RICOXIB 60/ 90/ 120

Film-Coated Tablets

Etoricoxib IP

The active ingredients of the RICOXIB is Etoricoxib. Anti-inflammatory and anti- rheumatic products, non-steroids, coxibs.

PRESENTATION

Each Film-Coated Tablet contains 60/ 90/ 120 mg Etoricoxib IP

Packing: 10*10 Blister.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics Properties

Pharmacotherapeutic Group: Anti-inflammatory and anti- rheumatic products, non-steroids, coxibs.

Mechanism of Action

Etoricoxib is an oral, selective cyclo-oxygenase-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.

Pharmacokinetic Properties

Absorption

Orally administered Etoricoxib Tablets is well absorbed. The absolute bioavailability is approximately 100%. Following 120 mg once-daily dosing to steady state, the peak plasma concentration (geometric mean Cmax = 3.6 μg/ml) was observed at approximately 1 hour (Tmax) after administration to fasted adults. The geometric mean area under the curve (AUC0-24hr) was 37.8 μg•hr/ml. The pharmacokinetics of Etoricoxib Tablets are linear across the clinical dose range.

Dosing with food (a high-fat meal) had no effect on the extent of absorption of Etoricoxib Tablets after administration of a 120-mg dose. The rate of absorption was affected, resulting in a 36% decrease in Cmax and an increase in Tmax by 2 hours. These data are not considered clinically significant. In clinical trials, Etoricoxib Tablets was administered without regard to food intake.

Distribution

Etoricoxib Tablets 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 (Vdss) was approximately 1,20l in humans.

Etoricoxib Tablets crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.

Biotransformation

Etoricoxib Tablets 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 indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyze 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 Tablets 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 tablets to healthy subjects, 70% of radioactivity was recovered in urine and 20% in faces, mostly as metabolites. Less than 2% was recovered as unchanged drug.

Elimination of Etoricoxib Tablets occurs almost exclusively through metabolism followed by renal excretion. Steady state concentrations Etoricoxib Tablets 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 patients: Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young.

Gender: The pharmacokinetics of Etoricoxib Tablets are similar between men and women.

Hepatic Impairment: Patients with mild hepatic dysfunction (Child-Pugh score 5-6) administered Etoricoxib Tablets 60 mg once daily had an approximately 16% higher mean AUC as compared to healthy subjects given the same regimen. Patients with moderate hepatic dysfunction (Child-Pugh score 7-9) administered Etoricoxib Tablets 60 mg every other day had similar mean AUC to the healthy subjects given Etoricoxib Tablets 60 mg once daily; Etoricoxib Tablets 30 mg once daily has not been studied in this population. There are no clinical or pharmacokinetic data in patients with severe hepatic dysfunction (Child-Pugh score ≥10).

Renal Impairment: The pharmacokinetics of a single dose of Etoricoxib Tablets 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).

Pediatrics Patients: The pharmacokinetics of Etoricoxib Tablets in pediatric patients (<12 years old) have not been studied.

In a pharmacokinetic study (n=16) conducted in adolescents (aged 12 to 17) the pharmacokinetics in adolescents weighing 40 to 60 kg given Etoricoxib Tablets 60 mg once daily and adolescents >60 kg given etoricoxib 90 mg once daily were similar to the pharmacokinetics in adults given Etoricoxib Tablets 90 mg once daily. Safety and effectiveness of Etoricoxib Tablets in pediatric patients have not been established.

INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Pharmacodynamics Interactions

Oral anticoagulants: In subjects stabilized on chronic warfarin therapy, the administration of Etoricoxib Tablets 120 mg daily was associated with an approximate 13% increase in prothrombin time International Normalized 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 Tablets is initiated or the dose of Etoricoxib Tablets is changed.

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 Tablets 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: In a study in healthy subjects, at steady state, Etoricoxib Tablets 120 mg once daily had no effect on the anti-platelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib Tablets 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 Tablets may result in an increased rate of GI ulceration or other complications compared to use of Etoricoxib Tablets. Concomitant administration of Etoricoxib Tablets with doses of acetylsalicylic acid above those for cardiovascular prophylaxis or with other NSAIDs is not recommended.

Cyclosporine and Tacrolimus: Although this interaction has not been studied with Etoricoxib Tablets, co administration of cyclosporine or tacrolimus with any NSAID may increase the nephrotoxic effect of cyclosporine or tacrolimus. Renal function should be monitored when Etoricoxib Tablets and either of these drugs is used in combination.

Pharmacokinetic Interactions

The effect of etoricoxib tablets 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: Two studies investigated the effects of Etoricoxib Tablets 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 Tablets at 60 and 90 mg had no effect on methotrexate plasma concentrations or renal clearance. In one study, Etoricoxib Tablets 120 mg had no effect, but in the other study, Etoricoxib Tablets 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 Tablets and methotrexate are administered concomitantly.

Oral contraceptives: Etoricoxib Tablets 60 mg given concomitantly with an oral contraceptive containing 35 micrograms ethinyl estradiol (EE) and 0.5 to 1 mg nor ethindrone for 21 days increased the steady state AUC0-24hr of EE by 37%. Etoricoxib Tablets 120 mg given with the same oral contraceptive concomitantly or separated by 12 hours, increased the steady state AUC0-24hr 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 Tablets 120 mg with hormone replacement therapy consisting of conjugated estrogens (0.625 mg PREMARINTM) 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 Etoricoxib Tablets (30, 60, and 90 mg) has not been studied. The effects of Etoricoxib Tablets 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 to 1.25 mg. The clinical significance of these increases is unknown, and higher doses of PREMARIN 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 Tablets because the increase in estrogen exposure might increase the risk of adverse events associated with HRT.

Prednisone/prednisolone: In drug-interaction studies, Etoricoxib Tablets did not have clinically important effects on the pharmacokinetics of prednisone/prednisolone.

Digoxin: Etoricoxib tablets 120 mg administered once daily for 10 days to healthy volunteers did not alter the steady-state plasma AUC0-24hr or renal elimination of digoxin. There was an increase in digoxin Cmax (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 Tablets and digoxin are administered concomitantly.

Effect of Etoricoxib Tablets on Drugs Metabolized By Sulfotransferases

Etoricoxib Tablets 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 Tablets concurrently with other drugs primarily metabolized by human sulfotransferases (e.g., oral salbutamol and minoxidil).

Effect of Etoricoxib Tablets on Drugs Metabolized By CYP Isoenzymes

Based on in vitro studies, Etoricoxib Tablets is not expected to inhibit cytochromes P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. In a study in healthy subjects, daily administration of Etoricoxib Tablets 120 mg did not alter hepatic CYP3A4 activity as assessed by the erythromycin breath test.

Effects of Other Drugs on the Pharmacokinetics of Etoricoxib Tablets

The main pathway of Etoricoxib Tablets 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 catalyze 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 Tablets (43% increase in AUC).

Voriconazole and Miconazole: Co-administration of either oral voriconazole or topical miconazole oral gel, strong CYP3A4 inhibitors, with Etoricoxib Tablets 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 Tablets with rifampicin, a potent inducer of CYP enzymes, produced a 65% decrease in Etoricoxib Tablets plasma concentrations. This interaction may result in recurrence of symptoms when Etoricoxib Tablets is co-administered 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 Tablets to a clinically relevant extent.

CLINICAL PARTICULARS

Therapeutic Indications

RICOXIB Tablets is indicated in Adults and adolescents 16 years of age and older for the symptomatic relief of:

• Osteoarthritis (OA),
• Rheumatoid arthritis (RA),
• Ankylosing spondylitis,
• The pain and signs of inflammation associated with acute gouty arthritis.
• RICOXIB Tablets is indicated in adults and adolescents 16 years of age and older for the short-term treatment of moderate pain associated with dental surgery.

The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks.

POSOLOGY AND METHOD OF ADMINISTRATION

Posology

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.

Osteoarthritis

The recommended dose is 30 mg once daily. In some patients with insufficient relief from symptoms, an increased dose of 60 mg once daily may increase efficacy. In the absence of an increase in therapeutic benefit, other therapeutic options should be considered.

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 stabilized, 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 stabilized, 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 Pain Conditions

For acute pain conditions, Etoricoxib Tablets should be used only for the acute symptomatic period.

Acute Gouty Arthritis

The recommended dose is 120 mg once daily. In clinical trials for acute gouty arthritis, Etoricoxib Tablets was given for 8 days.

Postoperative Dental Surgery Pain

The recommended dose is 90 mg once daily, limited to a maximum of 3 days. Some patients may require other postoperative analgesia in addition to Etoricoxib Tablets during the three day treatment period.

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 and ankylosing spondylitis should not exceed 90 mg daily.
• The dose for acute gout should not exceed 120 mg daily, limited to a maximum of 8 days treatment.
• The dose for postoperative acute dental surgery pain should not exceed 90 mg daily, limited to a maximum of 3 days.

Special Populations

Elderly Patients

No dosage adjustment is necessary for elderly patients. As with other drugs, caution should be exercised in elderly patients.

Patients with Hepatic Impairment

Regardless of indication, in patients with mild hepatic dysfunction (Child-Pugh score 5-6) a dose of 60 mg once daily should not be exceeded. In patients with moderate hepatic dysfunction (Child-Pugh score 7-9), regardless of indication, the dose of 30 mg once daily should not be exceeded.

Clinical experience is limited particularly in patients with moderate hepatic dysfunction and caution is advised. There is no clinical experience in patients with severe hepatic dysfunction (Child-Pugh score ≥10); therefore, its use is contraindicated in these patients.

Patients with Renal Impairment

No dosage adjustment is necessary for patients with creatinine clearance ≥30 ml/min. The use of Etoricoxib Tablets in patients with creatinine clearance <30 ml/min is contra-indicated.

Pediatrics Population:

Etoricoxib Tablets is contra-indicated in children and adolescents under 16 years of age.

Method of Administration

Etoricoxib Tablets is administered orally and may be taken with or without food. The onset of the effect of the medicinal product may be faster when Etoricoxib Tablets is administered without food. This should be considered when rapid symptomatic relief is needed.

UNDESIRABLE EFFECTS

Tabulated List of Adverse Reactions

The following undesirable effects were reported at an incidence greater than placebo in clinical trials in patients with OA, RA, chronic low back pain or ankylosing spondylitis treated with Etoricoxib Tablets 30 mg, 60 mg or 90 mg up to the recommended dose for up to 12 weeks; in the MEDAL Programme studies for up to 3½ years; in short term acute pain studies for up to 7 days; or in post-marketing experience:

OVERDOSE

In clinical studies, administration of single doses of Etoricoxib Tablets 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 over dosage with Etoricoxib Tablets, 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 Tablets (e.g. gastrointestinal events, cardio renal 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 Tablets is not dialysable by hemodialysis; it is not known whether Etoricoxib Tablets is dialysable by peritoneal dialysis.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Gastrointestinal Effects

Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them resulting in fatal outcome, have occurred in patients treated with etoricoxib tablets.

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 Tablets is taken concomitantly with acetylsalicylic acid (even at low doses). A significant difference in GI safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been demonstrated in long-term clinical trials.

Cardiovascular Effects

Clinical trials suggest that the 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 Tablets 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, hyperlipidemia, diabetes mellitus, and smoking) should only be treated with Etoricoxib Tablets 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 Tablets 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, Edema and Hypertension

As with other medicinal products known to inhibit prostaglandin synthesis, fluid retention, edema and hypertension have been observed in patients taking etoricoxib. All Non-steroidal Anti-inflammatory Drugs (NSAIDs), including Etoricoxib Tablets, can be associated with new onset or recurrent congestive heart failure. For information regarding a dose related response for Etoricoxib Tablets. Caution should be exercised in patients with a history of cardiac failure, left ventricular dysfunction, or hypertension and in patients with pre-existing edema from any other reason. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures including discontinuation of etoricoxib should be taken.

Etoricoxib Tablets 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 Tablets and special attention should be paid to blood pressure monitoring during treatment with Etoricoxib Tablets. 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 Tablets 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 Tablets should be discontinued.

General

If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken and discontinuation of Etoricoxib Tablets therapy should be considered. Medically appropriate supervision should be maintained when using Etoricoxib Tablets in the elderly and in patients with renal, hepatic, or cardiac dysfunction.

Caution should be used when initiating treatment with Etoricoxib Tablets in patients with dehydration. It is advisable to rehydrate patients prior to starting therapy with Etoricoxib Tablets.

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 Tablets. 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 Tablets should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Etoricoxib Tablets may mask fever and other signs of inflammation. Caution should be exercised when co-administering etoricoxib tablets with warfarin or other oral anticoagulants. The use of Etoricoxib Tablets, as with any medicinal product known to inhibit cyclooxygenase / prostaglandin synthesis, is not recommended in women attempting to conceive.

Fertility, Pregnancy and Lactation

Pregnancy

No clinical data on exposed pregnancies are available for Etoricoxib Tablets. Studies in animals have shown reproductive toxicity. The potential for human risk in pregnancy is unknown. Etoricoxib Tablets, as with other medicinal products inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Etoricoxib Tablets is contraindicated in pregnancy. If a woman becomes pregnant during treatment, etoricoxib must be discontinued.

Breastfeeding

It is not known whether Etoricoxib Tablets is excreted in human milk. Etoricoxib Tablets is excreted in the milk of lactating rats. Women who use etoricoxib must not breast feed.

Fertility

The use of Etoricoxib Tablets, as with any drug substance known to inhibit COX-2, is not recommended in women attempting to conceive.

Effects on Ability to Drive and Use Machines

Patients who experience dizziness, vertigo or somnolence while taking Etoricoxib Tablets should refrain from driving or operating machinery.

CONTRAINDICATIONS

• Hypersensitivity to the active substance or to any of the excipients.
• 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 edema, urticaria, or allergic-type reactions.
• Pregnancy and 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 ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.