effect within 2 hours following administration of single doses of 40 mg IV or IM of this medicine. 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 of parecoxib beyond 3 days Most trials were designed for dosing of parecoxib up to 3 days. Data from 3 randomised placebo‑controlled trials, where the protocols allowed treatment of parecoxib for >3 days was pooled and analysed. In the pooled analysis of 676 patients, 318 received placebo and 358 received parecoxib. Of the patients treated with parecoxib, 317 patients received parecoxib for up to 4 days, 32 patients for up to 5 days, while only 8 patients were treated for up to 6 days and 1 patient for 7 or more days. Of the patients treated with placebo, 270 patients received placebo for up to 4 days, 43 patients for up to 5 days, while only 3 patients were treated for up to 6 days and 2 patients for 7 or more 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 4-7 days for parecoxib and 4‑9 days for placebo. The occurrence of adverse events in patients receiving parecoxib for 4‑7 days (median duration 4 days) was low after treatment Day 3 and similar to placebo. Opioid-sparing effects In a placebo-controlled, orthopedic and general surgery study (n =1050), patients received this medicine 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. The reduction in opioid use with this medicine's 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. Added pain relief compared to opioids alone was shown. Additional studies in other surgical settings provided similar observations. There are no data indicating less overall adverse events associated with the use of parecoxib compared to placebo when used in conjunction with opioids. 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 with this medicine (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 for at least 3 days and then were transitioned to oral valdecoxib for a total duration of 10-14 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 40 mg bid for a minimum of 3 days, followed by treatment with valdecoxib 40 mg bid (parecoxib/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 initial dose of 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO (20 mg Q12H) (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). General surgery In a large (N=1050) major orthopaedic/general surgery trial, patients received an initial dose of parecoxib 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO (20 mg Q12H) (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/valdecoxib compared to placebo treatment in these post-surgical patients. Platelet studies In a series of small, multiple dose studies in healthy young and elderly subjects, parecoxib 20 mg or 40 mg twice daily had no effect on platelet aggregation or bleeding compared to placebo. In young subjects, parecoxib 40 mg twice daily had no clinically significant effect on acetylsalicylic acid‑mediated inhibition of platelet function (see section 4.5).