Celecoxib 100 & 200 Ascendis 100 mg. 200 mg Capsule

Symptomatic treatment of inflammation and pain in osteoarthritis and rheumatoid arthritis. Treatment of pain post dental surgery. Treatment of mild to moderate post-operative pain. Treatment of mild to moderate musculoskeletal pain. Treatment of mild to moderate primary dysmenorrhoea. Relief of signs and symptoms of ankylosing spondylitis.

Posology As the cardiovascular risks of CELECOXIB ASCENDIS may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used.

Osteoarthritis The recommended daily dose is 200 mg, administered as a single dose or as two divided doses. A maximum dose is 400 mg per day.

Rheumatoid arthritis The recommended daily dose is 100 mg or 200 mg twice per day.

Pain post dental surgery The recommended daily dose is 100 mg to 200 mg, up to a maximum daily dose of 400 mg. Dosing intervals should not be less than 4 hours.

Mild to moderate post-operative pain The recommended dose is 200 mg once daily. Some patients may benefit from an additional 200 mg dose.

Mild to moderate musculoskeletal pain The recommended dose is 200 mg twice daily.

Mild to moderate primary dysmenorrhea The recommended dose is 400 mg initially, followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily.

Ankylosing spondylitis The recommended daily dose is 200 mg, administered as a single dose or as 100 mg twice per day. Some patients may benefit from a total daily dose of 400 mg.

Special populations Elderly No dosage adjustment is necessary. However for elderly patients with a lower than average body weight (50 kg), it is advisable to initiate therapy at the lowest recommended dose. Hepatic impairment No dosage adjustment is necessary in patients with mild hepatic impairment. Introduce CELECOXIB ASCENDIS at the lowest recommended dose in patients with moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment (see section 4.3). Renal impairment No dosage adjustment is necessary in patients with mild or moderate renal impairment. There is no clinical experience in patients with severe renal impairment (see section 4.3). Paediatric population CELECOXIB ASCENDIS is not indicated for use in children under 18 years old.

Method of administration CELECOXIB ASCENDIS may be taken with or without food. For oral use.

• Hypersensitivity to celecoxib or to any of the excipients (see section 6.1)
• Known hypersensitivity to sulfonamides.
• Severe impairment of hepatic function (serum albumin < 25 g/L or Child-Pugh score u2265 10).
• Severe impairment of renal function (creatinine clearance < 30 ml/min).
• Asthma, urticaria or allergic-type reactions precipitated by aspirin or non-steroidal anti-inflammatory medicines, including other cyclooxygenase-2 (COX-2) specific inhibitors.
• Established ischaemic heart disease and/or cerebrovascular disease (stroke) and peripheral arterial disease.
• Peri-operative analgesia in the setting of coronary artery bypass surgery (CABG).
• Inflammatory bowel disease.
• Active peptic ulceration or gastrointestinal (GI) bleeding.
• In pregnancy and in women of childbearing potential unless using an effective method of contraception (see section 4.6)
• Breastfeeding (see section 4.6).

CELECOXIB ASCENDIS may predispose to cardiovascular events, gastrointestinal events, or cutaneous reactions which may be fatal.

Gastrointestinal (GI) effects Upper and lower gastrointestinal complications [perforations, ulcers or bleedings (PUBs)] can occur in patients treated with CELECOXIB ASCENDIS, resulting in fatal outcome. 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 (aspirin) 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 ASCENDIS (gastrointestinal ulceration or other gastrointestinal complications) when CELECOXIB ASCENDIS is taken concomitantly with acetylsalicylic acid (even at low doses).

Concomitant NSAID use The concomitant use of CELECOXIB ASCENDIS and a non-aspirin NSAID should be avoided.

Cardiovascular effects Increased numbers of serious cardiovascular (CV) events, mainly myocardial infarction, has been documented in long-term usage. As the cardiovascular risks of CELECOXIB ASCENDIS 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 sections 4.2, 4.3, and 4.8).

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with CELECOXIB ASCENDIS after careful consideration.

COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thromboembolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapies should not be discontinued.

Fluid retention and oedema As with other medicines known to inhibit prostaglandin synthesis, fluid retention and oedema have been observed in patients taking CELECOXIB ASCENDIS. Therefore, CELECOXIB ASCENDIS should be used with caution in patients with a 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.

Hypertension As with all NSAIDs, CELECOXIB ASCENDIS 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 with CELECOXIB ASCENDIS and throughout the course of therapy.

Hepatic and renal effects Compromised renal or hepatic function and especially cardiac dysfunction are more likely in the elderly and therefore medically appropriate supervision should be maintained. NSAIDs, including CELECOXIB ASCENDIS, may cause renal toxicity. Patients at greatest risk for renal toxicity are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors, angiotensin II receptor antagonists, and the elderly (see section 4.5). Such patients should be carefully monitored while receiving treatment with CELECOXIB ASCENDIS. 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 ASCENDIS. (see section 4.8). If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken, and discontinuation of CELECOXIB ASCENDIS therapy should be considered.

CYP2D6 inhibition CELECOXIB ASCENDIS inhibits CYP2D6. Although it is not a strong inhibitor of this enzyme, a dose reduction may be necessary for individually dose-titrated medicines that are metabolised by CYP2D6 (see section 4.5).

CYP2C9 poor metabolisers Patients known to be CYP2C9 poor metabolisers should be treated with caution (see section 5.2).

Skin and systemic hypersensitivity reactions Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported less frequently in association with the use of CELECOXIB ASCENDIS (see section 4.8). 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 (including anaphylaxis, angioedema and drug rash with eosinophilia and systemic symptoms (DRESS), or hypersensitivity syndrome), may occur in patients receiving CELECOXIB ASCENDIS (see section 4.8). Patients with a history of sulfonamide allergy or any medicine allergy may be at greater risk of serious skin reactions or hypersensitivity reactions (see section 4.3). CELECOXIB ASCENDIS should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

General CELECOXIB ASCENDIS may mask fever and other signs of inflammation.

Use with oral anticoagulants 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 ASCENDIS is initiated or CELECOXIB ASCENDIS 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 CELECOXIB ASCENDIS with warfarin or other oral anticoagulants, including novel anticoagulants (e.g. apixaban, dabigatran, and rivaroxaban).

Excipients CELECOXIB 100 ASCENDIS and CELECOXIB 200 ASCENDIS capsules contain lactose monohydrate (27,07 mg and 54,14 mg, respectively). Patients with rare hereditary problem of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take CELECOXIB ASCENDIS.

Pharmacodynamic interactions Anticoagulants Anticoagulant activity should be monitored particularly in the first few days after initiating or changing the dose of CELECOXIB ASCENDIS 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 ASCENDIS is initiated or the dose of CELECOXIB ASCENDIS is changed (see section 4.4). Bleeding events in association with increases in prothrombin time have been reported, predominantly in the elderly, in patients receiving CELECOXIB ASCENDIS concurrently with warfarin, some of them fatal.

Anti-hypertensives 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 CELECOXIB ASCENDIS (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.

Ciclosporin and tacrolimus 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 ASCENDIS and any of these medicines are combined.

Aspirin CELECOXIB ASCENDIS can be used with low-dose aspirin but is not a substitute for aspirin for CV prophylaxis. An increased risk of gastrointestinal ulceration or other gastrointestinal complications compared to use of CELECOXIB ASCENDIS alone is shown for concomitant administration of low-dose aspirin.

Pharmacokinetic interactions Effects of CELECOXIB ASCENDIS on other medicines. CYP2D6 inhibition Celecoxib is an inhibitor of CYP2D6. The plasma concentrations of medicines that are substrates of this enzyme may be increased when CELECOXIB ASCENDIS is used concomitantly. Examples of medicines which are metabolised by CYP2D6 are antidepressants (tricyclics and SSRIs), neuroleptics, anti-dysrhythmic medicines, etc. The dose of individually dose titrated CYP2D6 substrates may need to be reduced when treatment with CELECOXIB ASCENDIS is initiated or increased if treatment with CELECOXIB ASCENDIS is terminated.

Concomitant administration of CELECOXIB ASCENDIS can increase the plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates). These increases are due to CELECOXIB ASCENDIS inhibition of the CYP2D6 substrate metabolism.

Methotrexate Adequate monitoring for methotrexate-related toxicity should be considered when combining these two medicines.

Lithium Patients on lithium treatment should be closely monitored when CELECOXIB ASCENDIS is introduced or withdrawn.

Effects of other medicines on CELECOXIB ASCENDIS CYP2C9 poor metabolisers In individuals who are CYP2C9 poor metabolisers and demonstrate increased systemic exposure to CELECOXIB ASCENDIS, concomitant treatment with CYP2C9 inhibitors such as fluconazole could result in further increases in CELECOXIB ASCENDIS exposure. Such combinations should be avoided in known CYP2C9 poor metabolisers (see sections 4.2 and 5.2).

CYP2C9 inhibitors and inducers CELECOXIB ASCENDIS is predominantly metabolised by CYP2C9 and it should be used at half the recommended dose in patients receiving fluconazole. Concomitant use of inducers of CYP2C9 such as rifampicin, carbamazepine and barbiturates may reduce plasma concentrations of CELECOXIB ASCENDIS.

Pregnancy CELECOXIB ASCENDIS, 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 ASCENDIS may cause fetal 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 ASCENDIS 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 ASCENDIS should be discontinued.

Breastfeeding Limited data indicate that CELECOXIB ASCENDIS is excreted in breast milk and therefore CELECOXIB ASCENDIS should not be used during breastfeeding (see section 4.3).

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

CELECOXIB ASCENDIS may be associated with dizziness, vertigo or somnolence (see section 4.8). Therefore, patients must be cautious when driving or using machines and should be advised not to drive or operate machinery if they experience these symptoms.

Tabulated summary of adverse reactions

MedDRA system organ class Frequency Adverse reactions Infections and infestations Frequent Sinusitis, upper respiratory tract infection, pharyngitis, urinary tract infection Blood and lymphatic system disorders Less frequent Anaemia, leukopenia, thrombocytopenia, pancytopenia Immune system disorders Frequent Hypersensitivity Less frequent Anaphylactic shock, anaphylactic reaction, angioedema Metabolism and nutrition disorders Less frequent Hyperkalaemia Psychiatric disorders Frequent Insomnia Less frequent Anxiety, depression, fatigue, confusional state, hallucinations Nervous system disorders Frequent Dizziness, hypertonia, headache Less frequent Cerebral infarction, paraesthesia, somnolence, ataxia, dysgeusia, haemorrhage intracranial, (including fatal intracranial haemorrhage), meningitis aseptic, epilepsy (including aggravated epilepsy), ageusia, anosmia Eye disorders Less frequent Vision blurred, conjunctivitis, eye haemorrhage, retinal artery occlusion, retinal vein occlusion Ear and labyrinth disorders Less frequent Tinnitus, hypoacusis Cardiac disorders Frequent Myocardial infarction Less frequent Cardiac failure, palpitations, tachycardia, dysrhythmia Vascular disorders Frequent Hypertension (including aggravated hypertension) Less frequent Pulmonary embolism, flushing, vasculitis Respiratory, thoracic and mediastinal disorders Frequent Pharyngitis, sinusitis, upper respiratory tract infection, rhinitis, cough, dyspnoea Less frequent Bronchospasm, pneumonitis Gastrointestinal disorders Frequent Nausea, abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting, dysphagia Less frequent Constipation, gastritis, stomatitis, gastrointestinal inflammation (including aggravation of gastrointestinal inflammation), eructation, gastrointestinal haemorrhage, duodenal ulcer, gastric ulcer, oesophageal ulcer, intestinal ulcer, large intestinal ulcer, perforation, oesophagitis, melaena, pancreatitis, colitis Hepato-biliary disorders Less frequent Hepatic function abnormal, hepatic enzyme increased (including increased SGOT and SGPT), hepatitis, hepatic failure (sometimes fatal or requiring liver transplant), hepatitis fulminant (some with fatal outcome), hepatic necrosis, cholestasis, hepatitis cholestatic, jaundice Skin and subcutaneous tissue disorders Frequent Rash, pruritus (includes pruritus generalised) Less frequent Urticaria, ecchymosis, angioedema, alopecia, photosensitivity, dermatitis, exfoliative, erythema multiform, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP), dermatitis, bullous Musculoskeletal and connective tissue disorders Frequent Arthralgia Less frequent Muscle spasms (leg cramps), myositis Renal and urinary disorders Frequent Urinary tract infection Less frequent Blood creatinine increased, blood urea increased, renal failure acute, hyponatraemia, tubulointerstitial nephritis, nephrotic syndrome, glomerulonephritis minimal lesion Reproductive system and breast disorders Less frequent Menstrual disorder Frequency unknown Female fertility decreased General disorders and administration site conditions Frequent Influenza-like illness, oedema peripheral / fluid retention Less frequent Face oedema, chest pain Injury, poisoning and procedural complications Frequent Injury (accidental injury) 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 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

There is no clinical experience of overdose. Single doses up to 1 200 mg twice daily have been administered without any significant adverse effects. In the event of suspected overdose, appropriate supportive medical care should be provided. Dialysis is unlikely to be an efficient method of medicine removal.