Instructions Dynastat lyophilized powder for solution for injection 40 mg vial No. 10
Composition
active ingredient: parecoxib;
1 vial contains 40 mg of parecoxib as parecoxib sodium 42.36 mg;
excipients: sodium hydrogen phosphate anhydrous;
solvent: sodium chloride, water for injections.
Dosage form
Lyophilisate for solution for injection.
Main physicochemical properties: white to off-white solid in a sealed, clear glass vial of 5 ml (40 mg).
Solvent: clear, colorless solution.
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs. Coxibs. ATC code M01A H04.
Pharmacological properties
Pharmacodynamics.
Parecoxib is a prodrug of valdecoxib. Valdecoxib is a selective inhibitor of cyclooxygenase-2 in the clinical dose range. Cyclooxygenase is responsible for the formation of prostaglandins. Two isoforms of cyclooxygenase have been identified: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-2 is the enzyme isoform that has been shown to be induced by proinflammatory signals and is considered the main factor 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 (induction of fever, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissues surrounding gastric ulcers in humans, but its role in ulcer healing has not been proven.
The difference in antiplatelet activity between some nonsteroidal anti-inflammatory drugs that inhibit COX-1 and selective COX-2 inhibitors may be of clinical relevance in patients at risk for thromboembolic reactions. Selective COX-2 inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclins without affecting platelet thromboxane. The clinical relevance of these findings has not been established.
Parecoxib has been used in a variety of major and minor surgical procedures. Dynastat has been shown to be effective in dental, gynecological (hysterectomy), orthopedic (knee and hip replacement) procedures, and in pain following coronary artery bypass grafting. The first noticeable analgesic effect was observed within 7–13 minutes, and clinically significant analgesia was observed within 23–39 minutes, with peak effect occurring within 2 hours after single intravenous or intramuscular doses of Dynastat of 40 mg. The analgesic effect of a 40 mg dose was comparable to that of ketorolac 60 mg given intramuscularly or 30 mg given intravenously. The duration of analgesia after a single dose was dose- and clinical pattern-dependent and ranged from 6 to over 12 hours.
Use of parecoxib for more than 3 days.
Most clinical trials studied parecoxib for up to 3 days. Data from 3 randomized, placebo-controlled trials were pooled and analyzed, in which the protocols permitted parecoxib for more than 3 days. In the pooled analysis, 676 patients received 318 placebo and 358 parecoxib. Of the parecoxib-treated patients, 317 received parecoxib for up to 4 days, 32 for up to 5 days, while only 8 patients received parecoxib for up to 6 days, and 1 patient for 7 or more days. Of the placebo-treated patients, 270 received placebo for up to 4 days, 43 for up to 5 days, while only 3 patients received placebo for up to 6 days, and 2 patients for 7 or more days. Patient demographics were similar in both groups. The mean (SD) duration of treatment was 4.1 (0.4) days for the parecoxib group and 4.2 (0.5) days for the placebo group, with a range of 4–7 days for the parecoxib group and 4–9 days for the placebo group. The incidence of adverse reactions in patients treated with parecoxib for 4–7 days (median duration 4 days) was low after day 3 of treatment and was similar to that in the placebo group.
In a placebo-controlled study in orthopedic and general surgery (n=1050), patients received parenteral Dynastat initially at a dose of 40 mg and then at a dose of 20 mg twice daily for a minimum of 72 hours as an adjunct to standard treatment, which included additional controlled use of opioids in patients. The reduction in opioid use during 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 a significant reduction in opioid-related distress symptoms as reported by patients. Additional pain relief was demonstrated compared to opioids alone. Similar results were obtained in additional studies in other surgical pathologies. There is no evidence to suggest that parecoxib has fewer overall adverse events than placebo when given in combination with opiates.
Research into gastrointestinal tract pathology.
In short-term studies (7 days), the incidence of gastric and duodenal ulcers or erosions detected during endoscopy in healthy volunteers of young and elderly age (≥ 65 years) who were administered Dynastat (5-21%), although higher than in the placebo group (5-12%), was statistically significantly lower than the incidence observed with nonsteroidal anti-inflammatory drugs (66-90%).
Study of the safety of the drug after coronary artery bypass graft surgery.
In addition to the common adverse events reported, two placebo-controlled studies in which patients received parecoxib for at least 3 days and then switched to oral valdecoxib for a total of 10–14 days examined pre-specified categories of adverse reactions as determined by an independent expert committee. All patients received standard analgesic therapy during treatment.
Before randomization and during two studies, patients received low-dose acetylsalicylic acid during coronary artery bypass grafting.
The first study evaluated patients undergoing coronary artery bypass graft surgery who received parecoxib 40 mg intravenously twice daily for at least 3 days followed by valdecoxib 40 mg twice daily (parecoxib/valdecoxib group) (n=311) or placebo/placebo (n=151) in a 14-day, double-blind, placebo-controlled study. Nine pre-specified adverse reaction categories were evaluated (cardiovascular thromboembolic events, pericarditis, new or worsening congestive heart failure, renal failure/impairment, upper gastrointestinal ulcer complications, major non-gastrointestinal bleeding, infections, non-infectious pulmonary complications, and death). The parecoxib/valdecoxib treatment group had a significantly (p<0.05) higher incidence of cardiovascular/thromboembolic events (myocardial infarction, ischemia, acute cerebrovascular accident, deep vein thrombosis, and pulmonary embolism) during the intravenous period (2.2% and 0.0%, respectively) and throughout the study period (4.8% and 1.3%, respectively) compared to the placebo/placebo treatment group. Postoperative wound complications (including predominantly sternal wounds) were observed more frequently with parecoxib/valdecoxib treatment.
There was no significant difference between active treatment and placebo for any other pre-specified adverse reaction category (renal impairment/renal failure; upper gastrointestinal ulcer complications or surgical wound complications).
General surgery.
In a large (N=1050) study in major orthopedic/general surgery, patients received parecoxib intravenously at an initial dose of 40 mg followed by 20 mg intravenously every 12 hours for a minimum of 3 days, followed by oral valdecoxib (20 mg every 12 hours) (n=525) for the remainder of the 10-day treatment period, or placebo intravenously followed by oral placebo (n=525). There was no significant difference in the overall safety profile (including the four pre-specified adverse reaction categories described above for the second coronary artery bypass graft study) for parecoxib/valdecoxib compared to placebo in these patients after surgery.
Studies on the effects on platelets.
In a series of small multiple-dose studies in healthy young and elderly volunteers, Dynastat 20 mg or 40 mg twice daily had no effect on platelet aggregation or bleeding compared to placebo. In young patients, Dynastat 40 mg twice daily had no clinically significant effect on acetylsalicylic acid-mediated platelet inhibition (see section 4.5).
Pharmacokinetics.
After intravenous or intramuscular injection, parecoxib is rapidly converted to valdecoxib, the pharmacologically active substance, by enzymatic hydrolysis in the liver.
Absorption.
Valdecoxib exposure after single doses of Dynastat, as measured by area under the plasma concentration-time curve (AUC) and peak concentration (Cmax), is approximately linear over the clinical dose range. AUC and Cmax after twice daily dosing are linear up to 50 mg intravenously and 20 mg intramuscularly. Steady-state plasma concentrations were achieved within 4 days with twice daily dosing.
Following intravenous and intramuscular administration of single doses of parecoxib of 20 mg, Cmax of valdecoxib is reached after approximately 30 minutes and 1 hour, respectively. Valdecoxib exposure was similar after intravenous and intramuscular administration, based on AUC and Cmax. Parecoxib exposure was similar after intravenous or intramuscular administration, based on AUC. The mean Cmax of parecoxib after intramuscular administration was lower compared to intravenous bolus administration, which is associated with slower extravasal absorption after intramuscular administration. This decrease was not considered clinically important, as valdecoxib Cmax is comparable after intravenous and intramuscular administration of parecoxib.
Distribution.
The volume of distribution of valdecoxib following intravenous administration is approximately 55 liters. It is approximately 98% bound to plasma proteins over the concentration range achieved at the highest recommended dose of 80 mg/day. Valdecoxib, but not parecoxib, is extensively distributed into erythrocytes.
Biotransformation.
Parecoxib is rapidly and almost completely converted to valdecoxib and propionic acid in vivo with a plasma half-life of approximately 22 minutes. Valdecoxib is eliminated by extensive hepatic metabolism involving multiple pathways, including cytochrome P450 (CYP) 3A4 and CYP2C9, and glucuronidation (approximately 20%) of the sulfonamide moiety. A hydroxylated metabolite of valdecoxib (via the CYP pathway) has been identified in human plasma, which acts as a COX-2 inhibitor. This metabolite accounts for approximately 10% of valdecoxib concentrations; as the concentrations of this metabolite are low, it is not expected to contribute significantly to the clinical effect of parecoxib at therapeutic doses.
Breeding.
Valdecoxib is eliminated by hepatic metabolism, with less than 5% of unchanged valdecoxib recovered in the urine. Unchanged parecoxib is not recovered in the urine, and only traces of the drug are recovered in the feces. Approximately 70% of the dose is excreted in the urine as inactive metabolites. The plasma clearance (CLp) for valdecoxib is approximately 6 L/h. After intravenous or intramuscular administration of parecoxib, the elimination half-life (t1/2) of valdecoxib is approximately 8 hours.
Dynastat was administered to 335 elderly patients (65-96 years) in a pharmacokinetic and therapeutic effect study. In healthy elderly volunteers, the apparent oral clearance of valdecoxib was reduced, resulting in approximately 40% higher plasma valdecoxib exposure compared to healthy young volunteers. After adjusting for body weight, plasma valdecoxib exposure at steady state was 16% higher in elderly women compared to elderly men (see section 4.2).
Kidney failure.
In patients with varying degrees of renal impairment, parecoxib was rapidly eliminated from plasma after intravenous administration of 20 mg Dynastat. Since renal clearance of valdecoxib is not a major contributor to its distribution, no changes in valdecoxib clearance were observed even in patients with severe renal impairment or patients undergoing dialysis (see Dosage and Administration).
Liver failure.
Moderate hepatic impairment did not reduce the rate or extent of conversion of parecoxib to valdecoxib. In patients with moderate hepatic impairment (Child-Pugh score 7-9), treatment should be initiated at half the usual recommended dose of Dynastat and the maximum daily dose should be reduced to 40 mg, as valdecoxib exposure is more than 2-fold (130%) increased in these patients. Studies in patients with severe hepatic impairment have not been conducted, and Dynastat is not recommended for use in patients with severe hepatic impairment (see sections 4.2 and 4.3).
Indication
Treatment of acute pain. Preoperative (preventive) analgesia. Short-term treatment of postoperative pain in adults. Concomitant use with opiate analgesics to reduce the need for opiate.
The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of all the patient's individual risk factors.
Contraindication
Hypersensitivity to the active substance or to any of the excipients included in the preparation.
History of any severe allergic reaction to the drug, especially cutaneous reactions, including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), toxic epidermal necrolysis, erythema multiforme, or established hypersensitivity to sulfonamides in patients (see sections "Special warnings and precautions for use" and "Adverse reactions").
Active peptic ulcer or gastrointestinal bleeding.
History of bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria or other types of allergic reactions after taking acetylsalicylic acid or non-steroidal anti-inflammatory drugs, including COX-2 inhibitors.
Third trimester of pregnancy or breastfeeding (see section "Use during pregnancy or breastfeeding").
Severe hepatic impairment (serum albumin < 25 g/L or Child–Pugh score ≥ 10).
Inflammatory bowel diseases.
Congestive heart failure (NYHA II–IV).
Treatment of postoperative pain during coronary artery bypass grafting surgery (see sections "Adverse reactions" and "Pharmacodynamics").
Established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.
Interaction with other medicinal products and other types of interactions
Pharmacodynamic interactions.
Patients receiving warfarin or other anticoagulants should have their anticoagulant therapy monitored, especially during the first few days after initiation of Dynastat therapy, as these patients are at increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants should have their prothrombin time (INR) closely monitored, especially during the first few days after initiation of parecoxib therapy or after dose changes (see section 4.4).
Dynastat does not affect acetylsalicylic acid-mediated inhibition of platelet aggregation or bleeding time. Clinical studies suggest that Dynastat can be used with low-dose acetylsalicylic acid (£325 mg). Studies have shown that, as with other NSAIDs, concomitant use of low-dose acetylsalicylic acid is associated with an increased risk of gastrointestinal ulcers or other gastrointestinal events compared with parecoxib monotherapy (see section 5.1).
Inhibition of prostaglandins by nonsteroidal anti-inflammatory drugs, including COX-2 inhibitors, may reduce the effects of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists, beta-blockers and diuretics. This interaction should be considered in patients taking parecoxib concomitantly with ACE inhibitors, angiotensin II antagonists, beta-blockers and diuretics.
In elderly patients, patients with reduced circulating blood volume (especially those receiving diuretic therapy) or impaired renal function, the concomitant use of NSAIDs, including selective cyclooxygenase-2 inhibitors, with angiotensin-converting enzyme inhibitors or angiotensin II antagonists may lead to further deterioration of renal function, including the possible development of acute renal failure. These effects are usually reversible.
Therefore, caution should be exercised when these drugs are used concomitantly. Patients should drink sufficient fluids; the need for monitoring renal function should be assessed at the beginning of concomitant treatment and periodically during treatment.
Concomitant use of NSAIDs and cyclosporine or tacrolimus is thought to increase the nephrotoxic effects of cyclosporine and tacrolimus due to the effects of NSAIDs on renal prostaglandins. Renal function should be closely monitored when parecoxib is used concomitantly with any of these medicinal products.
Dynastat can be used concomitantly with opiate analgesics. In clinical studies, concomitant use with parecoxib significantly reduced the daily dose of opioids administered as needed.
Effect of other medicinal products on the pharmacokinetics of parecoxib (or its active metabolite valdecoxib).
Parecoxib is rapidly hydrolyzed to the active metabolite valdecoxib. Studies in humans indicate that valdecoxib is primarily metabolized by CYP2C9 and CYP3A4.
When the drug is used simultaneously with fluconazole (predominantly a CYP2C9 inhibitor), valdecoxib plasma exposure (AUC and Cmax) increases (by 62% and 19%, respectively), indicating the need to reduce the dose of parecoxib in patients receiving fluconazole therapy.
When the drug is used simultaneously with ketoconazole (predominantly a CYP3A4 inhibitor), valdecoxib plasma exposure (AUC and Cmax) increases (by 38% and 24%, respectively), but usually no dose adjustment is required in patients receiving ketoconazole.
The effect of enzyme induction has not been studied. The metabolism of valdecoxib may be increased when co-administered with enzyme inducers, including rifampicin, phenytoin, carbamazepine or dexamethasone.
Effect of parecoxib (or its active metabolite valdecoxib) on the pharmacokinetics of other drugs.
Treatment with valdecoxib (40 mg twice daily for 7 days) resulted in a 3-fold increase in plasma concentrations of dextromethorphan (a CYP2D6 substrate). Therefore, caution should be exercised when Dynastat is co-administered with medicinal products that are predominantly metabolised by CYP2D6 and have a narrow therapeutic window (e.g. flecainide, propafenone, metoprolol).
Plasma exposure of omeprazole (a CYP 2C19 substrate) 40 mg once daily increased by 46% after administration of valdecoxib 40 mg twice daily for 7 days, whereas plasma exposure of valdecoxib was unchanged. These results indicate that although valdecoxib is not metabolised by CYP2C19, it may inhibit this isoenzyme. Therefore, caution should be exercised when Dynastat is co-administered with medicinal products known to be substrates of CYP2C19 (such as phenytoin, diazepam or imipramine).
In two pharmacokinetic interaction studies, patients with rheumatoid arthritis receiving a stable weekly dose of methotrexate (5–20 mg per week as a single oral or intramuscular dose) were given oral valdecoxib (10 mg twice daily or 40 mg twice daily) with no or negligible effect on steady-state plasma concentrations of methotrexate. However, caution is advised when methotrexate is administered concomitantly with NSAIDs, as NSAIDs may increase plasma levels of methotrexate. Appropriate monitoring for methotrexate-related toxicity should be performed when parecoxib is administered concomitantly with methotrexate.
Concomitant use of valdecoxib and lithium resulted in a significant decrease in serum lithium clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium monotherapy. Serum lithium concentrations should be carefully monitored when initiating and switching parecoxib therapy in patients receiving lithium.
Concomitant use of valdecoxib and glibenclamide (a CYP3A4 substrate) did not affect the pharmacokinetics (exposure) or pharmacodynamics (blood glucose and insulin levels) of glibenclamide.
Co-administration of 40 mg intravenous parecoxib with propofol (a CYP2C9 substrate) or midazolam (a CYP3A4 substrate) did not affect the pharmacokinetics (metabolism and exposure) or pharmacodynamics (effects on electroencephalography, psychomotor tests and recovery from sedation) of intravenous propofol or midazolam. In addition, co-administration of valdecoxib did not have a clinically relevant effect on the CYP3A4-mediated hepatic and intestinal metabolism of oral midazolam.
Intravenous administration of parecoxib at a dose of 40 mg did not significantly affect the pharmacokinetics of fentanyl or alfentanil (CYP3A4 substrates) when administered intravenously.
Inhalation anesthetics.
No formal interaction studies have been conducted. In surgical studies in which parecoxib was administered preoperatively, no evidence of a pharmacodynamic interaction was observed in patients receiving parecoxib and the inhalational anesthetics nitrous oxide and isoflurane (see section 5.2).
Application features
Dynastat has been studied in dental, orthopedic, gynaecological (mainly hysterectomy) and coronary artery bypass grafting procedures. There is limited experience in other types of surgery, such as gastrointestinal or urological (see section 5.1).
Other routes of administration than intravenous and intramuscular (e.g. intraarticular, intrathecal) have not been studied and should not be used.
Since the likelihood of adverse reactions increases with higher doses of parecoxib, other COX-2 inhibitors and non-steroidal anti-inflammatory drugs, patients receiving parecoxib should be monitored after dose increases and, if efficacy does not improve, alternative treatment options should be considered (see section 4.2). Clinical experience with Dynastat for treatment beyond 3 days is limited (see section 5.2).
If patients experience deterioration in any of the organ systems described below during treatment, appropriate measures should be taken and discontinuation of parecoxib therapy should be considered.
Cardiovascular reactions.
Long-term use of COX-2 inhibitors has been associated with an increased risk of cardiovascular and thrombotic adverse events. The precise risk associated with a single dose has not been established, nor has the duration of treatment associated with the increased risk been precisely defined.
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking) should be treated with parecoxib after careful consideration (see section 5.1).
If these patients show clinical signs of deterioration in the form of specific symptoms, appropriate measures should be taken and discontinuation of parecoxib therapy should be considered. Dynastat has not been studied in cardiovascular revascularization procedures other than coronary artery bypass grafting. Studies of the drug in surgical settings other than coronary artery bypass grafting have included only patients with ASA (American Society of Anesthesiologists) physical performance status class I–III.
Acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs.
COX-2 inhibitors cannot replace acetylsalicylic acid in the prevention of cardiovascular thromboembolic diseases, because they do not reduce platelet aggregation. Therefore, antiplatelet therapy should not be discontinued (see section "Pharmacodynamics"). Dynastat should be used with caution with warfarin and other oral anticoagulants (see section "Interaction with other medicinal products and other forms of interaction"). The simultaneous use of parecoxib with other non-steroidal anti-inflammatory drugs, except acetylsalicylic acid, should be avoided.
Dynastat may mask fever and other signs of inflammation (see section 5.1). In isolated cases, worsening of soft tissue infections has been reported with the use of nonsteroidal anti-inflammatory drugs and in preclinical studies with Dynastat. In postoperative patients receiving Dynastat, the surgical site should be closely monitored for signs of infection.
Upper gastrointestinal complications (perforations, ulcers or bleeding), some of which were fatal, have been reported in patients treated with parecoxib. Caution is advised in patients at high risk of gastrointestinal complications with NSAIDs; the elderly or patients with a history of gastrointestinal disease, including ulcers and gastrointestinal bleeding, or patients receiving concomitant acetylsalicylic acid. The class of NSAIDs may also be associated with an increased risk of gastrointestinal complications when these drugs are used concomitantly with glucocorticoids, selective serotonin reuptake inhibitors, other antiplatelet agents, or when used in patients who consume alcohol. There is a further increased risk of gastrointestinal adverse events (gastrointestinal ulcers or other gastrointestinal complications) when parecoxib is used concomitantly with acetylsalicylic acid (even at low doses).
Skin reactions.
Severe skin reactions, including erythema multiforme, exfoliative dermatitis and Stevens-Johnson syndrome (some fatal), have been reported in patients treated with parecoxib during post-marketing surveillance. In addition, fatal cases of toxic epidermal necrolysis have been reported in patients treated with valdecoxib (the active metabolite of parecoxib) during post-marketing surveillance; and the occurrence of this condition cannot be excluded with parecoxib (see section 4.8). Based on other severe skin reactions reported with celecoxib and valdecoxib, DRESS syndrome may occur with parecoxib. Patients appear to be at highest risk of these reactions early in therapy; the reaction has predominantly occurred within the first month of treatment.
Appropriate measures should be taken to monitor for any severe skin reactions, such as additional patient counseling. Patients should be advised to report any skin changes they experience to their physician immediately.
Parecoxib treatment should be discontinued at the first appearance of skin rash, mucosal lesions or any sign of hypersensitivity. Severe skin reactions have been reported with nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors, as well as other medicinal products. However, the reported incidence of serious skin events is likely to be higher for valdecoxib (the active metabolite of parecoxib) than for other selective COX-2 inhibitors. Patients with a history of sulphonamide allergy may be at increased risk of developing skin reactions (see section 4.3). Patients without a history of sulphonamide allergy may also be at risk of developing severe skin reactions.
Hypersensitivity.
Hypersensitivity reactions (anaphylaxis and angioedema) have been reported in post-marketing experience with valdecoxib and parecoxib (see section 4.8). Some of these reactions have occurred in patients with a history of allergic-type reactions to sulfonamides (see section 4.3). Treatment with parecoxib should be discontinued at the first sign of hypersensitivity.
Cases of severe hypotension have been reported in the post-marketing setting of parecoxib shortly after administration of parecoxib. Some of these cases occurred without evidence of anaphylaxis. The physician should be prepared to treat severe hypotension.
Fluid retention, edema, renal reactions.
As with other medicinal products known to inhibit prostaglandin synthesis, fluid retention and oedema have been observed in individual patients treated with parecoxib. Therefore, parecoxib should be used with caution in patients with impaired cardiac function, pre-existing oedema and other conditions that contribute to or are aggravated by fluid retention, particularly in patients receiving diuretic therapy or who have other risk factors for hypovolaemia. If clinical signs of deterioration occur in these patients, appropriate measures should be taken, including discontinuation of parecoxib.
During post-marketing surveillance, cases of acute renal failure have been observed in patients treated with parecoxib (see section 4.8). Since inhibition of prostaglandin synthesis may lead to renal impairment and fluid retention, Dynastat should be used with caution in patients with impaired hepatic function (see section 4.2) or hypertension, or in patients with impaired hepatic or cardiac function or other conditions predisposing to fluid retention.
Dynastat should be used with caution in patients with dehydration at the beginning of treatment. In this case, it is recommended to first rehydrate and then start therapy with Dynastat.
As with all nonsteroidal anti-inflammatory drugs, parecoxib may cause or worsen pre-existing hypertension, which may increase the risk of cardiovascular events. Parecoxib should be used with caution in patients with hypertension. Blood pressure should be monitored closely at the start of parecoxib therapy and throughout the course of treatment. If blood pressure increases significantly, alternative treatments should be considered.
Liver failure.
Patients with moderate
