CELECOXIB

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 400mg 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. 2). Paediatric population Celecoxib is not indicated for use in children CYP2C9 poor metabolizers Patients who are known or suspected to be CYP2C9 poor metabolizers 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.

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). 2). Method of administration Celecoxib is for oral use. It 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 terminologies have been used in order to classify the occurrence of adverse reactions: Very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 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 Adverse Drug Reaction Frequency MedDRA System Very common Common Uncommon Rare Very Rare Organ Class Frequen cy not known Infections and Sinusitis, infestations upper respiratory tract infection, pharyngiti s, urinary tract infection Blood and lymphatic system disorders Anemia Leucopenia, Thrombocyto penia Pancytopeni a 4 Immune system disorders Hyper- sensitivity Anaphylacti c shock4 anaphylacti c reaction4 Metabolis m and nutrition disorders Hyperkalaem ia Psychiatri c disorders Insomnia Anxiety, depression, fatigue Confusional states, hallucination s4 Nervous system disorders Dizziness, hypertonia headache 4 Cerebral infarction1.

Paraesthesia, somnolence, Ataxia, dysgeusia Haemorrhag e intracranial (including fatal intracranial haemorrhag e), 4 meningitis aseptic 4,, epilepsy (including aggravated epilepsy)4, ageusia4, anosmia4 Eye disorders Vision blurred, conjunctivitis 4 Eye haemorrhage4 Retinal artery occlusion4, retinal vein occlusion4 Ear and labyrinth disorders Tinnitus, hypoacusis1 Cardiac disorders Myocardia l infarction1 Cardiac failure, palpitations, tachycardia Arrhythmia Vascular disorders Hypertension1( including aggravated hypertension) Hypertension aggravated Pulmonary embolism4, flushing4 Vasculitis Respirato ry, thoracic and mediastin al disorders Rhinitis, cough, dyspnoea1 Bronchospas m4 Pneumonitis4 Gastroint estinal disorders Nausea4, abdominal pain, diarrhea, dyspepsia, flatulence, vomiting1, dysphagia1 Constipation, gastritis, stomatitis, aggravation of gastrointestin al inflammation (including aggravation of gastrointestin al inflammation ), eructation Gastrointesti nal haemorrhage4 , duode, nal ulcer, gastric ulcer, oesophageal ulcer, intestinal ulcer, large ulcer intestinal perforation, oesophagitis, melaena, pancreatitis, colitis4 Hepatobil iary disorders Hepatic function, Abnormal hepatic function, (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 subcutaneo us tissue disorders Rash, pruritus (includes pruritus generalize d) Urticaria ecchymosis4 Angioedema4 , Alopecia, photosensitiv ity Dermatitis exfoliative4, erythema multiforme4 , Stevens- Johnson syndrome4, toxic epidermal necrolysis4, drug reaction with eosinophilia and systemic symptoms (DRESS)4, acute generalized exanthemat ous pustulosis (AGEP)4, dermatitis bullous4 Musculos keletal and connectiv e tissue disorders Arthralgia 4 Muscle spasms (leg cramps) Myositis4 Renal and urinary disorders Blood creatinine increased, blood urea increased Renal failure acute4, hyponatraemi a4 Tubulointer stitial nephritis4, nephrotic syndrome4, glomerulon ephritis minimal lesion4 Reproduc tive system and breast disorders Menstrual disorder Infertilit y female (female fertility decrease d)3 OS General disorders and administr ative site conditions Influenza- like illness, oedema/ peripheral fluid retention Face oedema, chest pain4 Chest pain Injury, poisoning and procedur al complicat ions 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).

The adverse drug reactions listed above for the polyp prevention trials are only those that have been previously recognised in the post-marketing surveillance experience, or have occurred more frequently than in the arthritis trials.

2 Furthermore the following previously unknown adverse reactions 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 […]

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). Patients with significant risk factors for cardiovascular events (e. 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.

Caution is also required in patients taking diuretic treatment or otherwise at risk of hypovolaemia. Hypertension 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 with celecoxib 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, may cause renal toxicity. Clinical trials with celecoxib have shown renal effects similar to those observed with comparator NSAIDs. Patients at greatest risk for renal toxicity are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, angiotensin converting enzyme ( ACE) inhibitors, angiotensin II receptor antagonists and the elderly.

Such patients should be carefully monitored while receiving treatment with celecoxib. 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.

8). If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken and discontinuation of celecoxib therapy should be considered. CYP2D6 inhibitions Celecoxib inhibits CYP2D6.

5). ). 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. 8). Patients with a history of sulphonamide allergy or any drug allergy may be at greater risk of serious skin reactions or […]

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 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.