Drug Class Description
Cox-2 selective cyclo-oxygenase inhibitors (coxib, non-steroidal anti-inflammatory drugs, NSAIDs).

Generic Name
Celecoxib

Drug Description
Each 100 mg capsule contains 149.7 mg lactose monohydrate. Each 200 mg capsule contains 49.8 mg lactose monohydrate

Presentation
Capsule, hard.Opaque, white with two blue bands marked 7767 and 100 (Celebrex 100 mg). Opaque, white with two gold bands marked 7767 and 200 (Celebrex 200 mg).

Indications
Symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks

Adult Dosage
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. The patient's need for symptomatic relief and response to therapy should be re-eva luated periodically, especially in patients with osteoarthritis.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.Celebrex may be taken with or without food.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. Experience in such patients is limited to cirrhotic patients.Renal impairment: Experience with celecoxib in patients with mild or moderate renal impairment is limited, therefore such patients should be treated with caution.CYP2C9 Poor Metabolizers: Patients who are known, or suspected to be CYP2C9 poor metabolizers based on 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.

Child Dosage
Celecoxib is not indicated for use in children.

Elderly Dosage
Elderly: (>65 years) 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.

Contra Indications
History of hypersensitivity to the active substance or to any of the excipients.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 or NSAIDs including COX-2 (cyclooxygenase-2) inhibitors.In pregnancy and in women of childbearing potential unless using an effective method of contraception. Celecoxib has been shown to cause malformations in the two animal species studied. The potential for human risk in pregnancy is unknown, but cannot be excluded.Breast feeding.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.

Special Precautions
Upper 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 acetylsalicylic acid concomitantly 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 a celecoxib and a non-aspirin NSAID should be avoided.Increased number of serious cardiovascular events, mainly myocardial infarction, has been found in a long-term placebo-controlled study in subjects with sporadic adenomatous polyps treated with celecoxib at doses of 200mg BID and 400mg BID compared to placebo.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. The patient's need for symptomatic relief and response to therapy should be re-eva luated periodically, especially in patients with osteoarthritis.Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with celecoxib after careful consideration.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. Therefore, antiplatelet therapies should not be discontinued.As with other drugs 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.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.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, 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. Among the cases that reported time to onset, most of the severe adverse hepatic events developed within one month after initiation of celecoxib treatment.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.Celecoxib inhibits CYP2D6. Although it is not a strong inhibitor of this enzyme, a dose reduction may be necessary for individually dose-titrated drugs that are metabolised by CYP2D6.Patients known to be CYP2C9 poor metabolisers should be treated with caution.Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of celecoxib. 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 (anaphylaxis and angioedema) have been reported in patients receiving celecoxib. Patients with a history of sulphonamide allergy or any drug allergy may be at greater risk of serious skin reactions or hypersensitivity reactions. Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.Celecoxib may mask fever and other signs of inflammation.In patients on concurrent therapy with warfarin, serious bleeding events have occurred. Caution should be exercised when combining celecoxib with warfarin and other oral anticoagulants.Celebrex 100 mg and 200 mg capsules contain lactose (149.7 mg and 49.8 mg, respectively). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interactions
Pharmacodynamic interactionsAnticoagulant 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.Bleeding events in association with increases in prothrombin time have been reported, predominantly in the elderly, in patients receiving celecoxib concurrently with warfarin, some of them fatal.NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products. 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 or elderly patients) when ACE inhibitors or angiotensin II receptor antagonists are combined with NSAIDs, including celecoxib. 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.In a 28-day clinical study in patients with lisinopril-controlled Stage I and II hypertension, administration of celecoxib 200 mg BID resulted in no clinically significant increases, when compared to placebo treatment, in mean daily systolic or diastolic blood pressure as determined using 24-hour ambulatory blood pressure monitoring. Among patients treated with celecoxib 200 mg BID, 48% were considered unresponsive to lisinopril at the final clinic visit (defined as either cuff diastolic blood pressure >90 mmHg or cuff diastolic blood pressure increased >10% compared to baseline), compared to 27% of patients treated with placebo; this difference was statistically significant.Co-administration of NSAIDs and ciclosporin or tacrolimus have been suggested to increase the nephrotoxic effect of ciclosporin and tacrolimus. Renal function should be monitored when celecoxib and any of these drugs are combined.Celecoxib can be used with low dose acetylsalicylic acid but is not a substitute for acetylsalicylic acid for cardiovascular 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.Pharmacokinetic interactionsEffects of celecoxib on other drugsCelecoxib is an inhibitor of CYP2D6. During celecoxib treatment, the plasma concentrations of the CYP2D6 substrate dextromethorphan were increased by 136%. The plasma concentrations of drugs that are substrates of this enzyme may be increased when celecoxib is used concomitantly. Examples of drugs which are metabolised by CYP2D6 are antidepressants (tricyclics and SSRIs), neuroleptics, anti-arrhythmic drugs, 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.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 drugs which are metabolised by CYP2C19 are diazepam, citalopram and imipramine.In an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of oral contraceptives (1 mg norethistherone /35 microg ethinylestradiol).Celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrate), or glibenclamide to a clinically relevant extent.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 drugs.In healthy subjects, co-administration of celecoxib 200 mg twice daily with 450 mg twice daily of lithium resulted in a mean increase in Cmax of 16% and in AUC of 18% of lithium. Therefore, patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn.Effects of other drugs on celecoxibIn individuals who are CYP2C9 poor metabolisers and demonstrate increased systemic exposure to celecoxib, concomitant treatment with CYP2C9 inhibitors could result in further increases in celecoxib exposure. Such combinations should be avoided in known CYP2C9 poor metabolisers.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.

Adverse Reactions
Adverse reactions are listed by system organ class and ranked by frequency below, reflecting data from the following sources:Adverse reactions reported in osteoarthritis patients and rheumatoid arthritis patients at incidence rates greater than 0.01% 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 below.Adverse reactions reported at incidence rates greater than placebo for subjects treated with celecoxib 400 mg daily in long-term polyp prevention trials of duration up to 3 years (the APC and PreSAP trials;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). Because not all adverse drug reactions are reported to the MAH and included in the safety database, the frequencies of these reactions cannot be reliably determined.Adverse Drug Reactions in Celecoxib Clinical Trials and Surveillance Experience (MedDRA Preferred Terms)1,2Infections and infestationsCommon (1/100 to <1/10): Sinusitis, upper respiratory tract infection, urinary tract infectionBlood and lymphatic system disorders Uncommon (1/1000 to <1/100): AnemiaRare (1/10,000 to <1/1000): Leucopenia, hrombocytopeniaFrequency Not Known (Post-marketing experience)3: PancytopeniaImmune system disorders Common (1/100 to <1/10): Allergy aggravatedFrequency Not Known (Post-marketing experience)3: Serious allergic reactions, anaphylactic shock, anaphylaxisPsychiatric disorders Common (1/100 to <1/10): InsomniaUncommon (1/1000 to <1/100): Anxiety, depression, tirednessRare (1/10,000 to <1/1000): ConfusionFrequency Not Known (Post-marketing experience)3: HallucinationsMetabolism and nutrition disordersUncommon (1/1000 to <1/100): HyperkaelemiaNervous system disordersCommon (1/100 to <1/10): Dizziness, hypertoniaUncommon (1/1000 to <1/100): Paraesthesia, somnolence, cerebral infarction1Rare (1/10,000 to <1/1000): Ataxia, taste alterationFrequency Not Known (Post-marketing experience)3: Headache, aggravated epilepsy, meningitis aseptic, ageusia, anosmia, fatal intracranial haemorrhageEye disordersUncommon (1/1000 to <1/100): Blurred visionFrequency Not Known (Post-marketing experience)3: Conjunctivitis, ocular haemorrhage, retinal artery or vein occlusionEar and labyrinth disorders Uncommon (1/1000 to <1/100): Tinnitus, hypoacusis1Cardiac disorders Common (1/100 to <1/10): Myocardial infarction1Uncommon (1/1000 to <1/100): Heart failure, palpitations, tachycardiaFrequency Not Known (Post-marketing experience)3: ArrhythmiaVascular disorders Very Common (1/10): Hypertension1Uncommon (1/1000 to <1/100): Hypertension aggravatedFrequency Not Known (Post-marketing experience)3: Flushing, vasculitisRespiratory, thoracic, and mediastinal disorders Common (1/100 to <1/10): Pharyngitis, rhinitis, cough, dyspnoea1Frequency Not Known (Post-marketing experience)3: BronchospasmGastrointestinal disorders Common (1/100 to <1/10): Abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting1 , dysphagia1Uncommon (1/1000 to <1/100): Constipation, eructation, gastritis, stomatitis, aggravation of gastrointestinal inflammationRare (1/10,000 to <1/1000): Duodenal, gastric, oesophageal, intestinal, and colonic ulceration, intestinal perforation, oesophagitis, melaena, pancreatitisFrequency Not Known (Post-marketing experience)3: Nausea, gastrointestinal haemorrhage, colitis/colitis aggravatedHepatobiliary disorders Uncommon (1/1000 to <1/100): Abnormal hepatic function, increased SGOT and SGPTRare (1/10,000 to <1/1000): Elevation of hepatic enzymesFrequency Not Known (Post-marketing experience)3: Hepatic failure (sometimes fatal or requiring liver transplant), fulminant hepatitis (some with fatal outcome), liver necrosis hepatitis, jaundice.Skin and subcutaneous tissue disorders Common (1/100 to <1/10): Rash, pruritusUncommon (1/1000 to <1/100): UrticariaRare (1/10,000 to <1/1000): Alopecia, photosensitivityFrequency Not Known (Post-marketing experience)3: Ecchymosis, bullous eruption, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, acute generalised exanthematous pustulosis.Musculoskeletal and connective tissue disorders Uncommon (1/1000 to <1/100): Leg CrampsFrequency Not Known (Post-marketing experience)3: Arthralgia, myositisRenal and urinary disorders Uncommon (1/1000 to <1/100): Increased creatinine, BUN increasedFrequency Not Known (Post-marketing experience)3: Acute renal failure, interstitial nephritis, hyponatraemiaReproductive system and breast disorders Frequency Not Known (Post-marketing experience)3: Menstrual disorder NOSGeneral disorders and administrative site conditions Common (1/100 to <1/10): Flu-like symptoms, peripheral oedema/ fluid retention1 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 for the polyp prevention trials are only those that 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 trials): Common: angina pectoris, irritable bowel syndrome, nephrolithiasis, blood creatinine increased, benign prostatic hyperplasia, weight increased. Uncommon: helicobacter infection, herpes zoster, erysipelas, bronchopneumonia, labyrinthitis, gingival infection, lipoma, vitreous floaters, conjunctival haemorrhage, deep vein thrombosis, dysphonia, haemorrhoidal haemorrhage, frequent bowel movements, mouth ulceration, allergic dermatitis, ganglion, nocturia, vaginal haemorrhage, breast tenderness, lower limb fracture, blood sodium increased.3 Adverse drug reactions spontaneously reported to the safety surveillance database over a period in which an estimated >70 million patients were treated with celecoxib (various doses, durations, and indications). As a result, the frequencies of these adverse drug reactions cannot be reliably determined. Adverse drug reactions listed for the post-marketing population are only those that are not already listed for the arthritis trials or the polyp prevention trials.In final data (adjudicated) from the APC and PreSAP trials in patients treated with celecoxib 400 mg daily for up to 3 year, the excess rate over placebo for myocardial infarction was 7.6 events per 1000 patients (uncommon) and there was no excess rate for stroke (types not differentiated) over placebo.

Manufacturer
Pfizer Limited

Drug Availability
(POM)

Updated
22 November 2011