Source: Health Sciences Authority (SG) Revision Year: 2025 Publisher: Organon Singapore Pte. Ltd., 16 Raffles Quay, #18-01 Hong Leong Building, Singapore 048581
Etoricoxib is contra-indicated in:
Clinical trials suggest that the selective COX-2 inhibitor class of drugs may be associated with an increased risk of thrombotic events (especially MI and stroke), relative to placebo and some NSAIDs (naproxen). As the cardiovascular risks of selective COX-2 inhibitors may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically.
Patients with significant risk factors for cardiovascular events (e.g., hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with etoricoxib after careful consideration.
Selective COX-2 inhibitors are not a substitute for aspirin for cardiovascular prophylaxis because of their lack of effect on platelets. Because etoricoxib, a member of this class, does not inhibit platelet aggregation, antiplatelet therapies should not be discontinued.
There is a further increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications) for etoricoxib, other selective COX-2 inhibitors and NSAIDs, when taken concomitantly with acetylsalicylic acid (even at low doses). The relative difference in gastrointestinal safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been adequately evaluated in long-term clinical trials.
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal prostaglandins may play a compensatory role in the maintenance of renal perfusion. Therefore, under conditions of compromised renal perfusion, administration of etoricoxib may cause a reduction in prostaglandin formation and, secondarily, in renal blood flow, and thereby impair renal function. Patients at greatest risk of this response are those with pre-existing significantly impaired renal function, uncompensated heart failure, or cirrhosis. Monitoring of renal function in such patients should be considered.
As with other drugs known to inhibit prostaglandin synthesis, fluid retention, oedema and hypertension have been observed in patients taking etoricoxib. All non-steroidal anti-inflammatory drugs (NSAIDs), including etoricoxib, can be associated with new onset or recurrent congestive heart failure. For information regarding a dose related response for etoricoxib see 5.1 'Pharmacodynamic properties'. Caution should be exercised in patients with a history of cardiac failure, left ventricular dysfunction, or hypertension and in patients with pre-existing oedema from any other reason. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures including discontinuation of etoricoxib should be taken. Etoricoxib may be associated with more frequent and severe hypertension than some other NSAIDs and selective COX-2 inhibitors, particularly at high doses. Therefore, hypertension should be controlled before treatment with etoricoxib (see 4.3 'Contra-indications') and special attention should be paid to blood pressure monitoring during treatment with etoricoxib. Blood pressure should be monitored within two weeks after initiation of treatment and periodically thereafter. If blood pressure rises significantly, alternative treatment should be considered.
In clinical studies, some patients treated with etoricoxib developed perforations, ulcers or bleeds (PUBs). Independent of treatment, patients with a history of gastrointestinal (GI) perforation, ulcers and bleeding (PUB) and patients greater than 65 years of age are known to be at a higher risk for a PUB.
Elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials treated for up to one year with etoricoxib 30, 60 and 90 mg daily.
Any patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred should be monitored. If signs of hepatic insufficiency occur, or if persistently abnormal liver function tests (three times the upper limit of normal) are detected, etoricoxib should be discontinued.
Medically appropriate supervision should be maintained when using etoricoxib in the elderly and in patients with renal, hepatic, or cardiac dysfunction. If these patients deteriorate during treatment, appropriate measures should be taken, including discontinuation of therapy.
Caution should be used when initiating treatment with etoricoxib in patients with dehydration. It is advisable to rehydrate patients prior to starting therapy with etoricoxib.
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs and some selective COX-2 inhibitors during post-marketing surveillance (see 4.8 'Undesirable effects'). These serious events may occur without warning. Patients appear to be at highest risk for these reactions early in the course of therapy, with the onset of the reaction occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving etoricoxib (see 4.8 'Undesirable effects'). Some selective COX-2 inhibitors have been associated with an increased risk of skin reactions in patients with a history of any drug allergy. Etoricoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Etoricoxib may mask fever and other signs of inflammation or infection.
The use of etoricoxib, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, is not recommended in women attempting to conceive (see 4.6 'Pregnancy and lactation', 5.1 'Pharmacodynamic properties', and 5.3 'Preclinical safety data').
The quantity of lactose in each tablet (1.4, 2.8, 4.2, and 5.6 mg in the 30, 60, 90, and 120 mg tablets, respectively) is probably not sufficient to induce specific symptoms of lactose intolerance.
Oral anticoagulants: In subjects stabilised on chronic warfarin therapy, the administration of etoricoxib 120 mg daily was associated with an approximate 13% increase in prothrombin time International Normalised Ratio (INR). Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with etoricoxib is initiated or the dose of etoricoxib is changed.
Diuretics, Angiotensin II antagonists and ACE inhibitors: Reports suggest that NSAIDs, including selective COX-2 inhibitors may reduce the antihypertensive effect of diuretics, ACE inhibitors and Angiotensin II antagonists. This interaction should be given consideration in patients taking etoricoxib concomitantly with these products.
In some patients with compromised renal function (e.g., elderly patients with compromised renal function or dehydrated patients, including those on diuretic therapy) the co-administration of an ACE inhibitor or Angiotensin II antagonists and agents that inhibit cyclooxygenase may result in further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution, especially in the elderly.
Acetylsalicylic acid: In a study in healthy subjects, at steady state, etoricoxib 120 mg once daily had no effect on the anti-platelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be used concomitantly with acetylsalicylic acid at doses used for cardiovascular prophylaxis (low-dose acetylsalicylic acid). However, concomitant administration of low-dose acetylsalicylic acid with etoricoxib results in an increased rate of GI ulceration or other complications compared to use of etoricoxib alone. Concomitant administration of etoricoxib with doses of acetylsalicylic acid above those for cardiovascular prophylaxis or with other NSAIDs is not recommended (see 5.1 'Pharmacodynamic properties' and 4.4 'Special warnings and precautions for use').
Cyclosporin and tacrolimus: Although this interaction has not been studied with etoricoxib, co-administration of cyclosporin or tacrolimus with any NSAID may increase the nephrotoxic effect of cyclosporin or tacrolimus. Renal function should be monitored when etoricoxib and either of these drugs is used in combination.
The effect of etoricoxib on the pharmacokinetics of other drugs
Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary, monitor blood lithium closely and adjust the lithium dosage while the combination is being taken and when the NSAID is withdrawn.
Methotrexate: Two studies investigated the effects of etoricoxib 60, 90 or 120 mg administered once daily for seven days in patients receiving once-weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at 60 and 90 mg had no effect on methotrexate plasma concentrations or renal clearance. In one study, etoricoxib 120 mg had no effect, but in the other study, etoricoxib 120 mg increased methotrexate plasma concentrations by 28% and reduced renal clearance of methotrexate by 13%. Adequate monitoring for methotrexate-related toxicity is recommended when etoricoxib and methotrexate are administered concomitantly.
Oral contraceptives: Etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35 mcg ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days increased the steady state AUC0-24hr of EE by 37%. Etoricoxib 120 mg given with the same oral contraceptive either concomitantly or separated by 12 hours, increased the steady state AUC0-24hr of EE by 50 to 60%. This increase in EE concentration should be considered when selecting an oral contraceptive for use with etoricoxib. An increase in EE exposure can increase the incidence of adverse events associated with oral contraceptives (e.g., venous thrombo-embolic events in women at risk).
Hormone replacement therapy: Administration of etoricoxib 120 mg with hormone replacement therapy consisting of conjugated estrogens (0.625 mg PREMARIN) for 28 days, increased the mean steady state AUC0-24hr of unconjugated estrone (41%), equilin (76%), and 17-β-estradiol (22%). The effect of the recommended chronic doses of etoricoxib (30, 60 and 90 mg) has not been studied. The effects of etoricoxib 120 mg on the exposure (AUC0-24hr) to these estrogenic components of PREMARIN were less than half of those observed when PREMARIN was administered alone and the dose was increased from 0.625 to 1.25 mg. The clinical significance of these increases is unknown, and higher doses of PREMARIN were not studied in combination with etoricoxib. These increases in estrogenic concentration should be taken into consideration when selecting post-menopausal hormone therapy for use with etoricoxib because the increase in estrogen exposure might increase the risk of adverse events associated with hormone replacement therapy.
Prednisone/prednisolone: In drug-interaction studies, etoricoxib did not have clinically important effects on the pharmacokinetics of prednisone/prednisolone.
Digoxin: Etoricoxib 120 mg administered once daily for 10 days to healthy volunteers did not alter the steady-state plasma AUC0-24hr or renal elimination of digoxin. There was an increase in digoxin Cmax (approximately 33%). This increase is not generally important for most patients. However, patients at high risk of digoxin toxicity should be monitored for this when etoricoxib and digoxin are administered concomitantly.
Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1 and has been shown to increase the serum concentrations of ethinyl estradiol. While knowledge about effects of multiple sulfotransferases is presently limited and the clinical consequences for many drugs are still being examined, it may be prudent to exercise care when administering etoricoxib concurrently with other drugs primarily metabolised by human sulfotransferases (e.g., oral salbutamol and minoxidil).
Based on in vitro studies, etoricoxib is not expected to inhibit cytochromes P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. In a study in healthy subjects, daily administration of etoricoxib 120 mg did not alter hepatic CYP3A4 activity as assessed by the erythromycin breath test.
The main pathway of etoricoxib metabolism is dependent on CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles have not been studied in vivo.
Ketoconazole: Ketoconazole, a potent inhibitor of CYP3A4, dosed at 400 mg once a day for 11 days to healthy volunteers, did not have any clinically important effect on the single-dose pharmacokinetics of 60 mg etoricoxib (43% increase in AUC).
Rifampicin: Co-administration of etoricoxib with rifampicin, a potent inducer of CYP enzymes, produced a 65% decrease in etoricoxib plasma concentrations. This interaction may result in recurrence of symptoms when etoricoxib is co-administered with rifampicin. While this information may suggest an increase in dose, doses of etoricoxib greater than those listed for each indication have not been studied in combination with rifampicin and are therefore not recommended (see 4.2 'Posology and method of administration').
Antacids: Antacids do not affect the pharmacokinetics of etoricoxib to a clinically relevant extent.
The use of etoricoxib, as with any drug known to inhibit COX-2, is not recommended in women attempting to conceive.
No clinical data on exposed pregnancies are available for etoricoxib. Studies in animals have shown reproductive toxicity (see 5.3 'Preclinical safety data'). The potential for human risk in pregnancy is unknown. Etoricoxib, as with other drugs inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Etoricoxib is contra-indicated in all trimesters of pregnancy (see 4.3 'Contra-indications'). If a woman becomes pregnant during treatment, etoricoxib should be discontinued.
Cases of fetal renal dysfunction that have resulted in reduction of amniotic fluid volume (oligohydramnios) have been reported in pregnant women treated with non-steroidal anti- inflammatory drugs (NSAIDs) at 20 weeks of gestation or later. In some cases, this may result in neonatal renal dysfunction. Such effects may occur shortly after NSAID treatment initiation; oligohydramnios is often reversible after treatment discontinuation. Use of etoricoxib is not recommended in pregnancy from 20 weeks of gestation onwards.
It is not known whether etoricoxib is excreted in human milk. Etoricoxib is excreted in the milk of lactating rats. Women who use etoricoxib should not breast-feed (see 4.3 'Contra-indications' and 5.3 'Preclinical safety data').
No studies on the effect of etoricoxib on the ability to drive or use machines have been performed. However, patients who experience dizziness, vertigo or somnolence while taking etoricoxib should refrain from driving or operating machinery.
In clinical trials, etoricoxib was evaluated for safety in 9,295 individuals, including 6,757 patients with OA, RA, chronic low back pain or ankylosing spondylitis (approximately 600 patients with OA or RA were treated for one year or longer).
In a cardiovascular safety outcomes program of pooled data from three active comparator controlled trials, 17,412 patients with OA or RA were treated with etoricoxib (60 mg or 90 mg) for a mean duration of approximately 18 months. The safety data and details from this program are presented in section 5.1.
In clinical studies the following undesirable effects were reported at an incidence greater than placebo in patients with OA, RA, chronic low back pain or ankylosing spondylitis treated with etoricoxib 30 mg, 60 mg or 90 mg for up to 12 weeks or in the MEDAL Program studies.
[Common (≥1/100, <1/10), Uncommon (≥1/1000, <1/100), Rare (≥1/10,000, <1/1,000), Very rare (<1/10,000), not known (cannot be estimated from the available data)]
Uncommon: gastroenteritis, upper respiratory infection, urinary tract infection.
Very rare: drug hypersensitivity.
Common: oedema/fluid retention.
Uncommon: appetite increase or decrease, weight gain.
Uncommon: anxiety, depression, mental acuity decreased.
Common: dizziness, headache.
Uncommon: dysgeusia, insomnia, paraesthesia/hypaesthesia, somnolence.
Uncommon: blurred vision.
Uncommon: tinnitus.
Uncommon: atrial fibrillation, congestive heart failure, non-specific ECG changes.
Very rare: myocardial infarction.
Common: hypertension.
Uncommon: flushing.
Very rare: cerebrovascular accident.
Uncommon: cough, dyspnoea, epistaxis.
Common: gastrointestinal disorders (e.g., abdominal pain, flatulence, heartburn), diarrhoea, dyspepsia, epigastric discomfort, nausea.
Uncommon: abdominal distention, acid reflux, bowel movement pattern change, constipation, dry mouth, gastroduodenal ulcer, irritable bowel syndrome, oesophagitis, oral ulcer, vomiting, gastritis.
Very rare: gastrointestinal perforation and bleeding.
Uncommon: ecchymosis, facial oedema, pruritus, rash.
Uncommon: muscular cramp/spasm, musculoskeletal pain/stiffness.
Uncommon: proteinuria.
Common: asthenia/fatigue, flu-like disease.
Uncommon: chest pain.
Common: ALT increased, AST increased.
Uncommon: blood urea nitrogen increased, creatine phosphokinase increased, haematocrit decreased, haemoglobin decreased, hyperkalaemia, leukocytes decreased, platelets decreased, serum creatinine increased, uric acid increased.
In clinical studies, the undesirable effects profile was similar in patients with OA or RA treated with etoricoxib for one year or longer.
In a combined analysis of phase IIb to V clinical studies of 4 weeks duration or longer (excluding the MEDAL Program Studies), there was no discernible difference in the rate of confirmed thrombotic cardiovascular serious adverse events between patients receiving etoricoxib ≥30 mg or non-naproxen NSAIDs. The rate of these events was higher in patients receiving etoricoxib compared with those receiving naproxen 500 mg twice daily.
In a clinical study for ankylosing spondylitis, patients were treated with etoricoxib 90 mg once daily for up to 1 year (N=126). In another clinical study for ankylosing spondylitis (N=857), patients were treated with etoricoxib 60 mg or 90 mg once daily for up to 26 weeks. The adverse experience profile in these studies was generally similar to that reported in chronic studies in OA, RA and chronic low back pain.
In a clinical study for acute gouty arthritis, patients were treated with etoricoxib 120 mg once daily for eight days. The adverse experience profile in this study was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.
In initial clinical studies for acute analgesia, patients were treated with etoricoxib 120 mg once daily for one to seven days. The adverse experience profile in these studies was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.
In additional clinical studies for acute post-operative pain including 1222 patients treated with etoricoxib (90 mg or 120 mg), the adverse experience profile was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.
In the combined studies for acute post-operative dental pain, the incidence of post-dental extraction alveolitis (dry socket) reported in patients treated with etoricoxib was similar to that of patients treated with active comparators.
The following serious undesirable effects have been reported in association with the use of NSAIDs and cannot be ruled out for etoricoxib: nephrotoxicity including interstitial nephritis and nephrotic syndrome; hepatotoxicity including hepatic failure and pancreatitis.
The following adverse reactions have been reported in post-marketing experience:
Blood and lymphatic system disorders: thrombocytopenia.
Immune system disorders: hypersensitivity reactions, anaphylactic/anaphylactoid reactions, including shock.
Metabolism and nutrition disorders: hyperkalemia.
Psychiatric disorders: anxiety, insomnia, confusion, hallucinations, depression, restlessness.
Nervous system disorders: dysgeusia, somnolence, intracranial hemorrhage.
Cardiac disorders: congestive heart failure, palpitations, angina, arrhythmia.
Vascular disorders: hypertensive crisis, deep vein thrombosis.
Respiratory, thoracic and mediastinal disorders: bronchospasm, pulmonary embolism.
Gastrointestinal disorders: abdominal pain, oral ulcers, peptic ulcers including perforation and bleeding (mainly in elderly patients), vomiting, diarrhea.
Hepatobiliary disorders: hepatitis, jaundice, hepatic failure.
Skin and subcutaneous tissue disorders: angioedema, pruritus, erythema, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, fixed drug eruption.
Renal and urinary disorders: renal insufficiency, including renal failure (see 4.4 'Special warnings and precautions for use').
To report any suspected adverse event, quality complaints or medical inquiries related to Organon's product, please reach out to dpoc.singapore@organon.com.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.