Extrib 30/60/90/120 mg FC tablet.

EXTRIB is indicated for:

• symptomatic relief of osteoarthritis and rheumatoid arthritis
• treatment of ankylosing spondylitis
• treatment of acute gouty arthritis
• short term relief of acute pain, treatment limited to a maximum period of 8 days
• treatment of primary dysmenorrhoea
• treatment of moderate to severe acute post-operative pain associated with dental surgery.

EXTRIB should be administered for the shortest duration possible and the lowest effective daily dose should be used.

Osteoarthritis (OA): The recommended dose is 30 mg once daily. In some patients, 60 mg once daily may provide adequate therapeutic benefit.

Rheumatoid arthritis (RA): The recommended dose is 90 mg once daily. In some patients, 60 mg once daily may provide adequate therapeutic benefit.

Ankylosing spondylitis: The recommended dose is 90 mg once daily. In some patients, 60 mg once daily may provide adequate therapeutic benefit.

Short term relief of acute pain: The recommended dose is 90 mg or 120 mg once daily, limited to a maximum of 8 days treatment.

Acute gouty arthritis: The recommended dose is 120 mg once daily, limited to a maximum of 8 days treatment.

Primary dysmenorrhoea: The recommended dose is 120 mg once daily.

Post-operative dental pain: The recommended dose is 90 mg once daily.

Doses of EXTRIB higher than those recommended above 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.
• RA should not exceed 90 mg daily.
• ankylosing spondylitis should not exceed 90 mg daily.
• acute gout should not exceed 120 mg daily.
• acute pain and primary dysmenorrhoea should not exceed 120 mg daily.
• post-operative acute dental surgery pain should not exceed 90 mg daily.

As the cardiovascular risks of EXTRIB 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 (see section 4.4).

Special populations

Elderly: No dosage adjustment in EXTRIB is necessary for the elderly although they may be more susceptible to renal, gastrointestinal and cardiovascular side effects. When using EXTRIB in the elderly and in patients with renal, hepatic or cardiac dysfunction, medically appropriate supervision should be intensified (see section 4.4). If patients show deterioration during treatment, appropriate measures should be undertaken, including discontinuation of EXTRIB.

Hepatic Insufficiency: In patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), a dose of 60 mg once daily should not be exceeded. In patients with moderate hepatic insufficiency (Child - Pugh score 7 to 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. Clinical experience is limited in patients with moderate hepatic dysfunction. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score > 9), therefore the use of EXTRIB is contraindicated in these patients (see sections 4.3 and 5.2).

Renal Insufficiency: No dosage adjustment is required for patients with creatinine clearance u2265 30 mL/min). The use of EXTRIB in patients with creatinine clearance < 30 mL/min is contraindicated (see section 4.3).

Paediatric population: EXTRIB is not indicated for use in children and adolescents under the age of 16 years (see section 4.3). The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patientu2019s overall risks (see section 4.4).

Method of administration: EXTRIB is administered orally and may be taken with or without food.

Missed dose: Doctors should advise patients who forget to take EXTRIB to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.

• known hypersensitivity to etoricoxib or to any of the ingredients of EXTRIB (see section 6.1)
• active peptic or a history of peptic ulceration or recurrent gastrointestinal perforation or bleeding (PUBs)
• severe hepatic dysfunction (Child-Pugh score > 9 or serum albumin < 25 g/litre)
• renal creatinine clearance < 30 mL/min
• signs of bronchospasm, asthma, acute rhinitis, nasal polyps, angioedema, urticaria or allergic-type reactions after taking aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) including EXTRIB
• uncontrolled hypertension
• inflammatory bowel disease
• congestive heart failure (NYHA II u2013 IV)
• ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease (see section 4.4)
• peri-operative analgesia in the setting of coronary artery bypass surgery (CABG)
• pregnancy and lactation (see section 4.6)
• children and adolescents under 16 years of age
• lithium therapy: concomitant administration with EXTRIB may lead to toxic blood concentrations of lithium (see section 4.5)
• digoxin: there was an approximate increase of 33 % in digoxin C max in healthy volunteers (see section 4.5).

EXTRIB may predispose to cardiovascular events, gastrointestinal events or cutaneous reactions which may be fatal. Long-term administration of NSAIDs such as EXTRIB have resulted in renal papillary necrosis and other renal injury. Renal prostaglandins may play a compensatory role in the maintenance of renal perfusion. Therefore, under conditions of compromised renal perfusion, administration of EXTRIB 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 liver cirrhosis. Monitoring of renal and hepatic function in such patients is indicated.

Hypokalaemia and renal tubular acidosis have also been reported due to prolonged use of etoricoxib, as in EXTRIB, at higher than recommended doses. Presenting signs and symptoms included reduced level of consciousness and generalised weakness.

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

Fluid retention, oedema and hypertension have been observed in patients taking etoricoxib, as in EXTRIB, due to inhibition of prostaglandin synthesis. All non-steroidal anti-inflammatory drugs (NSAIDs), including EXTRIB, can be associated with new onset or recurrent congestive heart failure (see section 4.8). Caution should be exercised in patients with a history of cardiac failure, left ventricular dysfunction or hypertension, and in patients with pre-existing oedema for any other reason. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures including discontinuation of EXTRIB should be taken.

EXTRIB may be associated with more frequent and severe hypertension than other NSAIDs and other selective COX-2 inhibitors. Therefore, special attention should be paid to blood pressure monitoring during treatment with EXTRIB. If blood pressure rises significantly, alternative treatment should be considered.

Clinical trials suggest that the selective COX-2 inhibitor class of medicines, such as EXTRIB, are associated with an increased risk of thrombotic events (especially myocardial infarction and stroke). As the cardiovascular risks of EXTRIB 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 EXTRIB after careful consideration.

EXTRIB is not a substitute for aspirin for cardiovascular prophylaxis due to its lack of effect on platelets. Because EXTRIB does not inhibit platelet aggregation, anti-platelet therapies should not be discontinued and if indicated, should be considered in patients at risk for or with a history of cardiovascular or other thrombotic events. There is no evidence that concurrent use of aspirin mitigates the increased risk of serious cardiovascular thrombotic events associated with EXTRIB (see section 4.5).

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in association with the use of selective COX-2 inhibitors such as EXTRIB. Patients appear to be at highest risk for these reactions early in the course of treatment, with the onset of reaction usually occurring within the first month of treatment. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving EXTRIB (see section 4.8).

Selective COX-2 inhibitors such as EXTRIB have been associated with an increased risk of skin reactions in patients with a history of any allergy. EXTRIB should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

When using EXTRIB in the elderly and in patients with renal, hepatic or cardiac dysfunction, medically appropriate supervision should be intensified. If these patients show deterioration during treatment, appropriate measures should be taken, including discontinuation of EXTRIB.

Gastrointestinal effects: Upper gastrointestinal complications (perforations, ulcers or bleedings), some of them resulting in fatal outcome, have occurred in patients treated with EXTRIB. Therefore, EXTRIB should be used with caution in patients with a history of, or at risk of developing, such events. Caution is advised with treatment of patients at risk of developing a gastrointestinal complication with EXTRIB; the elderly, patients using any other NSAID or (aspirin) acetylsalicylic acid concomitantly, or patients with a prior history of gastrointestinal disease, such as perforation, ulceration and gastrointestinal bleeding.

There is an increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications) when EXTRIB is taken concomitantly with the following medicines: aspirin (even at low doses), other NSAIDs, corticosteroids.

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 treated for up to 1 year with etoricoxib 60 mg and 90 mg daily, as in EXTRIB. Any patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test (3 times the upper limit of normal) has occurred, should be evaluated for persistently abnormal liver function tests. If persistently abnormal liver function tests are detected, EXTRIB should be discontinued.

EXTRIB may mask fever and other signs of inflammation or infection. The use of EXTRIB is not recommended in fertile women attempting to conceive (see section 4.6).

Information on excipients of EXTRIB: EXTRIB contains lactose. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take EXTRIB.

Ciclosporin and tacrolimus: The nephrotoxic effect of ciclosporin or tacrolimus may be increased if co-administered with any NSAID including EXTRIB. Renal function should be monitored when EXTRIB and either of these medicines is used in combination.

Warfarin: Warfarin therapy, when administered with EXTRIB is associated with an increase (13 %) in prothrombin time International Normalised Ratio (INR). Standard monitoring of INR values should be conducted when therapy with EXTRIB is initiated or changed in patients receiving warfarin or similar oral anticoagulants.

Rifampicin: Co-administration of EXTRIB with rifampicin, a potent inducer of hepatic metabolism, may significantly decrease the plasma AUC concentration of etoricoxib. This interaction should be considered when EXTRIB is co-administered with rifampicin.

Methotrexate: Monitoring for methotrexate-related toxicity should be considered when EXTRIB, at doses > 90 mg daily, and methotrexate are administered concomitantly, since EXTRIB may increase the plasma concentration and reduce the renal clearance of methotrexate. Two studies investigated the effects of etoricoxib 60 mg, 90 mg or 120 mg administered once daily, for seven days, in patients receiving once-weekly methotrexate doses of 7,5 mg to 20 mg for rheumatoid arthritis. Etoricoxib at 60 mg and 90 mg had no effect on methotrexate plasma concentrations (as measured by AUC) or renal clearance. In one study, etoricoxib 120 mg had no effect on methotrexate plasma concentrations (as measured by AUC) or renal clearance. In the other study, etoricoxib 120 mg increased methotrexate plasma concentrations by 28 % (as measured by AUC) and reduced renal clearance of methotrexate by 13 %.

Diuretics, Angiotensin Converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockers (ARBs): Reports suggest that non-selective NSAIDs and COX-2 selective inhibitors such as EXTRIB may reduce the antihypertensive effect of diuretics, ACE inhibitors and ARBs. This interaction should be given consideration in patients taking EXTRIB together with these medicines. In patients with compromised renal function (e.g. elderly patients or patients who are volume depleted, including those on diuretic therapy) who are being treated with EXTRIB, the co-administration of ACE inhibitors or ARBs may result in a further deterioration of renal function, including possible acute renal failure. These effects may be reversible. Therefore, the combination should be administered with caution, especially in the elderly and in patients with impaired renal function. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.

Lithium: Reports suggest that EXTRIB may increase plasma lithium levels. This interaction should be given consideration in patients taking EXTRIB concomitantly with lithium.

Aspirin, NSAIDs and other medications which may increase the risk of gastrointestinal adverse events: EXTRIB may be used concomitantly with aspirin at doses used for cardiovascular prophylaxis (low-dose aspirin). However, concomitant administration of low-dose aspirin with EXTRIB increases the rate of gastrointestinal ulceration, and other complications compared to use of EXTRIB alone. Concomitant administration of EXTRIB with doses of aspirin above those for cardiovascular prophylaxis or with other NSAIDs should be avoided. Corticosteroids may also increase the risk of gastrointestinal side effects (see section 4.4).

Oral Contraceptives: EXTRIB 60 mg given concomitantly with an oral contraceptive containing 35 u03bcg ethinylestradiol (EE) and 0,5 mg to 1 mg norethindrone (NET) for 21 days, increased the steady state AUC 0-24h of EE by 37 %. EXTRIB 120 mg given with the same oral contraceptive concomitantly or separated by 12 hours, increased the steady state AUC 0-24h of EE by 50 % to 60 %; however, (NET) concentrations generally did not increase to a clinically relevant degree. This increase in EE concentration should be considered when selecting an appropriate oral contraceptive for use with EXTRIB. An increase in EE exposure can increase the incidence of adverse events associated with oral contraceptives (e.g. venous thromboembolic events in women at risk).

Furosemide: Clinical studies have shown that NSAIDs such as EXTRIB reduce the natriuretic and antihypertensive effect of furosemide and thiazides in patients. This response has been attributed to inhibition of renal prostaglandin synthesis.

Hormone Replacement Therapy: Administration of EXTRIB 120 mg with hormone replacement therapy consisting of conjugated oestrogens (0,625 mg conjugated oestrogens for 8 days, increased the mean steady state AUC 0-24h of unconjugated oestrone (41 %), equilin (76 %) and 17-beta-oestradiol (22 %). The effect of the recommended chronic doses of EXTRIB (60 mg and 90 mg) has not been studied. The effects of EXTRIB 120 mg on the exposure (AUC 0-24h) to these oestrogenic components of conjugated oestrogens were less than half of those observed, when conjugated oestrogens were administered alone, and the dose was increased from 0,625 mg to 1,25 mg. The clinical significance of these increases is unknown, and higher doses of conjugated oestrogens were not studied in combination with EXTRIB. These increases in oestrogenic concentration should be taken into consideration when selecting post-menopausal hormone therapy for use with EXTRIB, because the increase in oestrogen exposure might increase the risk of adverse events associated with Hormone Replacement Therapy (HRT).

Effects of EXTRIB on medicines metabolised by sulfotransferases: EXTRIB is an inhibitor of sulfotransferase activity, particularly SULT1E1, and has been shown to increase the serum concentrations of ethinyl oestradiol. While knowledge about the effects of multiple sulfotransferases are presently limited, and the clinical consequences for many medicines are still being examined, it may be prudent to exercise care when administering EXTRIB concurrently with other medicines primarily metabolised by human sulfotransferases (e.g. oral salbutamol and minoxidil).

Other: Etoricoxib, as in EXTRIB, does not display clinically significant effects on the pharmacokinetics of prednisone/prednisolone, nor alter the steady-state plasma AUC 0-24hr or renal elimination of digoxin. An increase in digoxin C max (approximately 33 %) has been observed (see section 4.3). Patients at high risk of digoxin toxicity should be monitored for this when EXTRIB and digoxin are administered concomitantly. Antacids do not have clinically significant effects on the pharmacokinetics of EXTRIB.

Ketoconazole, a potent inhibitor of CYP3A4, does not have any clinically important effect on the single-dose pharmacokinetics of EXTRIB. Etoricoxib, as in EXTRIB, has been used concomitantly with a wide range of commonly prescribed medicines without evidence of clinical adverse interactions.

EXTRIB is contraindicated in pregnancy and lactation (see section 4.3).

Pregnancy: Regular use of non-steroidal anti-inflammatory drugs during the third trimester of pregnancy may result in premature closure of the foetal ductus arteriosus in utero, and possibly, persistent pulmonary hypertension of the newborn. The onset of labour may be delayed and its duration increased.

Breastfeeding: Mothers on EXTRIB should not breastfeed their infants.

Fertility: The use of EXTRIB is not recommended in fertile women attempting to conceive.

The effect of EXTRIB on the ability to drive or use machines has not been studied. Patients who experience dizziness, vertigo or somnolence while taking EXTRIB should refrain from driving or operating machinery.

Tabulated summary of adverse reactions

System Organ Class Frequency Side effects

Infections and Infestations Frequent Less frequent Alveolar osteitis Gastroenteritis, upper respiratory infection, urinary tract infection

Blood and lymphatic system disorders Less frequent Frequency unknown Anaemia (primarily associated with gastrointestinal bleeding), leukopenia Thrombocytopenia

Immune system disorders Frequency unknown Hypersensitivity, angioedema, anaphylactic/anaphylactoid reactions including shock

Metabolism and nutrition disorders Frequent Less frequent Frequency unknown Oedema/fluid retention Appetite increase or decrease, weight gain Hypokalaemia*

Psychiatric disorders Less frequent Frequency unknown Anxiety, depression, mental acuity decreased Confusion, hallucinations, restlessness

Nervous system disorders Frequent Less frequent Frequency unknown Dizziness, headache Insomnia, paraesthesia/hypaesthesia, dysgeusia Somnolence, cerebrovascular incidents (strokes)

Eye disorders Less frequent Frequency unknown Conjunctivitis Blurred vision

Ear and labyrinth disorders Less frequent Tinnitus, vertigo

Cardiac disorders Frequent Less frequent Frequency unknown Palpitations Atrial fibrillation, congestive heart failure, nonspecific ECG changes, myocardial infarction, angina pectoris, cardiovascular thrombotic events Dysrhythmia and tachycardia have been reported regardless of causality, congestive heart failure

Vascular disorders Frequent Less frequent Frequency unknown Hypertension, aggravated hypertension Flushing, transient ischaemic attack Hypertensive crisis, peripheral oedema

Respiratory, thoracic and mediastinal disorders Less frequent Frequency unknown Cough, dyspnoea, epistaxis Bronchospasm

Gastrointestinal disorders Frequent Less frequent Frequency unknown Gastrointestinal disorders (e.g. abdominal pain, flatulence, heartburn), diarrhoea, dyspepsia, epigastric discomfort, nausea Abdominal distension, acid reflux, bowel movement pattern change, dry mouth, gastro-duodenal ulcer, irritable bowel syndrome, peptic ulcer including GI perforation and bleeding, pancreatitis, constipation, gastritis, vomiting, oesophagitis, oral ulcer Melaena, haematemesis, ulcerative colitis, exacerbation of colitis and Crohnu2019s disease

Hepatobiliary disorders Frequency unknown Hepatotoxicity including hepatic failure, hepatitis, jaundice

Skin and subcutaneous tissue disorders Frequent Frequency unknown Ecchymosis Facial oedema, pruritus, rash, erythema, urticaria, bulbous reactions including Stevens Johnson syndrome and toxic epidermal necrolysis, fixed drug eruption

Musculoskeletal, connective tissue and bone disorders Less frequent Muscular cramp/spasm, musculoskeletal pain/stiffness

Renal and urinary disorders Less frequent Frequency unknown Proteinuria Renal insufficiency including renal failure, nephrotoxicity including interstitial nephritis and nephrotic syndrome, renal tubular acidosis*

General disorders and administrative site conditions Frequent Less frequent Asthenia/fatigue, flu-like disease Chest pain

Investigations Frequent Less frequent ALT increased, AST increased Blood urea increased, creatine phosphokinase increased, haematocrit decreased, haemoglobin decreased, hyperkalaemia, leukocytes decreased, platelets decreased, serum creatinine increased, uric acid increased

*Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting typically following prolonged use, at higher than recommended doses.

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

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the online service for adverse drug reaction reporting by following the link: https://www.sahpra.org.za/Publications/Index/8. An email can be sent directly to the company, [email protected], to ensure safety of the product.

Signs and symptoms: The most frequently observed adverse experiences were gastrointestinal and renovascular events. Prolonged use at higher than recommended doses may result in severe hypokalaemia and renal tubular acidosis. Symptoms may include reduced level of consciousness and generalised weakness (see section 4.4 and section 4.8).

Management of overdose: In the event of overdose, the usual supportive measures can be employed e.g. remove unabsorbed material from the gastrointestinal tract and clinically monitor, and institute supportive therapy if required. EXTRIB is not dialysable by haemodialysis; it is not known whether EXTRIB is dialysable by peritoneal dialysis.