Exxib 60, 90 & 120 mg FC tablets

EXXIB is indicated for the:

• symptomatic relief of rheumatoid arthritis (RA)
• treatment of ankylosing spondylitis (AS)
• 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
• 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)

Posology: EXXIB is administered orally and may be taken with or without food. Use the lowest effective dose for the shortest possible duration of treatment.

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.

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, which should only be used for the acute symptomatic period, 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 greater than those recommended for each indication have either not demonstrated additional efficacy or have not been studied. Therefore: The dose for RA should not exceed 90 mg daily. The dose for ankylosing spondylitis should not exceed 90 mg daily. The dose for acute gout should not exceed 120 mg daily. The dose for acute pain and primary dysmenorrhoea should not exceed 120 mg daily. The dose for post-operative acute dental surgery pain should not exceed 90 mg daily.

As the cardiovascular risks of EXXIB 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).

Elderly: No dosage adjustment in EXXIB is necessary for the elderly. Although the elderly may be more susceptible to renal, gastrointestinal and cardiovascular side effects (see sections 4.4 and 4.8).

When using EXXIB in the elderly and in patients with renal, hepatic or cardiac dysfunction, medically appropriate supervision should be maintained. If these patients deteriorate during treatment, appropriate measures should be taken, including discontinuation of therapy.

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. EXXIB should not be given to patients with severe hepatic impairment (Child-Pugh score > 9) (see section 4.3).

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

Method of administration: Oral.

• Known hypersensitivity to etoricoxib or to any of the inactive ingredients of EXXIB.
• Patients with active peptic ulceration or gastrointestinal (GI) bleeding.
• Patients with severe hepatic dysfunction (Child-Pugh score > 9 or serum albumin < 25 g/L).
• Patients with estimated creatinine clearance < 30 mL/min.
• Patients who have developed signs of asthma, acute rhinitis, nasal polyps, angioedema or urticaria following the administration of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors.
• Hypertension which has not been adequately controlled.
• Pregnancy and lactation (see section 4.6).
• Children and adolescents under the age of 16 years.
• Patients with inflammatory bowel disease.
• Patients with moderate to severe heart failure (NYHA class II u2013 IV).
• Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
• Perioperative analgesia in the setting of coronary artery bypass surgery.
• Lithium therapy: Concomitant administration with EXXIB may lead to toxic blood concentrations of lithium (see section 4.5).
• Digoxin: Co-administration with EXXIB may lead to toxic blood concentrations of digoxin (see section 4.5).

EXXIB may predispose to cardiovascular events, gastrointestinal (GI) events or cutaneous reactions, which may be fatal.

Gastrointestinal effects: Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them resulting in fatal outcome, have occurred in patients treated with EXXIB. Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs such as EXXIB: the elderly, patients using any other NSAID or aspirin 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 side effects (gastrointestinal ulceration or other gastrointestinal complications) when EXXIB is taken concomitantly with aspirin (even at low doses).

Cardiovascular effects: EXXIB may be associated with a risk of thrombotic events (especially myocardial infarction and stroke). As the cardiovascular risks of EXXIB 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. Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus or smoking) should only be treated with EXXIB after careful consideration. EXXIB is not a substitute for aspirin for prophylaxis of cardiovascular thromboembolic diseases, because of its lack of antiplatelet effect on platelets. Antiplatelet therapies should therefore not be discontinued (see section 4.5). There is no evidence that concurrent use of aspirin mitigates the increased risk of serious cardiovascular thrombotic events associated with EXXIB.

Renal effects: Renal prostaglandins may play a compensatory role in the maintenance of renal perfusion. Therefore, under conditions of compromised renal perfusion, administration of EXXIB 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.

Severe hypokalaemia and renal tubular acidosis (RTA) have been reported with the prolonged use of other NSAIDs (such as ibuprofen) at higher than recommended doses. Caution is advised with the use of EXXIB.

Fluid retention, oedema and hypertension: Caution should be exercised when initiating treatment with EXXIB in patients with dehydration. It is advisable to rehydrate patients prior to starting therapy with EXXIB. Due to inhibition of prostaglandin synthesis, fluid retention, oedema and hypertension have been observed in patients taking EXXIB. EXXIB should be used with caution in patients with compromised cardiac function and other conditions predisposing to, or worsened by fluid retention. Patients with pre-existing congestive heart failure or hypertension should be closely monitored. EXXIB 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 from any other reason. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures including discontinuation of EXXIB should be considered. EXXIB may be associated with more frequent and severe hypertension than some other NSAIDs and selective COX-2 inhibitors, particularly at high doses. Special attention should be paid to blood pressure monitoring during the treatment with EXXIB. If blood pressure rises significantly, alternative treatment should be considered.

Hepatic effects: Any patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored. EXXIB should be discontinued if signs of hepatic insufficiency occur, or if persistently abnormal liver function tests (three times the upper limit of normal) are detected. Elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately 3 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 60 mg or 90 mg.

Skin reactions: 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 EXXIB (see section 4.8). 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 EXXIB (see section 4.8). Selective COX-2 inhibitors have been associated with an increased risk of skin reactions in patients with a history of an allergy. EXXIB should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. EXXIB may mask fever and other signs of inflammation or infection.

When using EXXIB in the elderly and in patients with renal, hepatic or cardiac dysfunction, medically appropriate supervision should be maintained. If these patients deteriorate during treatment, appropriate measures should be taken, including discontinuation of therapy.

The use of EXXIB is not recommended in women attempting to conceive.

Excipient warnings: EXXIB contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose/galactose malabsorption should not take EXXIB.

Warfarin: Patients receiving warfarin should be closely monitored for their prothrombin time or international normalised ratio (INR), particularly in the first few days when therapy with EXXIB is initiated or the dose of EXXIB is changed.

Diuretics, ACE inhibitors and angiotensin II antagonists: EXXIB may diminish the antihypertensive effect of diuretics, ACE inhibitors and angiotensin receptor blockers. This interaction should be given consideration in patients taking EXXIB concomitantly with these medicines. 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 receptor blockers may result in further deterioration of renal function, including possible acute renal failure, which may be reversible. These interactions should be considered in patients taking EXXIB concomitantly with ACE inhibitors or angiotensin receptor blockers. Therefore the combination should be administered with caution, especially in the elderly and patients with impaired renal function. Patients should be adequately hydrated and monitoring of renal function at initiation and periodically thereafter could be considered with concomitant therapy.

Aspirin: EXXIB can be used concomitantly with aspirin at doses used for cardiovascular prophylaxis (low-dose aspirin). However, concomitant administration of low-dose aspirin with EXXIB may result in an increased rate of GI ulceration or other complications compared to use of EXXIB alone. Concomitant administration of EXXIB with doses of aspirin above those for cardiovascular prophylaxis or with other NSAIDs is not recommended (see section 4.4). Because of its lack of platelet effects, EXXIB is not a substitute for aspirin for cardiovascular prophylaxis. There is no evidence that concurrent use of aspirin mitigates the increased risk of serious cardiovascular thrombotic events associated with EXXIB.

Ciclosporin and tacrolimus: Although this interaction has not been studied with EXXIB, co-administration of ciclosporin or tacrolimus with any NSAID such as EXXIB may increase the nephrotoxic effect of ciclosporin or tacrolimus. Renal function should be monitored when EXXIB and either of these medicines are used in combination.

Lithium: NSAIDs and selective COX-2 inhibitors such as EXXIB may increase plasma lithium levels. This interaction should be considered in patients taking EXXIB concomitantly with lithium.

Methotrexate: EXXIB 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 EXXIB at dosages > 90 mg daily and methotrexate are administered concomitantly.

Oral contraceptives: EXXIB is an inhibitor of human sulphotransferase activity and has been shown to increase the plasma concentration of ethinyl oestradiol (EO). This increase in EO concentration should be considered when selecting an oral contraceptive for use with EXXIB. An increase in EO exposure can increase the incidence of side effects associated with oral contraceptives (e.g. venous thromboembolic events in women at risk).

Hormone replacement therapy (HRT): The effects of EXXIB 120 on the exposure (AUC 0-24hr) to conjugated oestrogens were less than half of those observed when conjugated oestrogen 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 conjugated oestrogens were not studied in combination with EXXIB. These increases in oestrogenic concentration should be taken into consideration when selecting post-menopausal hormone therapy for use with EXXIB because the increase in oestrogen exposure may increase the risk of side effects associated with HRT.

Prednisone or prednisolone: EXXIB did not have clinically important effects on the pharmacokinetics of prednisone or prednisolone.

Digoxin: EXXIB 120 did not alter the steady-state plasma AUC0-24hr or renal elimination of digoxin. There was an increase in digoxin C max in healthy volunteers (approximately 33 %) (see section 4.3).

Effect of EXXIB on medicines metabolised by sulphotransferases: EXXIB is an inhibitor of human sulphotransferase activity, and has been shown to increase the serum concentrations of ethinyl oestradiol. Care should be exercised when administering EXXIB concurrently with other medicines primarily metabolised by human sulphotransferases (e.g. oral salbutamol and minoxidil).

Ketoconazole: Ketoconazole, a potent inhibitor of CYP3A4, did not have any clinically important effect on the single-dose pharmacokinetics of 60 mg EXXIB (43 % increase in AUC).

Rifampicin: Co-administration of EXXIB with rifampicin, a potent inducer of CYP enzymes, produced a 65 % decrease in EXXIB plasma concentrations. This interaction should be considered when EXXIB is co-administered with rifampicin.

Antacids: Antacids do not affect the pharmacokinetics of EXXIB to a clinically relevant extent.

Furosemide: EXXIB may reduce the natriuretic effect of furosemide and hydrochlorothiazide.

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

Pregnancy: EXXIB is contraindicated in pregnancy (see section 4.3). Regular use of NSAIDs may result in:

First trimester: Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1 %, up to approximately 1,5 %. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

Second and Third trimester: During the third trimester of pregnancy, prostaglandin synthesis inhibitors, may expose the foetus to: cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); renal dysfunction, which may progress to renal failure with oligo-hydroamniosis. At the end of pregnancy, the mother and the neonate may be exposed to: possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; inhibition of uterine contractions resulting in delayed or prolonged labour.

Breastfeeding: Limited data indicate that EXXIB is excreted in breast milk and must therefore not be used during lactation.

Fertility: Based on the mechanism of action, the use of NSAIDs, including EXXIB, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women.

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

Tabulated list 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 the lymphatic system disorders Less frequent Frequency unknown Anaemia (primarily associated with gastrointestinal bleeding), leucopenia. Thrombocytopenia.
• Immune system disorders Frequent Frequency unknown Hypersensitivity reactions, including angioedema. Anaphylactic/anaphylactoid reactions including shock.
• Metabolism and nutrition disorders Frequent Less frequent Oedema/fluid retention. Appetite increase or decrease, weight gain.
• Psychiatric disorders Less frequent Frequency unknown Anxiety, depression, decreased mental acuity. Confusion, hallucinations, restlessness.
• Nervous system disorders Frequent Less frequent Frequency unknown Dizziness, headache. Insomnia, paraesthesia/hypaesthesia, cerebrovascular incidents (stroke). Somnolence, dysgeusia.
• 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, non-specific ECG changes, myocardial infarction, angina. Dysrhythmia, tachycardia, cardiovascular thrombotic events.
• Vascular disorders Frequent Less frequent Frequency unknown Hypertension. Flushing, transient ischaemic attack, hypertensive crisis. Aggravated hypertension, peripheral oedema.
• Respiratory, thoracic and mediastinal disorders Less frequent Frequency unknown Coughing, dyspnoea, epistaxis. Bronchospasm.
• Gastrointestinal disorders Frequent Abdominal pain, flatulence, heartburn, diarrhoea, Less frequent Frequency unknown dyspepsia, epigastric discomfort, nausea. Abdominal distention, acid reflux, bowel movement pattern change, constipation, dry mouth, gastroduodenal ulcer, irritable bowel syndrome, oesophagitis, oral ulcer, vomiting, gastritis, pancreatitis. Peptic ulcers including gastrointestinal perforation and Bleeding (mainly in the elderly).
• Hepato-biliary disorders Frequent Frequency unknown Increased ALT, increased AST. Hepatitis, jaundice, hepatic failure.
• Skin and subcutaneous tissue disorders Frequent Less frequent Frequency unknown: Ecchymosis. Facial oedema, pruritus, rash, erythema. Urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis, fixed drug eruption.
• Musculoskeletal, and connective tissue 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.
• General disorders and administration site conditions Frequent Less frequent Asthenia, fatigue, flu-like symptoms. Chest pain.
• Investigations Less frequent Increased blood urea, increased creatine phosphokinase, decreased haematocrit, decreased haemoglobin, hyperkalaemia, decreased leukocytes, decreased platelets, increased serum creatinine, increased uric acid, decreased blood sodium.

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

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. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

The most frequently observed side effects were consistent with the safety profile of EXXIB (e.g. GI events, renovascular events). In the event of overdose, appropriate supportive medical care should be provided (remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy if required). EXXIB is not dialysable by haemodialysis. It is not known whether EXXIB is dialysable by peritoneal dialysis.