ETOVEX Tablet

INDICATIONS AND USAGE:

For the symptomatic relief of osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis, and the pain and signs of inflammation associated with acute gouty arthritis.

DOSAGE AND 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 reevaluated periodically, especially in patients with osteoarthritis.

- Osteoarthritis: The recommended dose is 30mg once daily. In some patients with insufficient relief from symptoms an increased dose of 60mg 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 90mg once daily.

- Acute gouty arthritis: the recommended doseis 120mg once daily. Etoricoxib 120mg should be used only for the acute symptomatic period. In clinical trails for acute gouty arthritis. Etoricoxib was given for 8days.

- Ankylosing spondylitis: The recommended dose is 90mg 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 60mg daily. The dose for RA and ankylosing spondylitis should not exceed 90mg daily. The dose for acute gout should not exceed 120mg daily, limited to a maximum of 8days treatment.

METHOD OF ADMINISTRATION:

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

- Hypersensitivity to the active substance or to any of the excipients.

- Active peptic ulceration or active gastro-intestinal (GI) bleeding.

- patients who have experienced bronchospam, acute rhinitis, nasal polyps, angioneurotic edema, urticaria, or allergic-type reactions after taking acetylsalicylic acid or NSAIDs including COX-2 (cyclooxygenase-2) inhibitors.

- Pregnancy and lactation.

- Severe hepatic dysfunciton (serum albumin < 25g/l or Child-Pugh score ≥ 10)

- Estimated renal creatinine clearance < 30ml/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 140/90mmHg and has not been adequately controlled.

- Established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

* infections and infestations:

- Uncommon: gastroenteritis, upper respiratory infection, urinary tract infection.

* Blood and lymphatic system disorders:

- Uncommon: anemia (primarily associated with gastro-intestinal bleeding), leucopenia, thrombocytopenia.

* Immune system disorders:

- Very rare: hypersensitivity reactions, including angioedema, anaphylactic/anaphylactic reactions including shock.

* Metabolism and nutrition disorders:

- Common: oedema/fluid retention

- Uncommon: appetite increase or decrease weight gain.

* Psychiatric disorders:

- Uncommon: anxiety, depression, mental acuity decreased.

- Very rare: confusion, hallucinations.

- Not known: restleness.

* Nervous system disorders:

- Common: dizziness, headache.

- Uncommon: dysgeusia, insomnia, paresthaesia/hypaesthesia, somnolence.

* Eye disorders:

- Uncommon: blurred vision, conjunctivitis.

* Ear and labyrinth disorders:

- Uncommon: tinnitus, vertigo.

* Cardiac disorders:

- Common: palpitations.

- Uncommon: atrial fibrillation, congestive heart failure, non-specific ECG changes, angina pectoris, myocardial infarction.

- Not known tachycardia, arrhythmia

* Vascular disorders:

- Common: hypertension

- Uncommon: flushing, cerebrovascular accident, transient ischemic attack.

- Very rare: hypertensive crisis.

* Respiratory, thoracic and mediastinal disorders:

- Uncommon: cough, dyspnea, epistaxis.

- Very rare: Bronchospasm.

* Gastrointestinal disorders:

- Common: gastrointestinal disorders (e.g. abdominal pain, flatulence, heartburn), diarrhea, dyspepsia, epigastric discomfort, nausea.

- Uncommon: abdominal distention, acid reflux, bowel movement pattern change, constipation, dry mouth, gastro duodenal ulcer, irritable bowel syndrome, oesophagitis, oral ulcers including gastrointestinal perforation and bleeding (mainly in the elderly).

- Not known: pancreatitis.

* Hepatobiliary disorders:

- Common: ALT increased; AST increased.

- Very rare: hepatitis.

- Not known: jaundice.

* Skin and subcutaneous tissue disorders:

- Common: ecchymosis

- Uncommon: facial oedema, pruritus, rash.

- Rare: erythema.

- Very rare: urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis.

- Not known: fixed drug eruption

* Musculoskeletal and connective tissue disorders:

- Uncommon: muscular cramp/spasm, musculoskeletal pain/stiffness.

* Renal and urinary disorders:

- Uncommon: proteinuria, serum creatinine increased.

- Very rare: renal insufficiency, including renal failure.

* General disorders and administration site conditions:

- Common: asthenia/fatigue, flu-like disease.

- Uncommon: chest pain.

* Investigations:

- Uncommon: blood urea nitrogen increased, creatine phosphokinase increased, hyperkalaemia, uric acid increased.

- Rare: blood sodium decreased.

Pharmacodynamic interactions:

- Oral anticoagulants: in subjects stabilized on chronic warfarin therapy, the administration of Etoricoxib 120mg 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 is initiated or the dose of Etoricoxib 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 cyclo-oxygenase 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 antagonist. 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 120mg once daily had no effect on the anti-platelet activity of acetylsalicylic acid (81mg 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.

- Cyclosporine and tacrolimus: although this interaction has not been studied with Etoricoxib, coadministration of cyclosporine and tarcrolimus with any NSAID may increase the nephrotoxic effect of clyclosporine or tacrolimus. Renal function should be monitored when Etoricoxib and either of these drugs is used in combination.

Pregnancy and lactation are contraindicated.

Special precautions:

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

- Hepatic insufficiency: Regardless of indication, in the patients with mild hepatic dysfunction (Child-Pugh score 5-6) a dose of 60mg once daily should not be exceeded. In patients with moderate hepatic dysfunction (Child-Pugh score 7-9), regardless of indication, the dose of 60mg every other day should not be exceeded, administration of 30mg once daily can also be considered.

Clinical experience is limited particularly in patients with moderately 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.

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

- Pediatric patients: Etoricoxib is contra-indicated in children and adolescents under 16 years of age.

Warnings:

- Gastrointestinal effects: Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of the 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 NSAIDs 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). A signification 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 risk 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 reevaluated 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 after careful consideration.

COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thromboembolic 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 secondary, 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. Caution should be exercised inpatients with a history of cardiac failure, left ventricular dysfunction, or hypertension and in patients with pre-existing oedema from any other reason. If there is clinical evidence of deterioration in the condition of these patients, appropriate measure including discontinuation of Etoricoxib should be taken.

Etoricoxib may be associated with more frequent and severe hypertension than some other NSAIDs and selective COX-2 inhibitors, particularly at high doses. Therefore, hypertension should be controlled before treatment with Etoricoxib and special attention should be paid to blood pressure monitoring during treatment with Etoricoxib. Blood pressure should be monitored with 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.

- General: If during treatment, patients deteriorate in any of the organ system functions described above, 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 use 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.

The use of Etoricoxib, as with any medicinal product known to inhibit cyclooxygenase/prostaglandin synthesis, is not recommended in women attempting to conceive.

Etoricoxib is an oral selective cyclo-oxygenase-2 (COX-2) inhibitor within the clinical dose range. Across clinical pharmacology studies, it produced dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150mg daily. Etoricoxib did not inhibit gastric prostaglandin synthesis and had no effect on platelet function. Cyclooxygenase is responsible for generation 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 for pain, inflammation and fever. COX-2 has been identified in tissue around around gastric ulcers in man but its relevance to ulcer healing has not been established.