Etrobax

Etoricoxib.

ETROBAX 60: Each tablet contains Etoricoxib 60 mg.
ETROBAX 90: Each tablet contains Etoricoxib 90 mg.
ETROBAX 120: Each tablet contains Etoricoxib 120 mg.
Excipients/Inactive Ingredients: Microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium, magnesium stearate, opadry, purified water.

Pharmacology: Pharmacodynamics: Mechanism of Action: Etoricoxib is an oral, selective cyclooxygenase-2 (COX-2) inhibitor within the clinical dose range.
Across reported clinical pharmacology studies, etoricoxib produced dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily. Etoricoxib did not inhibit gastric prostaglandin synthesis and had no effect on platelet function.
Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by pro-inflammatory stimuli and has been postulated to be primarily 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 (fever induction, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in man but its relevance to ulcer healing has not been established.
Pharmacokinetics: Absorption: Orally administered etoricoxib is well absorbed. The absolute bioavailability is approximately 100%. Following 120-mg once-daily dosing to steady state, the peak plasma concentration (geometric mean C_max=3.6 mcg/mL) was reported at approximately 1 hour (T_max) after the administration to fasted adults. The geometric mean area under the curve (AUC_0-24hr) was 37.8 mcg•hr/mL. The pharmacokinetics of etoricoxib are linear across the clinical dose range.
Dosing with food (a high-fat meal) had no effect on the extent of absorption of etoricoxib after administration of a 120-mg dose. The rate of absorption was affected, resulting in a 36% decrease in C_max and an increase in T_max by 2 hours. These data are not considered clinically significant. In reported clinical trials, etoricoxib was administered without regard to food intake.
Distribution: Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of 0.05 to 5 mcg/mL. The volume of distribution at steady state (V_dss) is approximately 120 L in humans.
Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.
Metabolism: Etoricoxib is extensively metabolized with <1% of a dose recovered in urine as the parent drug. The major route of metabolism to form the 6'-hydroxymethyl derivative is catalyzed by CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies report that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles in vivo have not been reported.
Five metabolites have been identified in man. The principal metabolite is the 6'-carboxylicacid derivative of etoricoxib formed by further oxidation of the 6'-hydroxymethyl derivative. These principal metabolites either demonstrate no measurable activity or are only weakly active as COX-2 inhibitors. None of these metabolites inhibit COX-1.
Elimination: Following administration of a single 25-mg radiolabeled intravenous dose of etoricoxib to healthy subjects, 70% of radioactivity was recovered in urine and 20% in feces, mostly as metabolites. Less than 2% was recovered as unchanged drug.
Elimination of etoricoxib occurs almost exclusively through metabolism followed by renal excretion. Steady state concentrations of etoricoxib are reached within seven days of once daily administration of 120 mg, with an accumulation ratio of approximately 2, corresponding to a half-life of approximately 22 hours. The plasma clearance after a 25-mg intravenous dose is estimated to be approximately 50 mL/min.
Characteristics in Patients: Elderly: Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young. (See DOSAGE & ADMINISTRATION.)
Gender: The pharmacokinetics of etoricoxib are similar between men and women. (See DOSAGE & ADMINISTRATION.)
Hepatic Insufficiency: Patients with mild hepatic insufficiency (Child-Pugh score 5-6) administered etoricoxib 60 mg once daily had an approximately 16% higher mean AUC as compared to healthy subjects given the same regimen. Patients with moderate hepatic insufficiency (Child-Pugh score 7-9) administered etoricoxib 60 mg every other day had similar mean AUC to the healthy subjects given etoricoxib 60 mg once daily; etoricoxib 30 mg once daily has not been reported in this population. There are no clinical or pharmacokinetic data reported in patients with severe hepatic insufficiency (Child-Pugh score ≥10). (See DOSAGE & ADMINISTRATION.)
Renal Insufficiency: The pharmacokinetics of a single dose of etoricoxib 120 mg in patients with moderate-to-severe renal insufficiency and patients with end-stage renal disease on hemodialysis were not significantly different from those in healthy subjects. Hemodialysis contributed negligibly to elimination (dialysis clearance approximately 50 mL/min).
Pediatric Patients: The pharmacokinetics of etoricoxib in pediatric patients (<12 years old) have not been reported.
In the reported pharmacokinetic study (N=16) conducted in adolescents (aged 12 to 17) the pharmacokinetics in adolescents weighing 40 to 60 kg given etoricoxib 60 mg once daily and adolescents >60 kg given etoricoxib 90 mg once daily were similar to the pharmacokinetics in adults given etoricoxib 90 mg once daily. Safety and effectiveness of etoricoxib in pediatric patients have not been reported.

ETROBAX is indicated for: Acute and chronic treatment of the signs and symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA).
Treatment of ankylosing spondylitis (AS).
Treatment of acute gouty arthritis.
Relief of chronic musculo-skeletal pain, including chronic low back pain.
Relief of acute pain including dental surgery.
Treatment of primary dysmenorrhea.
Treatment of moderate to severe acute post-operative pain associated with abdominal gynecological surgery.
The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks (see PRECAUTIONS).

Etoricoxib is administered orally, etoricoxib may be taken with or without food. Etoricoxib should be administered for the shortest duration possible and the lowest effective daily dose should be used.
Osteoarthritis: The recommended dose is 30 mg or 60 mg once daily.
Rheumatoid Arthritis: The recommended dose is 60 mg or 90 mg once daily. The minimum effective daily dose is 60mg once daily. In some patients, 90 mg once daily may provide increased therapeutic benefit.
Ankylosing Spondylitis: The recommended dose is 60 mg or 90 mg once daily. The minimum effective daily dose is 60 mg once daily in some patients, 90 mg once daily may provide increased therapeutic benefit.
Chronic musculo-skeletal pain, including chronic low back pain: The recommended dose is 60 mg once daily.
Acute Pain: For acute pain conditions, the recommended dose is 90 mg or 120 mg once daily. Etoricoxib should be used only for the acute symptomatic period limited to a maximum of 8 days.
Acute Gouty Arthritis: The recommended dose is 120 mg once daily.
Primary Dysmenorrhea: The recommended dose is 120 mg once daily.
Post-operative Dental Pain: The recommended dose is 90 mg once daily.
Post-operative Gynecological Pain: The recommended dose is 90 mg once daily. The initial dose should be administered shortly before surgery. The dose can be increased to a maximum 120 mg once daily.
Doses greater than those recommended for each indication have either not demonstrated additional efficacy or have not been studied. Therefore, the dose for OA should not exceed 60 mg daily.
The dose for RA should not exceed 90 mg daily.
The dose for ankylosing spondylitis should not exceed 90 mg daily.
The dose for acute gout should not exceed 120 mg daily.
The dose for acute pain and primary dysmenorrhea should not exceed 120 mg daily.
The dose of chronic pain should not exceed 60 mg daily.
The dose for post-operative acute dental surgery pain should not exceed 90 mg daily.
The dose for post-operative acute gynecological surgery pain should not exceed 120 mg daily.
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 (see PRECAUTIONS).
Elderly, Gender, Race: No dosage adjustment in etoricoxib is necessary for the elderly or based on gender or race.
Hepatic Insufficiency: In patients with mild hepatic insufficiency (Child-Pugh score 5-6), a dose of 60 mg once daily should not be exceeded.
In patients with moderate hepatic insufficiency (Child-Pugh score 7-9), the dose should be reduced; a dose of 60 mg every other day should not be exceeded, administration of 30 mg once daily can also be considered. There are no clinical or pharmacokinetic data reported inpatients with severe hepatic insufficiency (Child-Pugh score >9) (see PRECAUTIONS).
Renal Insufficiency: In patients with advanced renal disease (creatinine clearance <30 mL/min), treatment with etoricoxib is not recommended. No dosage adjustment is necessary for patients with lesser degrees of renal insufficiency (creatinine clearance ≥30 mL/min).

In reported clinical studies, administration of etoricoxib at single doses up to 500 mg and multiple doses up to 150 mg/day for 21 days did not result in significant toxicity. There have been reports of acute overdosage with etoricoxib, although adverse experiences were not reported in the majority of cases. The most frequently observed adverse experiences were consistent with the safety profile for etoricoxib (e.g. gastrointestinal events, renovascular events).
In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.
Etoricoxib is not dialyzable by hemodialysis; it is not known whether etoricoxib is dialyzable by peritoneal dialysis.

Etoricoxib is contraindicated in: Patients with known hypersensitivity to any component of this product.
Patients with active peptic ulceration or gastro-intestinal (GI) bleeding.
Patients with severe hepatic dysfunction (Child-Pugh score >9).
Patients with estimated creatinine clearance <30 mL/min.
Patients who have developed signs of asthma, acute rhinitis, nasal polyps, angioneurotic oedema or urticaria following the administration of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).
Pregnancy and lactation.
Children under 16 years of age.
Patients with inflammatory bowel disease.
Patients with congestive heart failure (NYHA II-IV).
Patients with hypertension whose blood pressure has not been adequately controlled.
Patients with established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease (including patients who have recently undergone coronary artery bypass graft surgery or angioplasty).

The reported 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. 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 reported 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.
Caution should be used when initiating treatment with etoricoxib in patients with considerable dehydration. It is advisable to rehydrate patients prior to staring therapy with etoricoxib.
As with other drugs known to inhibit prostaglandin synthesis, fluid retention, edema and hypertension have been reported in some patients taking etoricoxib. The possibility of fluid retention, edema or hypertension should be taken into consideration when etoricoxib is used in patients with pre-existing edema, hypertension, or heart failure. All Nonsteroidal Anti-inflammatory Drugs (NSAIDs), including etoricoxib, can be associated with new onset or recurrent congestive heart failure. (see ADVERSE REACTIONS). 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.
Physicians should be aware that individual patients may develop upper gastrointestinal (GI) ulcers/ulcer complications irrespective of treatment. Although the risk of GI toxicity is not eliminated with etoricoxib, the results of the MEDAL Program demonstrate that in patient treated with etoricoxib, the risk of GI toxicity with etoricoxib 60 mg or 90 mg once daily is significantly less than with diclofenac 150 mg daily. In reported clinical studies with ibuprofen and naproxen the risk of endoscopically detected upper GI ulcers was lower in patients treated with etoricoxib 120 mg 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 120 mg, it was higher than in patients treated with placebo. Upper gastrointestinal complications (perforations, ulcers or bleedings (PUBs)), some of them resulting in fatal outcome, have occurred in patients treated with etoricoxib. These events can occur at anytime during use and without warning symptoms. Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; the elderly, patients using any other NSAID or acetylsalicylic acid concomitantly or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding.
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 reported clinical trials treated for up to one year with etoricoxib 30, 60 and 90 mg daily. In active comparator portions of reported clinical trials, the incidence of elevated AST and/or ALT in patients treated with etoricoxib 60 and 90 mg daily was similar to that of patients treated with naproxen 1000 mg daily, but notably less than the incidence in the diclofenac 150 mg daily group. These elevations resolved in patients treated with etoricoxib, with approximately half resolving while patients remained on therapy. In reported controlled clinical trials of etoricoxib 30 mg daily versus ibuprofen 2400 mg daily or celecoxib 200 mg daily, the incidence of elevations of ALT or AST was similar.
A patients 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 (three times the upper limit of normal) are detected, etoricoxib should be discontinued.
Etoricoxib should be used with caution in patients who have previously experienced acute asthmatic attacks, urticarial, or rhinitis, which were precipitated by salicylates or non-selective cyclooxygenase inhibitors. Since the pathophysiology of these reactions is unknown, physicians should weigh the potential benefits of prescribing etoricoxib versus the potential risk.
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, 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 ADVERSE REACTIONS). 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 inpatients receiving etoricoxib (see ADVERSE REACTIONS). 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, which is a sign of infection. The physician should be aware of this when using etoricoxib in patients being treated for infection.
The use of etoricoxib, as with any drug known to inhibit COX-2, is not recommended in woman attempting to conceive.

Pregnancy: The use of etoricoxib, as with any drug substance 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 reported reproductive toxicity. The potential for human risk in pregnancy is unknown. Etoricoxib, as with other medicinal products inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Etoricoxib is contraindicated in pregnancy. If a woman becomes pregnant during treatment, etoricoxib must be discontinued.
Reproductive studies conducted in rats have reported no evidence of developmental abnormalities at doses up to 15 mg/kg/day (approximately 1.5 times the human dose (90 mg) based on systemic exposure). At doses approximately 2 times the adult human exposure (90 mg) based on systemic exposure, a low incidence of cardiovascular malformations and increase in post implantation loss were observed in etoricoxib-treated rabbits. No developmental effects were seen at systemic exposure of approximately equal to or less than the daily human dosage (90 mg). However, there was a decrease in embryo/foetal survival at exposures greater than or equal to 1.5 times the human exposure. Animal reproduction studies are not always reported to be predictive of human response. There are no adequate and well-controlled studies in pregnant women.
Lactation: It is not known whether etoricoxib is excreted in human milk. Etoricoxib is excreted in the milk of lactating rats. Women who use etoricoxib must not breast feed.

In reported clinical trials, etoricoxib was evaluated for safety in 9295 individuals, including 5774 patients with OA, RA or chronic low back pain (approximately 600 patients with OA or RA were treated for one year or longer).
The following drug-related adverse experiences were reported in reported clinical studies inpatients with OA, RA, or chronic low back pain treated with etoricoxib 60 or 90 mg for up to 12 weeks. These common adverse experiences occurred in ≥1% and <10% of patients treated with etoricoxib and at an incidence greater than placebo: asthenia/fatigue, dizziness, oedema/fluid retention, lower extremity edema, flu-like disease, hypertension, abdominal pain, flatulence, diarrhea, dyspepsia, heartburn, epigastric discomfort, nausea, headache, ALT increased, AST increased.
The adverse experience profile was similar in patients with OA or RA treated with etoricoxib for one year or longer.
In the reported MEDAL Study, an endpoint driven CV outcomes trial involving 23,504 patients, the safety of etoricoxib 60 or 90 mg daily was compared to diclofenac 150 mg daily in patients with OA or RA (mean duration of treatment was 20 months). In this reported large trial, only serious adverse events and discontinuations due to any adverse events were reported. The rates of confirmed thrombotic cardiovascular serious adverse events were similar between etoricoxib and diclofenac. The incidence of discontinuations for hypertension-related adverse events was less than 3% in each treatment group; however, etoricoxib 60 and 90 mg demonstrated significantly higher rates of discontinuations for these events than diclofenac. The incidence of congestive heart failure adverse events (discontinuations and serious events) and the incidence of discontinuations due to edema occurred at similar rates on etoricoxib 60 mg compared to diclofenac; however, the incidences for these events were higher for etoricoxib 90 mg compared to diclofenac. The incidence of discontinuations due to atrial fibrillation was higher for etoricoxib compared to diclofenac.
The reported EDGE and EDGE II studies compared the GI tolerability of etoricoxib 90 mg daily (1.5 to 3 times the doses recommended for OA) and diclofenac 150 mg daily in 7111 patients with OA (EDGE Study; mean duration of treatment 9 months) and 4086 patients with RA (EDGE II; mean duration of treatment 19 months). In each of these reported studies, the adverse experience profile on etoricoxib was generally similar to that reported in the phase IIb/III placebo-controlled clinical studies; however, hypertension and edema-related adverse experiences occurred at a higher rate on etoricoxib 90 mg than on diclofenac 150 mg daily. The rate of confirmed thrombotic cardiovascular serious adverse events occurring in the two treatment groups was similar.
In a reported 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 reported clinical study for ankylosing spondylitis, patients were treated with etoricoxib 90 mg once daily for up to 1 year (N=126). In another reported 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 reported 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 reported 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 the additional reported clinical studies for acute post-operative pain associated with dental and abdominal gynecological surgeries 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 reported 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 adverse reactions occurred in less than 1% of patients and were reported at an incidence greater than placebo in reported clinical trials 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 have been reported in post-marketing experience.
Blood and lymphatic system disorders: thrombocytopenia.
Infections and infestation: gastroenteritis, upper respiratory infection, urinary tract infection.
Immune system disorders: hypersensitivity reactions, including angioedema, anaphylactic/anaphylactoid reactions including shock.
Metabolism and nutrition disorders: appetite increase or decrease, weight gain, hyperkalemia.
Psychiatric disorders: anxiety, depression, mental acuity decreased, confusion, hallucinations, restlessness.
Nervous system disorders: dysgeusia, insomnia, paresthaesia/hypaesthesia, somnolence.
Eye disorders: blurred vision.
Ear and labyrinth disorders: tinnitus.
Cardiac disorders: congestive heart failure, non-specific ECG changes, myocardial infarction, palpitations, angina, arrhythmia.
Vascular disorders: flushing, cerebrovascular accident, hypertensive crisis.
Respiratory, thoracic and mediastinal disorders: cough, dyspnoea, epistaxis, bronchospasm.
Gastrointestinal disorders: abdominal distention, acid reflux, bowel movement pattern change, constipation, dry mouth, gastroduodenal ulcer, irritable bowel syndrome, oesophagitis, oral ulcers, peptic ulcers including perforation and bleeding (mainly in elderly patients), vomiting, gastritis.
Hepatobiliary disorders: hepatitis, jaundice, hepatic failure.
Skin and subcutaneous tissue disorders: ecchymosis, facial oedema, pruritus, erythema, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticarial, fixed drug eruption.
Musculoskeletal, connective tissue and bone disorders: muscular cramp/spasm, musculoskeletal pain/stiffness.
Renal and urinary disorders: proteinuria, renal insufficiency, including renal failure (see PRECAUTIONS).
General disorders and administration site conditions: chest pain.
Investigations: blood urea nitrogen increased, creatinine phosphokinase increased, haematocrit decreased, haemoglobin decreased, hyperkalaemia, leukocytes decreased, platelets decreased, serum creatinine increased, uric acid increased.
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.

Warfarin: In subjects stabilized on chronic warfarin therapy, the administration of etoricoxib 120 mg daily was associated with an approximate 13% increase in prothrombin time International Normalized Ratio (INR). Standard monitoring of INR values should be conducted when therapy with etoricoxib is initiated or changed, particularly in the first few days, in patients receiving warfarin or similar agents.
Rifampin: Co-administration of etoricoxib with rifampin, a potent inducer of hepatic metabolism, produced a 65% decrease in etoricoxib plasma area under the curve (AUC). This interaction should be considered when etoricoxib is co-administered with rifampin.
Methotrexate: Two reported 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 (as measured by AUC) or renal clearance. In one reported study, etoricoxib 120 mg had no effect on methotrexate plasma concentrations (as measured by AUC) or renal clearance. In the other reported study, etoricoxib 120 mg increased methotrexate plasma concentrations by 28% (as measured by AUC) and reduced renal clearance of methotrexate by 13%. Monitoring for methotrexate-related toxicity should be considered when etoricoxib at doses greater than 90 mg daily and methotrexate are administered concomitantly.
Diuretics, Angiotensin Converting Enzyme (ACE) Inhibitors and Angiotensin II Antagonists (AIIAs): Reports suggest that NSAIDs including selective COX-2 inhibitors may diminish the antihypertensive effect of diuretics; ACE inhibitors and AIIAs. 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 or patients who are volume-depleted, including those on diuretic therapy) who are being treated with nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors, the co-administration of ACE inhibitors or AIIAs may result in a 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. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.
Lithium: Reports suggest that non-selective NSAIDs and selective COX-2 inhibitors may increase plasma lithium levels. This interaction should be given consideration in patients taking etoricoxib concomitantly with lithium.
Aspirin: Etoricoxib can be used concomitantly with low-dose aspirin at doses for cardiovascular prophylaxis. At steady state, etoricoxib 120 mg once daily had no effect on the anti-platelet activity of low-dose aspirin (81 mg once daily). However, concomitant administration of low-dose aspirin with etoricoxib increase the rate of GI ulceration or other complications compared to use of etoricoxib alone. Concomitant administration of etoricoxib with doses of aspirin above those for cardiovascular prophylaxis or with other NSAIDs is not recommended (see PRECAUTIONS).
Cyclosporin and tacrolimus: Although this interaction has not been reported with etoricoxib, coadministration 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 are used in combination.
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 AUC_0-24hr of EE by 37%. Etoricoxib 120 mg given with the same oral contraceptive, either concomitantly or separated by 12 hours, increased the steady state AUC_0-24hr 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) for 28 days, increased the mean steady state AUC_0-24hr 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 reported. The effects of etoricoxib 120 mg on the exposure (AUC_0-24hr) to these estrogenic components of conjugated estrogens were less than half of those observed when conjugated estrogens 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 conjugated estrogens 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 oestrogen exposure might increase the risk of adverse events associated with HRT.
Prednisone/prednisolone: In reported 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 after the steady-state plasma AUC_0-24hr or renal elimination of digoxin. There was an increase in digoxin C_max (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.
Effect of etoricoxib on drugs metabolised by sulfotransferases: 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).
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).
Antacids: do not have clinically important effects on the pharmacokinetics of etoricoxib.

Do not store above 30°C.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AH05 - etoricoxib ; Belongs to the class of non-steroidal antiinflammatory and antirheumatic products, coxibs.

D