Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: Sandoz SA (Pty) Ltd<sup>1</sup>, Waterfall 5-lr, Magwa Crescent West, Waterfall City, Jukskei View, 2090 1 Company Reg. No.: 1990/001979/07
COXLEON may predispose to cardiovascular events, cerebrovascular events, gastrointestinal events or cutaneous reactions which may be fatal.
The safety and efficacy of COXLEON have not been established for treatment exceeding 12 weeks in osteoarthritis and 24 weeks in rheumatoid arthritis.
During 20 weeks gestation or later in pregnancy may cause a rare but serious foetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Complications of prolonged oligohydramnios include limb contractures and delayed lung maturation, which may require invasive procedures such as exchange transfusion or dialysis, in some cases.
Upper and lower gastrointestinal complications (perforations, ulcers or bleedings [PUBs]), some of them resulting in fatal outcome, have occurred in patients treated with celecoxib. 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 antiplatelet drugs (such as acetylsalicylic acid) or glucocorticoids concomitantly, patients using alcohol, or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding.
There is further increase in the risk of gastrointestinal adverse effects for celecoxib (gastrointestinal ulceration or other gastrointestinal complications), when celecoxib 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.
The concomitant use of celecoxib and a non-aspirin NSAID should be avoided.
COXLEON may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction and stroke, which can be fatal. There is insufficient data to assess cardiovascular safety beyond one year of continuous treatment. As the cardiovascular risks of celecoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. NSAIDs, including COX-2 selective inhibitors, have been associated with increased risk of cardiovascular and thrombotic adverse events when taken long term. The exact magnitude of the risk associated with a single dose has not been determined, nor has the exact duration of therapy associated with increased risk. The patient’s need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis (see section 4.2, 4.3 and 4.8).
Caution is advised when COXLEON is prescribed to patients with cardiovascular risk factors e.g. hypertension, hyperlipidaemia, diabetes mellitus, and smoking. General practitioners and patients should remain alert for the development of such events, even in the absence of previous cardiovascular symptoms. COXLEON is not a substitute for aspirin for prophylaxis of cardiovascular thrombo-embolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapies should not be discontinued.
Due to inhibition of prostaglandin synthesis, fluid retention and oedema have been observed in patients taking celecoxib, therefore COXLEON should be used with caution in patients with history of cardiac failure, left ventricular dysfunction or hypertension, and in patients with pre-existing oedema from any other reason, since prostaglandin inhibition may result in deterioration of renal function and fluid retention. Caution is also required in patients taking diuretic treatment or otherwise at risk of hypovolaemia.
As with all NSAIDS, celecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events. Therefore, blood pressure should be monitored closely during the initiation of therapy and throughout the course of therapy.
Renal function should be closely monitored in patients with advanced renal disease who receive COXLEON. Caution should be used when initiating treatment in patients with dehydration. It is advisable to rehydrate patients first and then start therapy with COXLEON.
NSAIDs, including celecoxib, may cause renal toxicity. Patients at greatest risk for renal toxicity are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, ACEinhibitors, angiotensin II receptor antagonists, and the elderly. Such patients should be carefully monitored while receiving treatment with COXLEON.
A patient with symptoms and/or signs of liver dysfunction or in whom an abnormal liver function test has occurred, should be monitored carefully for evidence of the development of a severe hepatic reaction while on therapy with COXLEON.
Some cases of severe hepatic reactions, including fulminant hepatitis (some with fatal outcome), liver necrosis and, hepatic failure (some with fatal outcome or requiring liver transplant), have been reported with celecoxib.
If during treatment, patients deteriorate in any of the organ system functions (hepatic or renal) described above, appropriate measures should be taken and discontinuation of COXLEON therapy should be considered.
Patients known to be CYP2C9 poor metabolisers should be treated with caution.
In adult patients who are known or suspected to be poor CYP2C9 metabolisers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin), initiate treatment with half of the lowest recommended dose.
In patients with Juvenile Rheumatoid Arthritis who are known or suspected to be poor CYP2C9 metabolisers, consider using alternative treatments.
In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolised by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs. Patients known to be CYP2C9 poor metabolisers should be treated with caution.
Anaphylactic reactions have occurred in patients exposed to COXLEON (see section 4.3).
Serious skin reactions, some fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with the use of COXLEON (see section 4.8). Patients appear to be at highest risk for these events early in the course of therapy; the onset of the event occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (including anaphylaxis, angioedema and drug rash with eosinophilia and systemic symptoms (DRESS), or hypersensitivity syndrome), have been reported in patients receiving COXLEON. Patients with a history of sulfonamide allergy or any drug allergy may be at greater risk of serious skin reactions or hypersensitivity reactions.
COXLEON should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
By reducing inflammation, COXLEON may diminish the utility of diagnostic signs, such as fever, in detecting infections.
In patients on concurrent therapy with warfarin, serious bleeding events, some of them fatal, have been reported. Increased prothrombin time (INR) with concurrent therapy has been reported. Therefore, this should be closely monitored in patients receiving warfarin/coumarin-type oral anticoagulants, particularly when therapy with celecoxib is initiated or celecoxib dose is changed (see section 4.5). Concomitant use of anticoagulants with NSAIDS may increase the risk of bleeding. Caution should be exercised when combining COXLEON with warfarin or other oral anticoagulants, including novel anticoagulants (e.g. apixaban, dabigatran, and rivaroxaban).
COXLEON contains lactose monohydrate. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take COXLEON.
COXLEON contains lactose monohydrate, which may have an effect on the glycaemic control of patients with diabetes mellitus.
Anticoagulant activity should be monitored particularly in the first few days after initiating or changing the dose of celecoxib in patients receiving warfarin or other anticoagulants since these patients have an increased risk of bleeding complications.
Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with celecoxib is initiated or the dose of celecoxib is changed (see section 4.4). Bleeding events in association with increases in prothrombin time have been reported, predominantly in the elderly and in patients receiving celecoxib concurrently with warfarin, some of them fatal.
NSAIDs may reduce the effect of anti-hypertensive medicines including ACE-inhibitors, angiotensin II receptor antagonists, diuretics and beta-blockers. As for NSAIDs, the risk of acute renal insufficiency, which is usually reversible, may be increased in some patients with compromised renal function (e.g. dehydrated patients, patients on diuretics, or elderly patients) when ACE-inhibitors, angiotensin II receptor antagonists, and/or diuretics are combined with NSAIDs, including COXLEON (see section 4.4).
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.
COXLEON can be used with low dose aspirin. However, concomitant administration of aspirin with COXLEON may result in an increased rate of GI ulceration or other complications, compared to use of COXLEON alone. Because of its lack of platelet effects, COXLEON is not a substitute for aspirin for cardiovascular prophylaxis. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious cardiovascular thromboembolic events associated with COXLEON.
Celecoxib can be used with low-dose acetylsalicylic acid but is not a substitute for acetylsalicylic acid for CV prophylaxis. In the submitted studies, as with other NSAIDs, an increased risk of gastrointestinal ulceration or other gastrointestinal complications compared to use of celecoxib alone was shown for concomitant administration of low-dose acetylsalicylic acid.
Co-administration of NSAIDs and ciclosporin or tacrolimus may increase the nephrotoxic effect of ciclosporin or tacrolimus, respectively. Renal function should be monitored when celecoxib and any of these medicines are combined.
Celecoxib is an inhibitor of CYP2D6.
The plasma concentrations of medicines that are substrates of this enzyme may be increased when celecoxib is used concomitantly.
Examples of medicines which are metabolised by CYP2D6 are antidepressants (tricyclics and SSRIs), neuroleptics, anti-arrhythmic medicines, etc. The dose of individually dose-titrated CYP2D6 substrates may need to be reduced when treatment with celecoxib is initiated or increased if treatment with celecoxib is terminated.
Concomitant administration of celecoxib 200 mg twice daily resulted in 2.6-fold and 1.5-fold increases in plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates), respectively. These increases are due to celecoxib inhibition of the CYP2D6 substrate metabolism.
In vitro studies have shown some potential for celecoxib to inhibit CYP2C19 catalysed metabolism. The clinical significance of this in vitro finding is unknown. Examples of medicines which are metabolised by CYP2C19 are diazepam, citalopram and imipramine. Methotrexate: In patients with rheumatoid arthritis celecoxib had no statistically significant effect on the pharmacokinetics (plasma or renal clearance) of methotrexate (in rheumatologic doses). However, adequate monitoring for methotrexate-related toxicity should be considered when combining these two medicines.
Patients on lithium treatment should be closely monitored when COXLEON is introduced or withdrawn.
In an interaction study, celecoxib as in COXLEON had no clinically relevant effects on the pharmacokinetics of a prototype combination oral contraceptive (1 mg norethindrone/0,035 mg ethinyl estradiol).
Celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrate), or glibenclamide to a clinically relevant extent.
In individuals who are CYP2C9 poor metabolisers and demonstrate increased systemic exposure to celecoxib, concomitant treatment with CYP2C9 inhibitors such as fluconazole could result in further increases in celecoxib exposure. Such combinations should be avoided in known CYP2C9 poor metabolisers (see sections 4.2 and 5.2).
Concomitant administration of fluconazole at 200 mg four times daily resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via cytochrome P450 CYP2C9 by fluconazole. COXLEON should be introduced at the lowest recommended dose in patients receiving the CYP2C9 inhibitor fluconazole.
Since celecoxib is predominantly metabolised by CYP2C9 it should be used at half the recommended dose in patients receiving fluconazole. Concomitant use of 200 mg single dose of celecoxib and 200 mg once daily of fluconazole, a potent CYP2C9 inhibitor, resulted in a mean increase in celecoxib Cmax of 60% and in AUC of 130%.
Concomitant use of inducers of CYP2C9 such as rifampicin, carbamazepine and barbiturates may reduce plasma concentrations of celecoxib.
Ketoconazole or antacids have not been observed to affect the pharmacokinetics of celecoxib.
NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.
COXLEON as with other medicines inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus and should be avoided during pregnancy (see section 4.3). During the second or third trimester of pregnancy, NSAIDs including celecoxib may cause foetal renal dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe cases. Such effects may occur shortly after treatment initiation and are usually reversible. Celecoxib is contraindicated in pregnancy and in women who can become pregnant (see sections 4.3 and 4.4). If a woman becomes pregnant during treatment, celecoxib should be discontinued.
Limited data indicate that COXLEON is excreted in breast milk and therefore should not be used during lactation.
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including COXLEON, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including COXLEON, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Patients who experience dizziness, vertigo or somnolence while taking COXLEON should refrain from driving or operating machinery.
Frequent: Sinusitis, upper respiratory tract infection, pharyngitis, urinary tract infection.
Less frequent: Anaemia, ecchymosis, thrombocytopenia, leukopenia, pancytopenia.
Frequent: Allergy aggravated, hypersensitivity.
Less frequent: Angioedema, anaphylactic shock, anaphylactic reaction.
Less frequent: Hyperkalaemia.
Frequent: Insomnia.
Less frequent: Anxiety, somnolence, confusional state, depression, hallucinations, fatigue.
Frequent: Dizziness, hypertonia, headache.
Less frequent: Cerebral infarction, paraesthesia, somnolence, ataxia, dysgeusia. Frequency unknown: Haemorrhage intracranial (including fatal intracranial haemorrhage), meningitis aseptic, epilepsy (including aggravated epilepsy), ageusia, anosmia.
Less frequent: Blurred vision, conjunctivitis, eye haemorrhage, retinal artery occlusion, retinal vein occlusion.
Less frequent: Tinnitus, hypoacusis.
Frequent: Peripheral oedema, myocardial infarction.
Less frequent: Aggravated hypertension, dysrhythmia, hypertension, palpitations, tachycardia, cardiac failure.
Frequency unknown: Cardiovascular thrombotic events, arrhythmia.
Frequent: Hypertension (including aggravated hypertension)
Less frequent: Pulmonary embolism, flushing, vasculitis.
Frequent: Rhinitis, cough, dyspnoea
Less frequent: Bronchospasm, pneumonitis, bronchitis, coughing, pharyngitis, sinusitis, upper respiratory tract infection.
Frequent: Abdominal pain, diarrhoea, dyspepsia, flatulence, nausea, dysphagia, vomiting.
Less frequent: Constipation, gastritis, stomatitis, gastrointestinal inflammation (including aggravation of gastrointestinal inflammation), eructation, gastrointestinal haemorrhage, pancreatitis, gastric ulcer, duodenal ulcer, oesophageal ulceration, large intestinal ulcer, intestinal perforation, oesophagitis, melaena, colitis.
Less frequent: Abnormal hepatic function, increased hepatic enzyme (including increased SGOT and SGPT), hepatitis, hepatic failure (sometimes fatal or requiring liver transplant), hepatitis fulminant, hepatic necrosis, cholestasis, hepatitis cholestatic, jaundice.
Frequent: Rash, pruritus (includes pruritus generalised).
Less frequent: Alopecia, urticaria, ecchymosis, angioedema, photo-sensitivity, dermatitis exfoliative, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP), dermatitis bullous.
Frequent: Arthralgia.
Less frequent: Muscle spasms (leg cramps), myositis.
Less frequent: Urinary tract infection, blood creatinine increased, blood urea increased (BUN), renal failure acute, hyponatraemia, tubulointerstitial nephritis, nephrotic syndrome, glomerulonephritis minimal lesion.
Less frequent: Menstrual disorder.
Frequency unknown: Infertility female (female fertility decreased).
Frequent: Influenza-like illness, oedema peripheral/fluid retention.
Less frequent: Face oedema, chest pain.
Frequent: Accidental injury.
Reporting suspected adverse reactions after authorisation of the medicines is important. It allows continued monitoring of the benefit/risk balance of the medicines . Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.
Suspected adverse reactions can also be reported directly to the HCR via patientsafety.sacg@novartis.com
Not applicable.
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