CELECOXIB KRKA

Posology Posology As the cardiovascular (CV) risks of celecoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. 1). Osteoarthritis The usual recommended daily dose is 200 mg taken once daily or in two divided doses.

In some patients, with insufficient relief from symptoms, an increased dose of 200 mg twice daily may increase efficacy. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered.

Rheumatoid arthritis The initial recommended daily dose is 200 mg taken in two divided doses. The dose may, if needed, later be increased to 200 mg twice daily. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered.

Ankylosing Spondylitis The recommended daily dose is 200 mg taken once daily or in two divided doses. In a few patients, with insufficient relief from symptoms, an increased dose of 400 mg once daily or in two divided doses may increase efficacy.

In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered. The maximum recommended daily dose is 400 mg for all indications. Special populations Elderly As in younger adults, 200 mg per day should be used initially.

The dose may, if needed, later be increased to 200 mg twice daily. Particular caution should be exercised in elderly with a body weight less than 50 kg. 2). Hepatic impairment Treatment should be initiated at half the recommended dose in patients with established moderate liver impairment with a serum albumin of 25-35 g/l.

2). Renal impairment Experience with celecoxib in patients with mild or moderate renal impairment is limited; therefore such patients should be treated with caution. 2). Paediatric population Celecoxib is not indicated for use in children.

CYP2C9 poor metabolisers Patients who are known, or suspected to be CYP2C9 poor metabolisers based on genotyping or previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution as the risk of dose-dependent adverse effects is increased.

Consider reducing the dose to half the lowest recommended dose. 2). Method of administration Oral use Capsules should be swallowed whole with a drink of water. Celecoxib may be taken with or without food.

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) Table 1.

Adverse Drug Reactions in Celecoxib Clinical Trials and Surveillance Experience (MedDRA Preferred Terms)1,2 Very Common Common Uncommon Rare Very rare Infections and infestations Sinusitis, upper respiratory tract infection, pharyngitis, urinary tract infection Blood and lymphatic system disorders Anaemia Leucopenia, thrombocytopenia Pancytopenia4 Immune system disorders Hypersensitivity Anaphylactic shock4, anaphylactic reaction4) Metabolism and nutrition disorders Hyperkalaemia Psychiatric disorders Insomnia Anxiety, depression, fatigue Confusional state, hallucinations4 Nervous system disorders Dizziness, hypertonia, headache4 Cerebral infarction1, paraesthesia, somnolence Ataxia, dysgeusia Haemorrhage intracranial (including fatal intracranial haemorrhage)4, meningitis aseptic4, epilepsy (including aggravated epilepsy)4, ageusia4, anosmia Eye disorders Vision blurred, conjunctivitis4 Eye haemorrhage4 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 Bronchospasm4 Pneumonitis4 Gastrointestinal disorders Nausea4, abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting1, dysphagia1 Constipation, gastritis, stomatitis, gastrointestinal inflammation (including aggravation of gastrointestinal inflammation), eructation Gastro-intestinal haemorrhage4, 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 Angioedema4, alopecia, photosensitivity 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 bullous Musculoskeletal and connective tissue disorders Arthralgia4 Muscle spasms (leg cramps) Myositis4 Renal and urinary disorders Blood creatinine increased, blood urea increased Renal failure acute4, hyponatraemia4 Tubulointerstitial nephritis4, nephrotic syndrome4, glomerulonephriti minimal lesion4 Reproductive system and breast disorders Menstrual disorder4 General disorders and administration site conditions Influenza-like illness, oedema peripheral/ fluid retention Face oedema, chest pain4 Injury, poisoning and procedural complications Injury (accidental injury) SGOT - serum glutamic oxaloacetic transaminase SGPT - serum glutamic pyruvic transaminase 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).

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). 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.

1). g. 1). COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thrombo-embolic diseases because of their lack of antiplatelet effects. 1). Fluid retention and oedema As with other medicinal products known to inhibit prostaglandin synthesis, fluid retention and oedema have been observed in patients taking celecoxib.

Therefore, celecoxib 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.

1. Known hypersensitivity to sulfonamides. 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 other non-steroidal anti-inflammatory drugs (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 <25 g/l or Child-Pugh score ≥10). Patients with estimated creatinine clearance <30 ml/min. Inflammatory bowel disease.

Congestive heart failure (NYHA II-IV). Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease