CELECOXIB

01% and greater than those reported for placebo during 12 placebo- and/or active controlled clinical trials of duration up to 12 weeks at celecoxib daily doses from 100 mg up to 800 mg. In additional studies using non-selective NSAID comparators, approximately 7400 arthritis patients have been treated with celecoxib at daily doses up to 800 mg, including approximately 2300 patients treated for 1 year or longer.

The adverse reactions observed with celecoxib in these additional studies were consistent with those for osteoarthritis and rheumatoid arthritis patients listed in Table 1. 1, Cardiovascular safety – long-term studies involving patients with sporadic adenomatous polyps).

• Adverse drug reactions from post-marketing surveillance as spontaneously reported during a period in which an estimated >70 million patients were treated with celecoxib (various doses, durations, and indications). Even though these were identified as reactions from post-marketing reports, trial data was consulted to estimate frequency.

Frequencies are based on a cumulative meta-analysis with pooling of trials representing exposure in 38102 patients. The following table summarises adverse drug reactions of celecoxib divided into groups according to MedDRA terminology together with their frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data Post-marketing experience): Table 1.

Adverse Drug Reactions in Celecoxib Clinical Trials and Surveillance Experience (MedDRA Preferred Terms)1,2 Adverse Drug Reaction Frequency System Organ Class Very Common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1000 to <1/100) Rare (≥1/10,000 to <1/1000) Very Rare (<1/10000) Frequency Not Known (Post marketing experience) Infections and infestations Sinusitis, upper respiratory tract infection, pharyngitis, urinary tract infection Blood and lymphatic system disorders Anaemia Leukopenia, thrombocyto penia Pancytopenia4 Immune system disorders Hyper- sensitivity Anaphylactic shock4, anaphylactic reaction4 Metabolism and nutrition disorder Hyperkalaem ia Psychiatric disorders Insomnia Anxiety, depression, fatigue Confusional state, hallucination s4 Nervous system disorders Dizziness, hypertonia, headache4 Cerebral infarction1, paraesthesia, somnolence Ataxia, dysguesia Haemorrhage intracranial (including fatal intracranial)4, meningitis aseptic4, epilepsy (including aggravated epilepsy)4, ageusia4, anosmia4 Eye disorders Vision blurred, conjunctiviti s4 Eye haemorrhage 4 Retinal artery occlusion4, retinal vein occlusion4 Ear and labyrinth disorders Tinnitus, hypoacusis1 Cardiac disorders Myocardial infarction1 Cardiac failure, palpitations, tachycardia Arrhythmia4 Vascular disorders Hypertension1 (including aggravated hypertension) Pulmonary embolism4, flushing4 Vasculitis4 Respiratory, thoracic, and mediastinal disorders Rhinitis, cough, dyspnoea1 Bronchospas m4 Pneumonitis4 Gastrointestinal disorders Nausea4, abdominal pain, diarrhoea, Constipation, gastritis, stomatitis, Gastro- intestinal haemorrhage dyspepsia, flatulence, vomiting1, dysphagia1 gastrointestin al inflammation (including aggravation of gastrointestin al inflammation ), eructation 4, duodenal ulcer, gastric ulcer, oesophageal ulcer, intestinal ulcer, large intestinal ulcer, intestinal perforation; oesophagitis, melaena; pancreatitis, colitis4 Hepatobiliary disorders Hepatic function abnormal, hepatic enzyme increased (including increased SGOT and SGPT) Hepatitis4 Hepatic failure4 (sometimes fatal or requiring liver transplant), hepatitis fulminant4 (some with fatal outcome), hepatic necrosis4, cholestasis4, hepatitis cholestatic4, jaundice4 Skin and subcutaneous tissue disorders Rash, pruritus (includes pruritus generalised) Urticaria, ecchymosis4 Angioedema 4, alopecia, photosensitiv ity Dermatitis exfoliative4, erythema multiforme4, Stevens- Johnson syndrome4, toxic epidermal necrolysis4, drug reaction with eosinophilia and systemic symptoms (DRESS) 4, acute generalised exanthematous pustulosis (AGEP) 4, dermatitis bullous4 Musculoskeletal and connective tissue disorders Arthralgia4 Muscle Spasms (leg cramps) Myositis Renal and urinary disorders Blood creatinine increased, blood urea increased Renal failure acute4, hypo- natraemia4 Tubulointerstitial nephritits4, nephrotic syndrome4, glomerulonephritis minimal lesion4 Reproductive system and breast disorders Menstrua l disorder 4 Infertility female (female fertility decreased)3 General disorders and administrative site conditions Influenza like illness, Oedema peripheral/ fluid retention Face oedema, chest pain4 Injury, poisoning and procedural conditions Injury (accidental injury) 1 Adverse drug reactions that occurred in polyp prevention trials, representing subjects treated with celecoxib 400 mg daily in 2 clinical trials of duration up to 3 years (the APC and PreSAP trials).

1. • Known hypersensitivity to sulphonamides. • Active peptic ulceration or gastrointestinal (GI) bleeding. • Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid (aspirin) or NSAIDs including COX-2 inhibitors.

6). 3). The potential for human risk in pregnancy is unknown, but cannot be excluded. 3). • Severe hepatic dysfunction (serum albumin < 25g/l or Child-Pugh score ≥ 10). • Patients with estimated creatinine clearance < 30ml/min. • Inflammatory bowel disease.

• Congestive heart failure (NYHA II-IV). • Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease. 4Special warnings and precautions for use Gastrointestinal (GI) effects 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. 1). Concomitant NSAID use The concomitant use of celecoxib and a non-aspirin NSAID should be avoided. 1). NSAIDs, including COX-2 selective inhibitors, have been associated with increased risk of cardiovascular and thrombotic adverse events when taken long term.