Anti-inflammatory and antirheumatic products, non-steroids, coxibs

Etoricoxib

Each film-coated tablet contains 30, 60, 90 or 120 mg of etoricoxib. Excipient: 30 mg: lactose 1.4 mg 60 mg: lactose 2.8 mg 90 mg: lactose 4.2 mg 120 mg: lactose 5.6 mg

Film-coated tablet (tablet). 30 mg Tablets: Blue-green, apple-shaped biconvex tablets debossed '101' on one side and 'ACX 30' on the other side. 60 mg Tablets: Dark green, apple-shaped, biconvex tablets debossed '200' on one side and 'ARCOXIA 60' on the other side. 90 mg Tablets: White, apple-shaped, biconvex tablets debossed '202' on one side and 'ARCOXIA 90' on the other side. 120 mg Tablets: Pale-green, apple-shaped, biconvex tablets debossed '204' on one side and 'ARCOXIA 120' on the other side.

For the symptomatic relief of osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis, and the pain and signs of inflammation associated with acute gouty arthritis. The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks

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

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 90 mg once daily.

Acute gouty arthritis

The recommended dose is 120 mg once daily. Etoricoxib 120 mg should be used only for the acute symptomatic period. In clinical trials for acute gouty arthritis, etoricoxib was given for 8 days.

Ankylosing spondylitis

The recommended dose is 90 mg once daily.

Doses greater than those recommended for each indication have either not demonstrated additional efficacy or have not been studied. Therefore:

The dose for OA should not exceed 60 mg daily.

The dose for RA 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.

Hepatic insufficiency

Regardless of indication, in patients with mild hepatic dysfunction (Child-Pugh score 56) a dose of 60 mg once daily should not be exceeded. In patients with moderate hepatic dysfunction (Child-Pugh score 79), regardless of indication, the dose of 60 mg every other day should not be exceeded; administration of 30 mg once daily can also be considered.

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 contra-indicated in these patients.

Renal insufficiency

No dosage adjustment is necessary for patients with creatinine clearance 30 ml/min (see section 5.2). The use of etoricoxib in patients with creatinine clearance <30 ml/min is contra-indicated.

Paediatric patients

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

Etoricoxib is contraindicated in children and adolescents under 16 years of age.

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

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

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

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

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 140/90mmHg and has not been adequately controlled

Established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease

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). 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 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 Non-steroidal 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 section 5.1. 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. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures 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 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.

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 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.

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

ARCOXIA tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pharmacodynamic interactions

Oral anticoagulants: In subjects stabilised on chronic warfarin therapy, 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.

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 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 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.

Ciclosporin and tacrolimus: Although this interaction has not been studied with etoricoxib, coadministration of ciclosporin or tacrolimus with any NSAID may increase the nephrotoxic effect of ciclosporin 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: Two studies investigated the effects of etoricoxib 60, 90 or 120 mg administered once daily for seven days in patients receiving once-weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at 60 and 90 mg had no effect on methotrexate plasma concentrations or renal clearance. In one study, 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_024hr 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 PREMARIN^TM) for 28 days, increased the mean steady state AUC_0-24hr of unconjugated estrone (41%), equilin (76%), and 17β-estradiol (22%). The effect of the recommended chronic doses of etoricoxib (30, 60, and 90 mg) has not been studied. The effects of etoricoxib 120 mg on the exposure (AUC_0-24hr) 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 because the increase in oestrogen exposure might increase the risk of adverse events associated with HRT.

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

Digoxin: Etoricoxib 120 mg administered once daily for 10 days to healthy volunteers did not 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. In a study in healthy subjects, 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).

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 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 to a clinically relevant extent.

In clinical trials, etoricoxib was evaluated for safety in 7152 individuals, including 4614 patients with OA, RA, chronic low back pain or ankylosing spondylitis (approximately 600 patients with OA or RA were treated for one year or longer).

In clinical studies, the undesirable effects profile was similar in patients with OA or RA treated with etoricoxib for one year or longer.

In a clinical study for acute gouty arthritis, patients were treated with etoricoxib 120 mg once daily for eight days. The adverse experience profile in this study was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.

In a cardiovascular safety outcomes programme of pooled data from three active comparator controlled trials, 17, 412 patients with OA or RA were treated with etoricoxib (60 mg or 90 mg) for a mean duration of approximately 18 months.

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 30 mg, 60 mg or 90 mg for up to 12 weeks, or in the MEDAL Programme studies, or in post-marketing experience:

[Very Common (1/10) Common (1/100 to <1/10) Uncommon (1/1000 to <1/100) Rare (1/10,000 to <1/1,000) Very rare (<1/10,000), not known (cannot be estimated from the available data)]

Infections and infestations:

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

Immune system disorder:

Very rare: hypersensitivity reactions, including angioedema, anaphylactic/anaphylactoid 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.

Nervous system disorder:

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, myocardial infarction*.

Vascular disorders:

Common: hypertension.

Uncommon: flushing, cerebrovascular accident*, transient ischaemic attack.

Very rare: hypertensive crisis.

Respiratory, thoracic and mediastinal disorders:

Uncommon: cough, dyspnoea, 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, gastroduodenal ulcer, irritable bowel syndrome, oesophagitis, oral ulcer, vomiting, gastritis.

Very rare: peptic ulcers including gastrointestinal perforation and bleeding (mainly in the elderly).

Hepatobiliary disorders:

Very rare: hepatitis.

Skin and subcutaneous tissue disorders:

Common: ecchymosis.

Uncommon: facial oedema, pruritus, rash.

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

Musculoskeletal, connective tissue and bone disorders:

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

Renal and urinary disorders:

Uncommon: proteinuria.

Very rare: renal insufficiency, including renal failure, usually reversible upon discontinuation of treatment.

General disorders and administration site conditions:

Common: asthenia/fatigue, flu-like disease.

Uncommon: chest pain.

Investigations:

Common: ALT increased, AST increased.

Uncommon: blood urea nitrogen increased, creatine phosphokinase increased, haematocrit decreased, haemoglobin decreased, hyperkalaemia, leukocytes decreased, platelets decreased, serum creatinine increased, uric acid increased.

Rare: blood sodium decreased.

The following serious undesirable effects have been reported in association with the use of NSAIDs and cannot be ruled out for etoricoxib: nephrotoxicity including interstitial nephritis and nephrotic syndrome; hepatotoxicity including hepatic failure, jaundice and pancreatitis.

* Based on analyses of long-term placebo and active controlled clinical trials, selective COX-2 inhibitors have been associated with an increased risk of serious thrombotic arterial events, including myocardial infarction and stroke. The absolute risk increase for such events is unlikely to exceed 1% per year based on existing data (uncommon).

Merck Sharp & Dohme Limited

(POM)

11 August 2009