Arcoxia

Arcoxia

etoricoxib

Manufacturer:

Merck Sharp & Dohme

Marketer:

Transfarma Medica Indah
Full Prescribing Info
Contents
Etoricoxib.
Action
Arcoxia (etoricoxib) is a member of a class of arthritis/analgesia medications called coxibs. It is a highly selective inhibitor of cyclooxygenase-2 (COX-2).
Pharmacology: Mechanism of Action: Arcoxia is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activities in animal models. Arcoxia is a potent, orally active, highly selective COX-2 inhibitor within and above the clinical dose range. Two isoforms of cyclooxygenase have been identified: Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is responsible for prostaglandin-mediated normal physiologic functions eg, gastric cytoprotection and platelet aggregation. Inhibition of COX-1 by nonselective NSAIDs has been associated with gastric damage and platelet inhibition. COX-2 has been shown to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation and fever. Selective inhibition of COX-2 by etoricoxib decreases these clinical signs and symptoms with decreased GI toxicity and without effects on platelet function.
Across clinical pharmacology studies, Arcoxia produced dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily.
The influence on gastroprotective COX-1 activity was also assessed in a clinical study where prostaglandin synthesis was measured in gastric biopsy samples from subjects administered either Arcoxia 120 mg daily, naproxen 500 mg twice daily or placebo. Arcoxia did not inhibit gastric prostaglandin synthesis as compared to placebo. In contrast, naproxen inhibited gastric prostaglandin synthesis by approximately 80% compared with placebo. These data further support the COX-2 selectivity of Arcoxia.
Platelet Function: Multiple doses of Arcoxia up to 150 mg administered daily up to 9 days had no effect on bleeding time relative to placebo. Similarly, bleeding time was not altered in a single-dose study with Arcoxia 250 or 500 mg. There was no inhibition of ex vivo arachidonic acid- or collagen-induced platelet aggregation at steady-state with doses of Arcoxia up to 150 mg. These findings are consistent with the COX-2 selectivity of etoricoxib.
Pharmacokinetics: Absorption: Orally administered etoricoxib is well absorbed. The mean oral bioavailability is approximately 100%. Following 120-mg once-daily dosing to steady-state, the peak plasma concentration (geometric mean Cmax = 3.6 mcg/mL) was observed at approximately 1 hr (Tmax) after administration to fasted adults. The geometric mean AUC0-24hr was 37.8 mcg·hr/mL. The pharmacokinetics of etoricoxib are linear across the clinical dose range.
In studies specifically designed to measure the onset of action of etoricoxib, the onset of action occurred as early as 29 min after dosing.
A standard meal had no clinically meaningful effect on the extent or rate of absorption of a dose of etoricoxib 120 mg. In clinical trials, etoricoxib was administered without regards to food.
The pharmacokinetics of etoricoxib in 12 healthy subjects were similar (comparable AUC, Cmax within approximately 20%) when administered alone, with a magnesium/aluminum hydroxide antacid or a calcium carbonate antacid (approximately 50 mEq acid-neutralizing capacity).
Distribution: Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of 0.05-5 mcg/mL. The volume of distribution at steady-state (Vdss) 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 cytochrome P-450 (CYP) enzymes.
Five metabolites have been identified in man. The principal metabolite is the 6'-carboxylic acid 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 IV 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 7 days of once-daily administration of 120 mg, with an accumulation ratio of approximately 2, corresponding to an accumulation t½ of approximately 22 hrs. The plasma clearance is estimated to be approximately 50 mL/min.
Characteristics in Patients (Special Populations): Gender: The pharmacokinetics of etoricoxib are similar between men and women (see Dosage & Administration).
Elderly: Pharmacokinetics in the elderly (≥65 years) are similar to those in the young. No dosage adjustment is necessary for elderly patients (see Dosage & Administration).
Race: There is no clinically important effect of race on the pharmacokinetics of etoricoxib (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. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9). (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) have not been studied.
In a pharmacokinetic study (N=16) conducted in adolescents (12-17 years) the pharmacokinetics in adolescents weighing 40-60 kg given etoricoxib 60 mg once daily and in 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 established.
Toxicology: Acute Toxicity: The approximate oral LD50 was 1499 mg/kg in both female mice and rats, while the intraperitoneal approximate oral LD50 was 599 mg/kg in female mice and 238 mg/kg in female rats. The approximate oral LD50 in rats and mice are >12 times the acute daily adult human dose (120 mg) based on systemic exposure.
Chronic Toxicity: The toxicity potential of etoricoxib was evaluated in a series of repeated-dose oral toxicity studies up to 53 weeks in dogs and rats. In each species, the principal treatment-related changes were associated with renal and gastrointestinal toxicity. Both the renal and gastrointestinal lesions were shown to occur at dosages above the intended chronic clinical dose of 90 mg daily.
In dogs, etoricoxib administered orally at dosages of 200 mg/kg/day (approximately 20 times the daily adult human dose [90 mg] based on systemic exposure) for 14 weeks, toxicity was characterized by gastritis, gastrointestinal ulceration and renal papillary necrosis. No toxicity was seen in dogs administered 50 mg/kg/day (approximately 3 times the daily adult human dose based on systemic exposure) for 53 weeks.
In rats, etoricoxib administered orally at dosages of 30 mg/kg/day (approximately 3 times the daily adult human dose [90 mg] based on systemic exposure) following 27 weeks of administration produced gastrointestinal ulceration, as well as increased hepatic weights in female rats. At 53 weeks, the increased hepatic weights observed correlated with centrilobular hepatocellular hypertrophy due to hepatic CYP enzyme induction. No renal or gastrointestinal changes were noted in rats administered 10 mg/kg/day for 53 weeks (approximately equivalent to the daily adult human dose based on systemic exposure).
Teratogenicity: No teratogenic effects were observed in rabbits and rats administered etoricoxib at doses up to 10 mg/kg/day and 15 mg/kg/day, respectively (approximately equal to and approximately 1.5 times, respectively, the daily adult human dose [90 mg] based on systemic exposure).
Indications/Uses
Symptomatic relief in the treatment of osteoarthritis (OA). Relief of chronic musculoskeletal pain and acute pain associated with dental surgery.
Dosage/Direction for Use
Arcoxia is administered orally. It may be taken with or without food. Recommended Dose: Arthritis/Osteoarthritis: 60 mg once daily. Analgesia/Acute Pain Associated with Dental Surgery: 120 mg once daily. Arcoxia 120 mg should be used only for the acute symptomatic period.
Chronic Musculoskeletal Pain: 60 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 each indication is the maximum recommended dose.
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. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9). (See Precautions.)
Renal Insufficiency: In patients with advanced renal disease (CrCl <30 mL/min), treatment with Arcoxia is not recommended. No dosage adjustment is necessary for patients with lesser degrees of renal insufficiency (CrCl ≥30 mL/min). (See Precautions.)
Elderly, Gender, Race: No dosage adjustment in Arcoxia is necessary.
Overdosage
No overdoses of Arcoxia were reported during clinical trials. In clinical studies, administration of Arcoxia at single doses up to 500 mg and multiple doses up to 150 mg/day for 21 days did not result in significant toxicity.
In the event of an overdose, it is reasonable to employ the usual supportive measures eg, removing unabsorbed material from the gastrointestinal tract, employing clinical monitoring, and instituting supportive therapy, if required.
Etoricoxib is not dialyzable by hemodialysis; it is not known whether etoricoxib is dialyzable by peritoneal dialysis.
Contraindications
Patients with hypersensitivity to any component of Arcoxia; congestive heart failure (NYHA II-IV); established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease [including patients who have recently undergone coronary artery bypass graft (CABG) surgery or angioplasty].
Warnings
Cardiovascular Effects: Cardiovascular Thrombotic Events: Clinical trials of several COX-2 selective and nonselective NSAIDs up to 3 years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events.
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of MI and stroke (see Contraindications).
Hypertension: NSAIDs, including Arcoxia, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Arcoxia, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Edema: Fluid retention and edema have been observed in some patients taking NSAIDs. Arcoxia should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects: Risk of Ulceration, Bleeding and Perforation: NSAIDs, including Arcoxia, can cause serious GI adverse events including inflammation, bleeding, ulceration and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only 1 in 5 patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for 1 year. These trends continue with longer duration of use, 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.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a >10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
To reduce the risk of gastrointestinal effect on NSAID therapy, the lowest effective dose must be given in short term therapy. Doctor and patients must be cautioned on signs and symptoms of ulceration and GI bleeding during NSAID therapy. If there is serious GI effects suspected, evaluate immediately and give additional treatment. For high-risk patients, alternative therapy that does not include NSAID can be considered.
Special Precautions
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.
Use In Pregnancy & Lactation
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.
Adverse Reactions
In clinical trials, Arcoxia was evaluated for safety in approximately 4800 individuals, including approximately 3400 patients with OA, RA or chronic low back pain (approximately 600 patients with OA or RA were treated for 1 year or longer).
The following drug-related adverse experiences were reported in clinical studies in patients with OA, RA or chronic low back pain treated for up to 12 weeks. These occurred in ≥1% of patients treated with Arcoxia and at an incidence greater than placebo: Asthenia/fatigue, dizziness, lower extremity edema, hypertension, dyspepsia, heartburn, nausea, headache, increased ALT and AST.
The adverse experience profile was similar in patients with OA or RA treated with Arcoxia for 1 year or longer.
Seven thousand one hundred eleven (7111) patients were enrolled in an additional study in OA that compared the GI tolerability of etoricoxib 90 mg once daily (1.5 times above the dose recommended for OA) and diclofenac sodium 50 mg 3 times daily over a mean period of 9 months. The adverse experience profile on Arcoxia was generally similar to that reported in the Phase IIb/III placebo-controlled clinical studies; however, hypertension adverse experiences occurred at a higher rate on Arcoxia than on diclofenac.
In the initial clinical development program, approximately 3100 patients were treated with etoricoxib 60 mg daily for 12 weeks or longer. There was no discernible difference in the rate of serious thrombotic cardiovascular events between patients receiving etoricoxib 60 mg or non-naproxen NSAIDs. However, 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 Arcoxia 90 mg once daily for up to 1 year (n=126). The adverse experience profile in this study 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 Arcoxia 120 mg once daily for 8 days.
In clinical studies for acute analgesia, patients were treated with Arcoxia 120 mg once daily for 1-7 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.
Post-Marketing Experience: The following adverse reactions have been reported in post-marketing experience: Immune System Disorders: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions.
Psychiatric Disorders: Anxiety, insomnia, confusion, hallucinations.
Nervous System Disorders: Dysgeusia, somnolence.
Cardiac Disorders: Congestive heart failure.
Vascular Disorders: Hypertensive crisis.
Respiratory, Thoracic and Mediastinal Disorders: Bronchospasm.
Gastrointestinal Disorders: Abdominal pain, oral and peptic ulcers including perforation and bleeding (mainly in elderly patients), vomiting, diarrhea.
Hepatobiliary Disorders: Hepatitis.
Skin and Subcutaneous Tissue Disorders: Angioedema, pruritus, rash, Stevens-Johnson syndrome, urticaria.
Renal and Urinary Disorders: Renal insufficiency, including renal failure, usually reversible upon discontinuation of therapy (see Precautions).
Drug Interactions
Warfarin: In subjects stabilized on chronic warfarin therapy, the administration of Arcoxia 120 mg daily was associated with an approximate 13% increase in International Normalized Ratio (INR) prothrombin time. Standard monitoring of INR values should be conducted when therapy with Arcoxia is initiated or changed, particularly in the first few days, in patients receiving warfarin or similar agents.
Rifampin: Co-administration of Arcoxia 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 Arcoxia is co-administered with rifampin.
Methotrexate: Two studies investigated the effects of Arcoxia 60, 90 or 120 mg administered once daily for 7 days in patients receiving once-weekly methotrexate doses of 7.5-20 mg for rheumatoid arthritis. Arcoxia at 60 mg and 90 mg had no effect on methotrexate plasma concentrations (as measured by AUC) or renal clearance. In one study, Arcoxia 120 mg had no effect on methotrexate plasma concentrations (as measured by AUC) or renal clearance. In the other study, Arcoxia 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 Arcoxia at doses >90 mg daily and methotrexate are administered concomitantly.
Diuretics, Angiotension 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 Arcoxia concomitantly with these products.
Lithium: Reports suggest that nonselective NSAIDs and selective COX-2 inhibitors may increase plasma lithium levels. This interaction should be given consideration in patients taking Arcoxia concomitantly with lithium.
Aspirin: Arcoxia can be used concomitantly with low-dose aspirin at doses for cardiovascular prophylaxis. However, concomitant administration of low-dose aspirin with Arcoxia results in an increased rate of GI ulceration or other complications compared to use of Arcoxia alone. At steady-state, etoricoxib 120 mg once daily had no effect on the antiplatelet activity of low-dose aspirin (81 mg once daily). (See Precautions).
Oral Contraceptives: Arcoxia 60 mg given concomitantly with an oral contraceptive containing 35 mcg ethinyl estradiol (EE) and 0.5-1 mg norethindrone for 21 days increased the steady state AUC0-24hr of EE by 37%. Arcoxia 120 mg given with the same oral contraceptive concomitantly or separated by 12 hrs, increased the steady-state AUC0-24hr of EE by 50-60%. 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 (eg, venous thromboembolic events in women at risk).
Hormone Replacement Therapy: Administration of Arcoxia 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 Arcoxia (60 mg and 90 mg) has not been studied. The effects of Arcoxia 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 0.625-1.25 mg. The clinical significance of these increases is unknown and higher doses of Premarin were not studied in combination with Arcoxia. These increases in estrogenic concentration should be taken into consideration when selecting postmenopausal hormone therapy for use with Arcoxia.
Others: In drug interaction studies, Arcoxia did not have clinically important effects on the pharmacokinetics of prednisone/prednisolone or digoxin.
Antacids and ketoconazole (a potent inhibitor of CYP3A4) did not have clinically important effects on the pharmacokinetics of Arcoxia.
Storage
Store below 30°C.
MIMS Class
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
ATC Classification
M01AH05 - etoricoxib ; Belongs to the class of non-steroidal antiinflammatory and antirheumatic products, coxibs.
Presentation/Packing
Form
Arcoxia FC tab 120 mg
Packing/Price
30's (Rp363,000/pak)
Form
Arcoxia FC tab 60 mg
Packing/Price
30's (Rp257,400/pak)
Form
Arcoxia FC tab 90 mg
Packing/Price
30's (Rp280,500/pak)
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