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Clinical trial suggests 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 patients need symptomatic relief and response to therapy should be re-evaluated periodically.
Patients with significant risk factors for cardiovascular events (eg, hypertension, hyperlipidemia, diabetes mellitus, smoking) or peripheral arterial disease 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 does not inhibit platelet aggregation, antiplatelet therapies should not be discontinued.
There is a further increase in the risk of GI adverse effects (GI ulceration or other GI complications) for etoricoxib, other selective COX-2 inhibitors and NSAIDs, when taken concomitantly with acetylsalicylic acid (even at low doses). The relative differences in gastrointestinal safety between selective COX-2 inhibitors + acetylsalicylic acid vs NSAIDs + acetylsalicylic acid has not been adequately evaluated in long term clinical trials.
In patients with advanced renal disease, treatment with Arcoxia is not recommended. Clinical experience in patients with estimated CrCl of <30 mL/min is very limited. If therapy with Arcoxia must be initiated in such patients, close monitoring of the patient's renal function is advisable.
Renal prostaglandins may play a compensatory role in the maintenance of renal perfusion. Therefore, under conditions of compromised renal perfusion, administration of Arcoxia 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 preexisting 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, discontinuation of therapy with Arcoxia would be expected to be followed by recovery to the pre-treatment state.
Caution should be used when initiating treatment with Arcoxia in patients with considerable dehydration. It is advisable to rehydrate patients prior to starting therapy with Arcoxia.
As with other drugs known to inhibit prostaglandin synthesis, fluid retention, edema and hypertension have been observed in some patients taking Arcoxia. The possibility of fluid retention, edema or hypertension should be taken into consideration when Arcoxia is used in patients with preexisting edema, hypertension or heart failure.
Etoricoxib may be associated with more frequent and severe hypertension than some other NSAIDs and selective COX-2 inhibitors, particularly at high doses. Therefore, special attention should be paid to blood pressure monitoring during treatment with etoricoxib. If blood pressure rises significantly, alternative treatment should be considered.
Caution should be exercised in patients with a medical history of ischemic heart disease because of the pharmacodynamic profile of COX-2 selective inhibitors noted previously.
Physicians should be aware that individual patients may develop upper GI ulcer complications irrespective of treatment. In clinical studies, the risk of endoscopically detected upper GI ulcers was lower in patients treated with Arcoxia 120 mg once daily than in patients treated with nonselective NSAIDs. While the risk of endoscopically detected ulcers was lower in patients treated with Arcoxia 120 mg than in patients treated with placebo. Upper GI ulcer complications have occurred in patients treated with Arcoxia. Independent of treatment, patients with a prior history of GI perforation, ulcers and bleeding (PUB) and patients >65 years are known to be at a higher risk for a PUB.
Elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately ≥3 times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials treated for up to 1 year with Arcoxia 60 mg and 90 mg daily. In active comparator portions of clinical trials, the incidence of elevated AST and/or ALT in patients treated with Arcoxia 60 mg and 90 mg daily was similar to that of patients treated with naproxen, but notably less than the incidence in the diclofenac group. These elevations resolved in patients treated with Arcoxia, with approximately half resolving while patients remained on therapy.
A patient with symptoms and/or signs suggesting liver dysfunction or in whom an abnormal liver function test has occurred, should be evaluated for persistently abnormal liver function tests. If persistently abnormal liver function tests (3 times the upper limit of normal) are detected, Arcoxia should be discontinued.
Arcoxia should be used with caution in patients who have previously experienced acute asthmatic attacks, urticaria or rhinitis, which were precipitated by salicylates or nonselective cyclooxygenase inhibitors. Since the pathophysiology of these reactions is unknown, physicians should weigh the potential benefits of prescribing Arcoxia versus the potential risks.
Arcoxia may mask fever, which is a sign of infection. The physician should be aware of this when using Arcoxia in patients being treated for infection.
Effects on the Ability to Drive or Operate Machinery: There is no information to suggest that Arcoxia affects a patient's ability to drive or operate machinery.
Carcinogenicity: Etoricoxib was not carcinogenic in mice. Rats developed hepatocellular and thyroid follicular cell adenomas at >6 times the daily human dose (90 mg) based on systemic exposure when dosed daily for approximately 2 years. Tumors of these types are a species-specific consequence of hepatic CYP enzyme induction in the rat. These findings are consistent with other compounds associated with this induction. Etoricoxib has not been shown to cause hepatic CYP enzyme induction in humans.
Mutagenicity: Etoricoxib was found to be neither genotoxic nor mutagenic as described as follows. Etoricoxib was negative in the in vitro microbial and the TK6 human cell mutagenesis assays, with and without metabolic activation. There was no evidence of genotoxicity in the in vitro alkaline elution assay in rat hepatocytes and the in vitro chromosomal aberration assays in Chinese hamster ovary cells, with or without metabolic activation. In the in vivo alkaline elution/rat liver damage assays, etoricoxib did not induce DNA strand breaks in rat liver cells after oral administration of doses up to 300 mg/kg (1770 mg/m2; >20 times the daily adult dose [90 mg] based on systemic exposure). Similarly, there was no induction of chromosomal aberrations in bone marrow cells of male or female mice after the administration of oral doses of up to 1000 mg/kg (3000 mg/m2; approximately 10 times the daily adult dose [90 mg] based on systemic exposure).
Impairment of Fertility: In female rats administered etoricoxib, there were no adverse effects for maternotoxicity, fertility and embryonic/fetal survival at dosages of 10 mg/kg/day (approximately equivalent to the daily adult human dose [90 mg] based on systemic exposure). At dosages of 30 mg/kg/day (approximately 3 times the daily adult human dose [90 mg] based on systemic exposure), there were treatment-related decreases in the number of implants.
High placental transfer of etoricoxib occurred in rabbits treated with 45 mg/kg/day (approximately 3 times the daily adult human dose [90 mg] based on systemic exposure), as evidenced by rabbit fetal plasma levels of approximately 60-70% of the mean maternal plasma drug levels. In pregnant rats treated with 15 mg/kg/day (approximately 1.5 times the daily adult human dose [90 mg] based on systemic exposure), there was approximately 70-80% placental transfer of etoricoxib.
Significant concentrations of etoricoxib were observed in the milk of lactating rats. The mean milk drug concentrations were approximately 2-fold the mean maternal plasma concentrations in rats administered doses up to 15 mg/kg/day (approximately 1.5 times the daily adult human dose [90 mg] based on systemic exposure).
There were no treatment-related effects on mating performance, fertility indices, embryonic/fetal survival, sperm count, motility, testicular/epididymal organ weights or histology in male rats administered dosages of etoricoxib up to 100 mg/kg/day (>6 times the daily adult human dose [90 mg] based on systemic exposure).
Use in pregnancy: As with other drugs known to inhibit prostaglandin synthesis, use of Arcoxia should be avoided in late pregnancy because it may cause premature closure of the ductus arteriosus.
Reproductive studies conducted in rats and rabbits have demonstrated no evidence of developmental abnormalities at doses up to 15 mg/kg/day and 45 mg/kg/day, respectively (approximately 1.5 times [rat] and approximately 3 times [rabbit] the human dose [90 mg] based on systemic exposure). However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Arcoxia should be used during the first 2 trimesters of pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in lactation: Etoricoxib is excreted in the milk of lactating rats. It is not known whether Arcoxia is excreted in human milk. Because many drugs are excreted in human milk and because of the possible adverse effects of drugs that inhibit prostaglandin synthesis on nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Use in children: Safety and effectiveness of etoricoxib in pediatric patients have not been established.
Use in the elderly: Pharmacokinetics in the elderly (≥65 years) are similar to those in the young. In clinical studies, no overall differences in safety or effectiveness were observed between elderly and younger patients.
