Maracoxa 50 mg, 90 mg, 120 mg FC tablet

MARACOXA is indicated for:

• Symptomatic relief of osteoarthritis (OA) and 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 dysmenorrhea.
• Treatment of moderate to severe acute post-operative pain associated with dental surgery.

The decision to prescribe a selective COX-2 inhibitor, such as MARACOXA, should be based on an assessment of the individual patientu2019s overall risks (see section 4.4).

Posology

MARACOXA is administered orally. MARACOXA may be taken with or without food. MARACOXA should be administered for the shortest duration possible and the lowest effective daily dose should be used.

• Osteo-arthritis (OA): The recommended dose is 60 mg once daily.
• Rheumatoid arthritis (RA): The recommended dose is 90 mg once daily.
• 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, 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 OA should not exceed 60 mg daily.
• 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 selective COX-2 inhibitors, as in MARACOXA may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patientu2019s need for symptomatic relief and response to therapy should be re-evaluated periodically (see section 4.4).

Special populations

Elderly: No dosage adjustment in MARACOXA is necessary for the elderly or based on gender or race. Although the elderly may be more susceptible to renal, gastrointestinal and cardiovascular side effects (see section 4.4 and 4.8). When using MARACOXA 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. Clinical experience is limited particularly in patients with moderate dysfunction and caution is advised. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score greater than 9), therefore its use is contraindicated in these patients (see section 4.3 and 5.2).

Renal insufficiency: No dosage adjustment is necessary for patients with lesser degrees of renal insufficiency (creatinine clearance greater than or equal to 30 ml/min). The use of etoricoxib, as in MARACOXA, in patients with creatinine clearance less than 30 ml/min is contraindicated (see section 4.3).

Method of administration

For oral use.

MARACOXA is contraindicated in:

• Patients with known hypersensitivity to etoricoxib or any of the excipients of MARACOXA.
• Patients with active peptic ulceration or gastro-intestinal (GI) bleeding.
• Patients with severe hepatic dysfunction (Child-Pugh score greater than 9 or serum albumin less than 25 g/u2113).
• Patients with estimated creatinine clearance less than 30 ml/min.
• Patients who have developed signs of asthma, acute rhinitis, nasal polyps, angioneurotic oedema or urticaria following the administration of aspirin or other non-steroidal anti-inflammatory medicines (NSAIMs) including COX-2 inhibitors.
• Hypertension which has not been adequately controlled.
• Pregnancy and lactation.
• Children and adolescents under 16 years of age.
• Patients with inflammatory bowel disease.
• Patients with congestive heart failure (NYHA II-IV).
• Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease (see section 4.4).
• Perioperative analgesia in the setting of coronary artery bypass surgery (CABG).
• Lithium therapy: Concomitant administration with MARACOXA may lead to toxic blood concentration of lithium (see section 4.5).
• Digoxin: There was an increase in digoxin Cmax (approximately 33 %) in healthy volunteers (see section 4.5).

MARACOXA may predispose to cardiovascular events, gastro-intestinal events or cutaneous reactions which may be fatal.

Renal effects

Long-term administration of NSAIDs, such as MARACOXA, has 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 MARACOXA 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.

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

Severe hypokalaemia and renal tubular acidosis have been reported due to prolonged use of NSAIDs at higher than recommended doses. This risk is increased with the use of codeine/NSAIDs as patients may become dependent on the codeine component. Presenting signs and symptoms included reduced level of consciousness and generalised weakness. NSAIDs induced renal tubular acidosis should be considered in patients with unexplained hypokalaemia and metabolic acidosis.

Opioid use disorder with codeine/NSAIDs combinations (abuse and dependence)

Codeine is a narcotic analgesic. No more than the stated dose of this medicine should be taken. Tolerance, physical and psychological dependence and opioid use disorder (OUD) may develop upon repeated administration of opioids such as codeine. Abuse or intentional misuse of codeine/NSAIDs combinations may result in overdose and/or death. Serious clinical outcomes, including fatalities, have been reported in association with abuse and dependence with codeine/NSAIDs combinations, particularly when taken for prolonged periods at higher than recommended doses. These have included reports of gastrointestinal perforations, gastrointestinal haemorrhages, severe anaemia, renal failure, renal tubular acidosis and severe hypokalaemia associated with the NSAIDs component.

Patients should be informed about the risks and signs of opioid use disorder (OUD) with the use of codeine in codeine/NSAIDs combinations, as well as serious clinical outcomes. If these signs occur, patients should be advised to contact their doctor.

Withdrawal symptoms, such as restlessness and irritability may occur once the codeine/NSAIDs combinations is stopped.

Fluid retention, oedema and hypertension

Fluid retention, oedema and hypertension have been observed in patients taking etoricoxib, as in MARACOXA. All non-steroidal anti-inflammatory medicines (NSAIDs), including MARACOXA, can be associated with new onset or recurrent congestive heart failure. 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 MARACOXA should be taken.

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

Cardiovascular effects

Clinical trials suggest that the selective COX-2 inhibitor class of medicines, such as MARACOXA, may be associated with an increased risk of thrombotic events (especially MI and stroke). As the cardiovascular risks of selective COX-2 inhibitors, such as MARACOXA, may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patientu2019s 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, smoking and hypercholesterolaemia) should only be treated with MARACOXA after careful consideration. MARACOXA is not a substitute for aspirin for cardiovascular prophylaxis because of its lack of effect on platelets. Because etoricoxib, as in MARACOXA, does not inhibit platelet aggregation, antiplatelet 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 consistent evidence that concurrent use of aspirin mitigates the increased risk of serious cardiovascular thrombotic events associated with etoricoxib, as in MARACOXA (see section 4.5).

General

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 NSAIDs and some selective COX-2 inhibitors, such as MARACOXA during post-marketing surveillance (see section 4.8). These serious events may occur without warning. Patients appear to be at highest risk for these reactions early in the course of therapy: 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, as in MARACOXA (see section 4.8). Some selective COX-2 inhibitors, such as MARACOXA have been associated with an increased risk of skin reactions in patients with a history of any medicine allergy. MARACOXA should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

MARACOXA may mask fever and other signs of inflammation or infection. The use of MARACOXA is not recommended in women attempting to conceive. When using MARACOXA 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.

Gastro-intestinal effects

Upper gastro-intestinal complications (perforations, ulcers or bleedings (PUBs)), some of them resulting in fatal outcome, have occurred in patients treated with etoricoxib, as in MARACOXA. Caution is advised with treatment of patients at risk of developing a gastro-intestinal complication with NSAIDs such as MARACOXA; the elderly, patients using any other NSAID or aspirin (acetylsalicylic) acid concomitantly or patients with a prior history of gastro-intestinal disease, such as perforation, ulceration and GI bleeding. There is a further increase in risk of gastro-intestinal adverse effects (gastro-intestinal ulceration or other gastro-intestinal complications) when etoricoxib, as in MARACOXA, is taken concomitantly with aspirin (acetylsalicylic acid) (even at low doses).

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

Warfarin: In patients stabilised on chronic warfarin therapy, the administration of etoricoxib as contained in MARACOXA 120 mg daily was associated with an approximate 13 % increase in prothrombin time International Normalised Ratio (INR). Standard monitoring of INR values should be conducted when therapy with MARACOXA is initiated or changed in patients receiving warfarin or similar medicines.

Rifampicin: Co-administration of etoricoxib such as MARACOXA with rifampicin, a potent inducer of hepatic metabolism, produced a 65 % decrease in etoricoxib plasma area under the curve (AUC). This interaction should be considered when MARACOXA is co-administered with rifampicin.

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 %. Monitoring for methotrexate-related toxicity should be considered when etoricoxib, as in MARACOXA, at doses greater than 90 mg daily and methotrexate are administered concomitantly.

Diuretics, Angiotensin Converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockers (ARBs): Reports suggest that non-selective NSAIDs and COX-2 selective inhibitors such as etoricoxib may diminish the antihypertensive effect of diuretics, ACE inhibitors and ARBs. This interaction should be given consideration in patients taking MARACOXA concomitantly with these medicines. In some 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 non-steroidal anti-inflammatory medicines, including selective COX-2 inhibitors, 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 renal function at initiation of concomitant administration and periodically thereafter.

Lithium: Reports suggest that NSAIDs and selective COX-2 inhibitors such as MARACOXA may increase plasma lithium levels (see section 4.3).

Aspirin: In a study in healthy subjects, at steady state, etoricoxib 120 mg once daily had no effect on the anti-platelet activity of aspirin (81 mg once daily). MARACOXA can be used concomitantly with aspirin at doses used for cardiovascular prophylaxis (low-dose aspirin). However, concomitant administration of low-dose aspirin with etoricoxib, as in MARACOXA, increases the rate of GI ulceration or other complications compared to use of etoricoxib alone. Concomitant administration of etoricoxib, as in MARACOXA, with doses of aspirin above those for cardiovascular prophylaxis or with other NSAIDs should be avoided (see section 4.4).

Oral contraceptives: Etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35 mcg ethinyl estradiol (EE) and 0,5 mg to 1 mg norethindrone for 21 days increased the steady state AUC0-24hr of EE by 37 %. Etoricoxib 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, as in MARACOXA. 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).

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

Hormone replacement therapy: Administration of etoricoxib 120 mg with hormone replacement therapy consisting of conjugated oestrogens (0,625 mg for 28 days, increased the mean steady state AUC0-24hr of unconjugated oestrone (41 %), equilin (76 %), and 17-beta-estradiol (22 %). The effect of the recommended chronic doses of MARACOXA, (60 mg and 90 mg), has not been studied. The effects of etoricoxib 120 mg on the exposure (AUC0-24hr) to these oestrogenic components of conjugated oestrogens were less than half of those observed when conjugated oestrogens was 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 etoricoxib. These increases in oestrogenic concentration should be taken into consideration when selecting post-menopausal hormone therapy for use with etoricoxib, as in MARACOXA, because the increase in oestrogen exposure might increase the risk of adverse events associated with Hormone Replacement Therapy (HRT).

Effects of MARACOXA on medicines 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 medicines are still being examined, it may be prudent to exercise care when administering etoricoxib, as in MARACOXA, concurrently with other medicines primarily metabolised by human sulfotransferases (e.g. oral salbutamol and minoxidil).

Digoxin: Etoricoxib 120 mg administered once daily for 10 days to healthy volunteers did not alter the steady plasma AUC0-24 hr or renal elimination of digoxin. There was an increase in digoxin Cmax (approximately 33 %) (see section 4.3).

Other: In medicine interaction studies, etoricoxib did not have clinically important effects on the pharmacokinetics of prednisone/prednisolone. Antacids did not have clinically important effects on the pharmacokinetics of etoricoxib. Ketoconazole, a potent inhibitor of CYP3A4, dosed at 400 mg once a day for 11 days to healthy volunteers did not have a clinically important effect on the single dose pharmacokinetics of 60 mg etoricoxib, such as MARACOXA (43 % increase in AUC).

Pregnancy

MARACOXA is contraindicated in pregnancy and lactation (see section 4.3). The potential for human risk in pregnancy is unknown. Etoricoxib may cause uterine inertia and premature closure of the ducts arteriosus during the last trimester. If a woman becomes pregnant during treatment, MARACOXA must be discontinued.

Breastfeeding

Mothers on MARACOXA should not breastfeed their infants.

No studies on the effect of etoricoxib on the ability to drive or use machines have been performed. However, patients who experience dizziness, vertigo or somnolence while taking MARACOXA should refrain from driving or operating machinery.

Tabulated list of adverse reactions

Description of selected adverse reactions

The following serious undesirable effects have been reported in association with the use of NSAIDs and cannot be ruled out for MARACOXA: nephrotoxicity including interstitial nephritis and nephrotic syndrome; hepatotoxicity including hepatic failure, and pancreatitis. *Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting typically following prolonged use of the NSAIDs component at higher than recommended doses due to dependence on the codeine component.

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 providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8). The most frequently observed adverse experiences were consistent with the safety profile for etoricoxib (e.g. gastro-intestinal events, 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). Treatment should be symptomatic and supportive.

In the event of overdose, it is reasonable to employ the usual supportive measures, e.g. remove unabsorbed material from the gastro-intestinal tract, employ clinical monitoring, and institute supportive therapy, if required. Etoricoxib is not dialysable by haemodialysis; it is not known whether etoricoxib is dialysable by peritoneal dialysis.