Ericox

Etoricoxib.

ERICOX 90 mg Tablets: Etoricoxib 90 mg.
ERICOX 120 mg Tablets: Etoricoxib 120 mg.
Excipients/Inactive Ingredients: Dibasic Anhydrous Calcium phosphate, Microcrystalline cellulose, Croscarmellose Sodium, Hydroxypropyl cellulose, Magnesium stearate, Opadry II 32K580000 White (90 mg strength), Opadry II 32K510022 Green (120 mg strength).

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, nonsteroids, coxibs. ATC code: M01AH05.
Pharmacology: Pharmacodynamics: Etoricoxib is an oral, selective cyclooxygenase-2 (COX-2) inhibitor within the clinical dose range.
Across 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 μg/ml) was observed at approximately 1 hour (T_max) after administration to fasted adults. The geometric mean area under the curve (AUC_0-24hr) was 37.8 μg·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.
Distribution: Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of 0.05 to 5 μg/ml. The volume of distribution at steady-state (V_dss) was approximately 1.20 L in humans. Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.
Biotransformation: Etoricoxib is extensively metabolised 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 indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles in vivo have not been studied.
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 intravenous dose of etoricoxib to healthy subjects, 70% of radioactivity was recovered in urine and 20% in faeces, 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.

Etoricoxib 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.
Treatment of acute pain, including that related to primary dysmenorrhoea and minor dental procedures.
The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks.

Recommended Dosage: Arthritis: Osteoarthritis: The recommended dose is 30 mg or 60 mg once daily.
Rheumatoid Arthritis: The recommended dose is 60 mg once daily. In some patients with insufficient relief from symptoms, an increased dose of 90 mg once daily may increase efficacy. Once the patient is clinically stabilised, down-titration to a 60 mg once daily dose may be appropriate. In the absence of an increase in therapeutic benefit, other therapeutic options should be considered.
Ankylosing Spondylitis: The recommended dose is 60 mg once daily. In some patients with insufficient relief from symptoms, an increased dose of 90 mg once daily may increase efficacy. Once the patient is clinically stabilised, down-titration to a 60 mg once daily dose may be appropriate. In the absence of an increase in therapeutic benefit, other therapeutic options should be considered.
Acute Gouty Arthritis: The recommended dose is 120 mg once daily. Etoricoxib 120 mg should be used only for the acute symptomatic period, limited to a maximum of 8 days treatment.
Analgesia: Acute Pain and Primary Dysmenorrhea: The recommended dose is 120 mg once daily. Etoricoxib 120 mg should be used only for the acute symptomatic period, limited to a maximum of 8 days treatment.
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.
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.
Minor Dental Procedure: The recommended dose is 90 mg once daily. Etoricoxib 90 mg should be used only for the acute symptomatic period, limited to a maximum of 8 days treatment.
The dose for minor dental procedures should not exceed 90 mg daily.
Given the association between cardiovascular risk and exposure to COX-2 Inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment.
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 in patients with severe hepatic insufficiency (Child-Pugh score >9).
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).
Safety and effectiveness of etoricoxib in pediatric patients have not been established.
Mode of Administration: Oral. Etoricoxib may be taken with or without food.

Administration of single doses of etoricoxib 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, cardiorenal events).
In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the GI tract, employ clinical monitoring, and institute supportive therapy, if required.
Etoricoxib is not dialysable by haemodialysis; it is not known whether etoricoxib is dialysable by peritoneal dialysis.

Hypersensitivity to the etoricoxib or to any of the following excipients listed in Description.
Active peptic ulceration or active gastro-intestinal (GI) bleeding.
Patients who, after taking acetylsalicylic acid or NSAIDs including COX-2 (cyclooxygenase-2) inhibitors, experience bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria, or allergic-type reactions.
Pregnancy and lactation (see Use in Pregnancy & Lactation).
Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score ≥10).
Estimated renal creatinine clearance <30 ml/min.
Children and adolescents under 16 years of age.
Inflammatory bowel disease.
Congestive heart failure (NYHA II-IV).
Patients with hypertension whose blood pressure is persistently elevated above 140/90 mmHg and has not been adequately controlled.
Established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.
Patients who have increased risk of cardiovascular disease (ischeamic heart disease and stroke).
Contraindication for Etoricoxib in patients with hypertension (high blood pressure) whose blood pressure is not under control.

Gastrointestinal effects: Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them resulting in fatal outcome, have occurred in patients treated with etoricoxib.
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.
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).
Cardiovascular effects: Selective COX-2 inhibitor class of drugs may be associated with a risk of thrombotic events (especially myocardial infarction (MI) and stroke), relative to placebo and some NSAIDs. 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, especially in patients with osteoarthritis.
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with etoricoxib after careful consideration.
COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thrombo-embolic diseases because of their lack of antiplatelet effect. Therefore antiplatelet therapies should not be discontinued.
Renal effects: 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.
Fluid retention, oedema and hypertension: As with other medicinal products known to inhibit prostaglandin synthesis, fluid retention, oedema and hypertension have been observed in patients taking etoricoxib. All Nonsteroidal Anti-inflammatory Drugs (NSAIDs), including etoricoxib, can be associated with new onset or recurrent congestive heart failure. For information regarding a dose related response for etoricoxib see Pharmacology: Pharmacodynamics under Actions. 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.
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 30, 60 and 90 mg daily.
Any patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored. If signs of hepatic insufficiency occur, or if persistently abnormal liver function tests (three times the upper limit of normal) are detected, etoricoxib should be discontinued.
Risk of GI Ulceration, Bleeding and Perforation with NSAID: Serious GI toxicity such as bleeding, ulceration and perforation can occur at any time, with or without warning symptoms, in patients treated with NSAID therapy. Although minor upper GI problems (e.g. dyspepsia) are common, usually developing early in therapy, prescribers should remain alert for ulceration and bleeding in patients treated with NSAIDs even in the absence of previous GI tract symptoms. Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Patients with prior history of serious GI events and other risk factors associated with peptic ulcer disease (e.g. alcoholism, smoking, and corticosteroid therapy) are at increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less than other individuals and account for most spontaneous reports for fatal GI events.
General: If during treatment, patients deteriorate in any of the organ system functions described previously, appropriate measures should be taken and discontinuation of etoricoxib therapy should be considered. Medically appropriate supervision should be maintained when using etoricoxib in the elderly and in patients with renal, hepatic, or cardiac dysfunction.
Caution should be used when initiating treatment with etoricoxib in patients with dehydration. It is advisable to rehydrate patients prior to starting therapy with etoricoxib.
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs and some selective COX-2 inhibitors during post-marketing surveillance. Patients appear to be at highest risk for these reactions early in the course of therapy with the onset of the reaction occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving etoricoxib. Some selective COX-2 inhibitors have been associated with an increased risk of skin reactions in patients with a history of any drug allergy. Etoricoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Etoricoxib may mask fever and other signs of inflammation.
Caution should be exercised when co-administering etoricoxib with warfarin or other oral anticoagulants (see Interactions).
The use of etoricoxib, as with any medicinal product known to inhibit cyclooxygenase/prostaglandin synthesis, is not recommended in women attempting to conceive.
Etoricoxib tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Warning to prescriber when prescribing COX-2 Inhibitors to patients with risk factors of heart disease, hypertension (high blood pressure), hyperlipidemia, diabetes, smoking patient and patient with peripheral arterial disease.
Effects on ability to drive and use machines: Patients who experience dizziness, vertigo or somnolence while taking etoricoxib should refrain from driving or operating machinery.

Pregnancy: No clinical data on exposed pregnancies are available for etoricoxib. Studies in animals have shown 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 (see Contraindications). If a woman becomes pregnant during treatment, etoricoxib must be discontinued.
Breastfeeding: 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 breastfeed (see Contraindications).
Fertility: The use of etoricoxib, as with any drug substance known to inhibit COX-2, is not recommended in women attempting to conceive.

Tabulated list of adverse reactions: The following undesirable effects were reported (see table):

Click on icon to see table/diagram/image

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.

Pharmacodynamic interactions: Oral anticoagulants: The administration of etoricoxib 120 mg daily was associated with an approximate 13% increase in prothrombin time International Normalised Ratio (INR). Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with etoricoxib is initiated or the dose of etoricoxib is changed (see Precautions).
Diuretics, ACE inhibitors and Angiotensin II Antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclooxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking etoricoxib concomitantly with ACE inhibitors or angiotensin II antagonists. 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.
Acetylsalicylic Acid: Etoricoxib 120 mg once daily had no effect on the anti-platelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be used concomitantly with acetylsalicylic acid at doses used for cardiovascular prophylaxis (low-dose acetylsalicylic acid). However, concomitant administration of low-dose acetylsalicylic acid with etoricoxib may result in an increased rate of GI ulceration or other complications compared to use of etoricoxib alone. Concomitant administration of etoricoxib with doses of acetylsalicylic acid above those for cardiovascular prophylaxis or with other NSAIDs is not recommended (see Pharmacology: Pharmacodynamics under Actions and Precautions).
Cyclosporin and tacrolimus: Although this interaction has not been studied 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 is used in combination.
Pharmacokinetic interactions: The effect of etoricoxib on the pharmacokinetics of other drugs: Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary, monitor blood lithium closely and adjust the lithium dosage while the combination is being taken and when the NSAID is withdrawn.
Methotrexate: Etoricoxib at 60 and 90 mg had no effect on methotrexate plasma concentrations or renal clearance. Etoricoxib 120 mg had no effect, but in the other study, etoricoxib 120 mg increased methotrexate plasma concentrations by 28% and reduced renal clearance of methotrexate by 13%. Adequate monitoring for methotrexate-related toxicity is recommended when etoricoxib and methotrexate are administered concomitantly.
Oral contraceptives: Etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35 micrograms 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 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 (HRT): 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 studied.
Prednisone/prednisolone: Etoricoxib did not have clinically important effects on the pharmacokinetics of prednisone/prednisolone.
Digoxin: Etoricoxib 120 mg administered once daily for 10 days to healthy volunteers did not alter the steady-state plasma 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).
Effect of etoricoxib on drugs metabolised by CYP isoenzymes: Based on in vitro studies, etoricoxib is not expected to inhibit cytochromes P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. Daily administration of etoricoxib 120 mg did not alter hepatic CYP3A4 activity as assessed by the erythromycin breath test.
Effects of other drugs on the pharmacokinetics of etoricoxib: The main pathway of etoricoxib metabolism is dependent on CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles have not been studied in vivo.
Ketoconazole: Ketoconazole, a potent inhibitor of CYP3A4, dosed at 400 mg once a day for 11 days to healthy volunteers, did not have any clinically important effect on the single-dose pharmacokinetics of 60 mg etoricoxib (43% increase in AUC).
Voriconazole and Miconazole: Co-administration of either oral voriconazole or topical miconazole oral gel, strong CYP3A4 inhibitors, with etoricoxib caused a slight increase in exposure to etoricoxib, but is not considered to be clinically meaningful based on published data.
Rifampicin: Co-administration of etoricoxib with rifampicin, a potent inducer of CYP enzymes, produced a 65% decrease in etoricoxib plasma concentrations. This interaction may result in recurrence of symptoms when etoricoxib is coadministered with rifampicin. While this information may suggest an increase in dose, doses of etoricoxib greater than those listed for each indication have not been studied in combination with rifampicin and are therefore not recommended.
Antacids: Antacids do not affect the pharmacokinetics of etoricoxib to a clinically relevant extent.

Store below 30°C.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

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

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