Coxicare Special Precautions

Cardiovascular effects: Clinical trials suggest that the selective COX-2 inhibitor class of drugs may be associated with a risk of thrombotic events (especially MI and stroke), relative to placebo and some NSAIDs. Long term safety data beyond one year are not currently available for etoricoxib compared to placebo or NSAIDs other than diclofenac. In the MEDAL Program, there was no significant difference between etoricoxib and diclofenac in the rate of cardiovascular thrombotic events over a mean treatment duration of 18 months.
As the cardiovascular risks of etoricoxib 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. A combined analysis of controlled clinical trials in which patients were treated with etoricoxib ≥30mg daily for 4 weeks or longer was conducted to compare the incidence rate of serious thrombotic cardiovascular events among patients taking etoricoxib, placebo, naproxen or non-naproxen NSAIDs. This analysis was not powered to provide a precise estimate of the relative risk of CV events in patients taking etoricoxib versus the other treatments. The analysis showed a statistically significant increase in relative risk with etoricoxib vs. naproxen 1000mg with respect to the Anti-Platelet Trialists' Collaboration (APTC) combined endpoint (ie. cardiovascular, haemorrhagic and unknown death, non-fatal myocardial ischaemia, and non-fatal stroke) [RR 2.72 (95% CI 1.18, 6.27)]. This analysis did not demonstrate any statistically significant increase in the rate of serious thrombotic cardiovascular events in patients taking etoricoxib over those taking non-naproxen NSAIDs. Etoricoxib should be used with caution for patients with significant risk factors for cardiovascular events (including those with diabetes, hypertension, hypercholesterolaemia, a first degree relative with ischaemic heart disease, cardiac failure or who are smokers).
Aspirin substitution: COX-2 selective 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.
Gastrointestinal effects: Physicians should be aware that individual patients may develop upper gastrointestinal (GI) ulcers/ulcer complications irrespective of treatment. Although the risk of upper GI toxicity is not eliminated with Etoricoxib, the results of the MEDAL Program demonstrate that in patients treated with Etoricoxib, the risk of upper GI toxicity with Etoricoxib 60mg or 90mg once daily is significantly less than with diclofenac 150mg daily.
In clinical studies with ibuprofen and naproxen, the risk of endoscopically detected upper GI ulcers was lower in patients treated with Etoricoxib 120mg once daily than in patients treated with the non-selective NSAIDs. While the risk of endoscopically detected ulcers was low in patients treated with Etoricoxib 120mg it was higher than in patients treated with placebo. Upper GI ulcers/ulcer complications have occurred in patients treated with Etoricoxib. These events can occur at any time during use and without warning symptoms. Independent of treatment, patients with a prior history of 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.
Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
There is a further increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications) when etoricoxib is taken concomitantly with acetylsalicylic acid (even at low doses). A significant difference in GI safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been demonstrated in long-term clinical trials.
Renal effects: 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.
Caution should be used when initiating treatment with Etoricoxib in patients with considerable dehydration. It is advisable to rehydrate patients prior to starting therapy with Etoricoxib.
Fluid retention, oedema, hypertension: As with other drugs known to inhibit prostaglandin synthesis, fluid retention, oedema and hypertension have been observed in patients taking Etoricoxib. All Nonsteroidal Antiinflammatory Drugs (NSAIDs), including etoricoxib, can be associated with new onset or recurrent congestive heart failure. For information regarding a dose related response for etoricoxib.
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 CONTRAINDICATIONS) 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.
Hepatic effects: 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 90 mg and 120mg daily. In active comparator portions of clinical trials, the incidence of elevated AST and/or ALT in patients treated with Etoricoxib 90mg daily was similar to that of patients treated with naproxen 1000mg daily, but notably less than the incidence in the diclofenac 150mg daily group. These elevations resolved in patients treated with etoricoxib, with approximately half resolving while patients remained on therapy.
General: When using etoricoxib in the elderly and in patients with renal, hepatic, or cardiac dysfunction, medically appropriate supervision should be maintained. If these patients deteriorate during treatment, appropriate measures should be taken, including discontinuation of therapy.
Serious skin reactions: 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. These serious events may occur without warning. Patients appear to be at highest risk for these reactions early in the course of therapy: 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. 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.
Use in patients with Inflammatory Bowel Disease (IBD): NSAIDs have been associated with an exacerbation of IBD associated with spondyloarthropathies. There has only been limited study of etoricoxib in patients with IBD.
Use in patients with fever and infection: Etoricoxib may mask fever, which is a sign of infection. The physician should be aware of this when using etoricoxib in patients being treated for infection.
Effects on ability to drive and operate machinery: The effect of etoricoxib on the ability to drive or use machinery has not been studied. However, based on its pharmacodynamic properties and overall safety profile it is unlikely to have an effect on these activities.
Genotoxicity: Etoricoxib was not genotoxic in assays for gene mutations (in vitro bacterial and human lymphoblast [TK locus] cell assays), chromosomal damage (CHO cells in vitro, rat bone marrow in vivo) and other genotoxic effects (alkaline elution assay of DNA damage in vitro and in vivo, DNA adduct formation in vitro).
Carcinogenicity: When etoricoxib at doses ≥30mg/kg/day (>6 times the daily human dose [90mg]) was administered orally for up to 2 years in rats liver adenomas were observed in the males and females and thyroid follicular cell adenomas were observed in the males, as well. At the lower dose tested in this species (10mg/kg/day) hepatic cell and thyroid follicular cell hypertrophy were observed in both sexes, and were associated with systemic exposure (AUC0-24h) lower than that expected in humans at the maximum recommended dose of 120mg.
Etoricoxib was not carcinogenic in mice given oral doses up to 400mg/kg/day for males and up to 600mg/kg/day for females for two years. Systemic exposure (AUC0-24h) at these dose levels was similar to that in humans at the maximum recommended dose of 120mg.
Effects on fertility: Etoricoxib administered to male rats at oral doses up to 100mg/kg/day (systemic exposure about 4-fold greater than that in humans at the maximum recommended dose of 120mg/day, based on AUC0-24h) had no effects on mating performance, fertility, testicular/epididymal weights, or histology, or sperm count and motility. Etoricoxib produced post-implantation losses in female rats at oral doses of 30mg/kg/day (approximately 3-fold human exposure at 120mg daily based on the AUC0-24hr). These changes are expected with inhibition of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function (see PRECAUTIONS, Use in pregnancy as follows).
Use in pregnancy: Category C: Medicines which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis and, when given during the latter part of pregnancy, may cause closure of the foetal ductus arteriosis, foetal renal impairment, inhibition of platelet aggregation, and delay labour and birth.
There are no adequate and well-controlled studies in pregnant women. Etoricoxib should not be used during the first two trimesters of pregnancy unless the potential benefit justifies the potential risk to the foetus. As with other agents that inhibit prostaglandin synthesis, treatment with etoricoxib during the third trimester should be avoided because it may cause closure of the foetal ductus arteriosus.
High placental transfer of etoricoxib has been demonstrated in pregnant rats and rabbits. Etoricoxib treatment at oral doses ≥ 30mg/kg/day prior to or during gestation in pregnant rats or rabbits caused an increase in embryofetal resorptions and reduced the number of foetuses. Exposure to etoricoxib at the no-effect dose for increased resorption (10mg/kg/day in either species) was lower than that expected in humans after 120mg, based on AUC. Etoricoxib was not teratogenic in rats at oral doses of 45mg/kg/day (approximately 4-fold the expected human exposure at a dose of 120mg/day, based on AUC). A low incidence of ventricular septal defects and other cardiovascular malformations has been observed in rabbits given etoricoxib at oral doses producing exposure levels comparable to that expected in humans. Increased post-natal pup mortality with etoricoxib was observed at doses of 15 and 45mg/kg/day in rats. Maternal drug exposure at the no-effect dose for increased pup mortality (5mg/kg/day) was lower than human exposure at a dose of 120mg/day, based on AUC. In addition, reduced pup weights were observed after oral treatment of pregnant rats with etoricoxib doses of 45mg/kg/day during gestation and lactation.
Use in lactation: Etoricoxib is excreted in the milk of lactating rats at concentrations up to two-fold greater than the maximal maternal plasma concentration. 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: The pharmacokinetics of etoricoxib in paediatric patients (<12 years of age) have not been studied.
The pharmacokinetics in adolescents (aged 12 to 17) weighing 40 to 60kg given etoricoxib 60mg once daily and in adolescents >60kg given etoricoxib 90mg once daily were similar to the pharmacokinetics in adults given etoricoxib 90mg once daily.
Safety and effectiveness in patients aged below 18 years have not been established.
Use in the elderly: In each of these datasets, a higher incidence of adverse events was seen in older patients compared to younger patients; the relative differences between the etoricoxib and control groups were similar in the elderly and the young. Greater sensitivity of some older individuals cannot be ruled out. As with any NSAID, caution should be exercised in treating the elderly (65 years and older).