Chemical formula: C₁₉H₁₈N₂O₄S Molecular mass: 370.422 g/mol PubChem compound: 119828
Parecoxib interacts in the following cases:
The concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding. Oral anticoagulants include warfarin/coumarin-type and novel oral anticoagulants (e.g. apixaban, dabigatran, and rivaroxaban).
Patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with parecoxib is initiated or the dose of parecoxib is changed.
Plasma exposure of omeprazole (CYP2C19 substrate) 40 mg once daily was increased by 46% following administration of valdecoxib 40 mg twice daily for 7 days, while the plasma exposure to valdecoxib was unaffected. These results indicate that although valdecoxib is not metabolised by CYP2C19, it may be an inhibitor of this isoenzyme. Therefore, caution should be observed when administering parecoxib with medicinal products known to be substrates of CYP2C19 (e.g. phenytoin, diazepam, or imipramine).
Treatment with valdecoxib (40 mg twice daily for 7 days) produced a 3-fold increase in plasma concentrations of dextromethorphan (CYP2D6 substrate). Therefore, caution should be observed when coadministering parecoxib and medicinal products that are predominantly metabolised by CYP2D6 and which have narrow therapeutic margins (e.g. flecainide, propafenone, metoprolol).
In patients with severe renal impairment (creatinine clearance <30 ml/min) or patients who may be predisposed to fluid retention, parecoxib should be initiated at the lowest recommended dose (20 mg) and the patient’s kidney function should be closely monitored.
Parecoxib should be introduced with caution and at half the usual recommended dose in patients with moderate hepatic impairment (Child-Pugh score 7-9) and the maximum daily dose should be reduced to 40 mg.
Inhibition of prostaglandins by NSAIDs, including COX-2 inhibitors, may diminish the effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, beta-blockers and diuretics. This interaction should be given consideration in patients receiving parecoxib concomitantly with ACE-inhibitors, angiotensin II antagonists, beta-blockers and diuretics.
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors or Angiotensin-II antagonists, may result in further deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Therefore, the concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.
The use of parecoxib, as with any medicinal product known to inhibit cyclooxygenase/prostaglandin synthesis, is not recommended in women attempting to conceive.
Based on the mechanism of action, the use of NSAIDs, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs, including parecoxib should be considered.
Coadministration of NSAIDs and ciclosporin or tacrolimus has been suggested to increase the nephrotoxic effect of ciclosporin and tacrolimus because of NSAID effects on renal prostaglandins. Renal function should be monitored when parecoxib and any of these medicinal products are coadministered.
Plasma exposure (AUC and Cmax) to valdecoxib was increased (62% and 19%, respectively) when coadministered with fluconazole (predominantly a CYP2C9 inhibitor), indicating that the dose of parecoxib should be reduced in those patients who are receiving fluconazole therapy.
Coadministration of valdecoxib and lithium produced significant decreases in lithium serum clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium alone. Lithium serum concentration should be monitored closely when initiating or changing parecoxib therapy in patients receiving lithium.
In two pharmacokinetic interaction studies in rheumatoid arthritis patients receiving a stable weekly methotrexate dose (5-20 mg/week, as a single oral or intramuscular dose), orally administered valdecoxib (10 mg twice daily or 40 mg twice daily) had little or no effect on the steady-state plasma concentrations of methotrexate. However caution is advised when methotrexate is administered concurrently with NSAIDs, because NSAID administration may result in increased plasma levels of methotrexate. Adequate monitoring of methotrexate-related toxicity should be considered when coadministering parecoxib and methotrexate.
The effect of enzyme induction has not been studied. The metabolism of valdecoxib (active metabolite of parecoxib) may increase when coadministered with enzyme inducers such as rifampicin, phenytoin, carbamazepine or dexamethasone.
As with other medicinal products known to inhibit prostaglandin synthesis, fluid retention and oedema have been observed in some patients taking parecoxib. Therefore, parecoxib should be used with caution in patients with compromised cardiac function, preexisting oedema, or other conditions predisposing to, or worsened by, fluid retention including those taking diuretic treatment or otherwise at risk of hypovolemia. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures including discontinuation of parecoxib should be taken.
Caution should be used when initiating treatment with parecoxib in patients with dehydration. In this case, it is advisable to rehydrate patients first and then start therapy with parecoxib.
As with all NSAIDs, parecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events. Parecoxib should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with parecoxib and throughout the course of therapy. If blood pressure rises significantly, alternative treatment should be considered.
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with parecoxib after careful consideration.
Appropriate measures should be taken and discontinuation of parecoxib therapy should be considered if there is clinical evidence of deterioration in the condition of specific clinical symptoms in these patients. Parecoxib has not been studied in cardiovascular revascularization procedures other than coronary artery bypass graft (CABG) procedures. Studies in types of surgery other than CABG procedures included patients with American Society of Anaesthesiology (ASA) Physical Status Class I-III only.
Parecoxib is suspected to cause serious birth defects when administered during the last trimester of pregnancy because as with other medicinal products known to inhibit prostaglandin, it may cause premature closure of the ductus arteriosus or uterine inertia.
NSAID use during the second or third trimester of pregnancy may cause foetal renal dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe cases. Such effects may occur shortly after treatment initiation and are usually reversible. Pregnant women on NSAIDs should be closely monitored for amniotic fluid volume.
Parecoxib is contraindicated in the third trimester of pregnancy.
There are no adequate data from the use of parecoxib in pregnant women or during labour. However, inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of miscarriage after use of prostaglandin synthesis inhibitors in early pregnancy. In animals, administration of prostaglandin synthesis inhibitors, including parecoxib, has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. During the first and second trimester of pregnancy, parecoxib should not be given unless clearly necessary.
Administration of a single dose of parecoxib to lactating women following caesarean section resulted in the transfer of a relatively small amount of parecoxib and its active metabolite valdecoxib into human milk, and this resulted in a low relative dose for the infant (approximately 1% of the weight-adjusted maternal dose). Parecoxib must not be administered to women who breast-feed.
The use of parecoxib, as with any medicinal product known to inhibit cyclooxygenase/prostaglandin synthesis, is not recommended in women attempting to conceive.
Based on the mechanism of action, the use of NSAIDs, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs, including parecoxib should be considered.
Patients who experience dizziness, vertigo or somnolence after receiving parecoxib should refrain from driving or operating machines.
The most common adverse reaction for parecoxib is nausea. The most serious reactions occur uncommonly to rarely, and include cardiovascular events such as myocardial infarction and severe hypotension, as well as hypersensitivity events such as anaphylaxis, angioedema and severe skin reactions. Following coronary artery bypass graft surgery, patients administered parecoxib have a higher risk of adverse reactions such as: cardiovascular/thromboembolic events (including myocardial infarction, stroke/TIA, pulmonary embolus, and deep vein thrombosis, deep surgical infections, and sternal wound healing complications.
The following adverse reactions were reported for patients who received parecoxib (N=5,402) in 28 placebo-controlled clinical trials. Reports from post-marketing experience have been listed as “frequency not known” because the respective frequencies cannot be estimated from the available data. Within each frequency grouping, adverse reactions are listed using MedDRA terminology and presented in order of decreasing seriousness.
Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), Rare (≥1/10,000 to <1/1000), Not known.
Common: Pharyngitis, alveolar osteitis (dry socket)
Uncommon: Abnormal sternal serous wound drainage, wound infection
Common: Anaemia postoperative
Uncommon: Thrombocytopenia
Rare: Anaphylactoid reaction
Common: Hypokalaemia
Uncommon: Hyperglycaemia, anorexia
Common: Agitation, insomnia
Common: Hypoaesthesia, dizziness
Uncommon: Cerebrovascular disorder
Uncommon: Ear pain
Uncommon: Myocardial infarction, bradycardia
Not known: Circulatory collapse, congestive heart failure, tachycardia
Common: Hypertension, hypotension
Uncommon: Hypertension (aggravated), orthostatic hypotension
Common: Respiratory insufficiency
Uncommon: Pulmonary embolism
Not known: Dyspnoea
Very Common: Nausea
Common: Abdominal pain, vomiting, constipation, dyspepsia, flatulence
Uncommon: Gastroduodenal ulceration, gastrooesophageal reflux disease, dry mouth, gastrointestinal sounds abnormal
Rare: Pancreatitis, oesophagitis, oedema mouth (perioral swelling)
Common: Pruritus, hyperhidrosis
Uncommon: Ecchymosis, rash, urticaria
Not known: Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis
Common: Back pain
Uncommon: Arthralgia
Common: Oliguria
Rare: Renal failure acute
Not known: Renal failure
Common: Oedema peripheral
Uncommon: Asthenia, injection site pain, injection site reaction
Not known: Hypersensitivity reactions including anaphylaxis and angioedema
Common: Blood creatinine increased
Uncommon: Blood CPK increased, blood LDH increased, SGOT increased, SGPT increased, BUN increased
Uncommon: Post procedural complication (skin)
In post-marketing experience, toxic epidermal necrolysis has been reported in association with the use of valdecoxib, and cannot be ruled out for parecoxib. In addition, the following rare, serious adverse reactions have been reported in association with the use of NSAIDs and cannot be ruled out for parecoxib: bronchospasm and hepatitis.
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