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Indications/Uses
Symptomatic relief in the treatment of: Osteoarthritis, rheumatoid arthritis, ankylosing spondylitis.
The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks (see Contraindications and Precautions).
The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks (see Contraindications and Precautions).
Dosage/Direction for Use
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-evaluated periodically, especially in patients with osteoarthritis (see Pharmacology: Pharmacodynamics under Actions, Contraindications, Precautions and Adverse Reactions).
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. Celecoxib may be taken with or without food.
Elderly Older than 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 (see Pharmacology: Pharmacokinetics under Actions and Precautions).
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 (see Pharmacology: Pharmacokinetics under Actions, Contraindications and Precautions).
Renal Impairment: Experience with celecoxib in patients with mild or moderate renal impairment is limited, therefore such patients should be treated with caution (see Pharmacology: Pharmacokinetics under Actions, Contraindications and Precautions).
Children: Celecoxib is not indicated for use in children.
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. Celecoxib may be taken with or without food.
Elderly Older than 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 (see Pharmacology: Pharmacokinetics under Actions and Precautions).
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 (see Pharmacology: Pharmacokinetics under Actions, Contraindications and Precautions).
Renal Impairment: Experience with celecoxib in patients with mild or moderate renal impairment is limited, therefore such patients should be treated with caution (see Pharmacology: Pharmacokinetics under Actions, Contraindications and Precautions).
Children: Celecoxib is not indicated for use in children.
Overdosage
There is no clinical experience of overdose. Single doses up to 1,200 mg and multiple doses up to 1,200 mg twice daily have been administered to healthy subjects for nine days without clinically significant adverse effects. In the event of suspected overdose, appropriate supportive medical care should be provided e.g. by eliminating the gastric contents, clinical supervision and, if necessary, the institution of symptomatic treatment. Dialysis is unlikely to be an efficient method of active substance removal due to high protein binding.
Administration
May be taken with or without food: Dose of OA/RA may be given w/ or w/o meals.
Contraindications
Absolute Contraindications: Not be given to those patients who have history of: Stroke, cerebrovascular accident (CVA); heart attack, myocardial infarction (MI); coronary artery bypass graft (CABG); uncontrolled hypertension; congestive heart failure (CHF) NYHA II-IV.
Contraindications: Hypersensitivity to any of the active substance.
Known hypersensitivity to sulphonamides.
Active peptic ulceration or gastrointestinal (GI) bleeding.
Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic edema, urticaria or other allergic-type reactions after taking acetylsalicylic acid or NSAIDs including COX-2 (cyclooxygenase-2) inhibitors.
Pregnancy and in women of childbearing potential unless using effective method of contraception (see Use in Pregnancy & Lactation).
Lactation (see Pharmacology: Toxicology: Preclinical Safety Data and Use in Pregnancy & Lactation).
Severe hepatic dysfunction (serum albumin <25 g/L or Child-Pugh score ≥10).
Patients with renal impairment 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.
Contraindications: Hypersensitivity to any of the active substance.
Known hypersensitivity to sulphonamides.
Active peptic ulceration or gastrointestinal (GI) bleeding.
Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic edema, urticaria or other allergic-type reactions after taking acetylsalicylic acid or NSAIDs including COX-2 (cyclooxygenase-2) inhibitors.
Pregnancy and in women of childbearing potential unless using effective method of contraception (see Use in Pregnancy & Lactation).
Lactation (see Pharmacology: Toxicology: Preclinical Safety Data and Use in Pregnancy & Lactation).
Severe hepatic dysfunction (serum albumin <25 g/L or Child-Pugh score ≥10).
Patients with renal impairment 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 NSA1Ds; the elderly, patients using another NSAID or acetylsalicylic acid concomitantly or patients with 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 (see Pharmacology: Pharmacodynamics under Actions).
The concomitant use of 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 200 mg twice daily and 400 mg twice daily compared to placebo (see Pharmacology: Pharmacodynamics under Actions).
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-evaluated periodically, especially in patients with osteoarthritis (see Pharmacology: Pharmacodynamics under Actions, Dosage & Administration, Contraindications and Adverse Reactions).
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with celecoxib after careful consideration (see Pharmacology: Pharmacodynamics under Actions).
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 (see Pharmacology: Pharmacodynamics under Actions).
As with other active substances known to inhibit prostaglandin synthesis fluid retention and edema 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 edema 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 hypovolemia.
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 (same 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 (see Adverse Reactions).
If during treatment, patients deteriorate in any of the organ system functions described previously, 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 medicinal products that are metabolized by CYP2D6 (see Interactions).
Patients known to be CYP2C9 poor metabolisers should be treated with caution (see Pharmacology: Pharmacokinetics under Actions).
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 (see Adverse Reactions). 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 (see Adverse Reactions). Patients with a history of sulphonamide allergy or any medicinal product allergy may be at greater risk of serious skin reactions or hypersensitivity reactions (see Adverse 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 (see Interactions).
Special Warning Regarding Excipients: Celecoxib 200 mg capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Effects on Ability to Drive and Use Machines: Patients who experience dizziness, vertigo or somnolence while taking celecoxib should refrain from driving or operating machinery.
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 (see Pharmacology: Pharmacodynamics under Actions).
The concomitant use of 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 200 mg twice daily and 400 mg twice daily compared to placebo (see Pharmacology: Pharmacodynamics under Actions).
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-evaluated periodically, especially in patients with osteoarthritis (see Pharmacology: Pharmacodynamics under Actions, Dosage & Administration, Contraindications and Adverse Reactions).
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with celecoxib after careful consideration (see Pharmacology: Pharmacodynamics under Actions).
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 (see Pharmacology: Pharmacodynamics under Actions).
As with other active substances known to inhibit prostaglandin synthesis fluid retention and edema 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 edema 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 hypovolemia.
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 (same 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 (see Adverse Reactions).
If during treatment, patients deteriorate in any of the organ system functions described previously, 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 medicinal products that are metabolized by CYP2D6 (see Interactions).
Patients known to be CYP2C9 poor metabolisers should be treated with caution (see Pharmacology: Pharmacokinetics under Actions).
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 (see Adverse Reactions). 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 (see Adverse Reactions). Patients with a history of sulphonamide allergy or any medicinal product allergy may be at greater risk of serious skin reactions or hypersensitivity reactions (see Adverse 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 (see Interactions).
Special Warning Regarding Excipients: Celecoxib 200 mg capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Effects on Ability to Drive and Use Machines: Patients who experience dizziness, vertigo or somnolence while taking celecoxib should refrain from driving or operating machinery.
Use In Pregnancy & Lactation
Use in Pregnancy: No clinical data on exposed pregnancies are available for celecoxib. Studies in animals (rats and rabbits) have shown reproductive toxicity, including malformations (see Pharmacology: Toxicology: Preclinical Safety Data under Actions and Contraindications). The potential for human risk in pregnancy is unknown, but cannot be excluded. Celecoxib, as with other active substances inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Celecoxib is contraindicated in pregnancy and in women who can become pregnant (see Contraindications and Precautions). If a woman becomes pregnant during treatment, celecoxib should be discontinued.
Use in Lactation: There are no studies on the excretion of celecoxib in human milk. Celecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. Women who take celecoxib should not breastfeed.
Use in Lactation: There are no studies on the excretion of celecoxib in human milk. Celecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. Women who take celecoxib should not breastfeed.
Adverse Reactions
Approximately 7,400 patients were treated with celecoxib in controlled trials and of those approximately 2,300 have received it for 1 year or longer. The following events have been reported in patients receiving celecoxib in 12 placebo and/or active controlled trials. Side-effects listed have a rate equal or greater than placebo, and the discontinuation rate due to side-effects was 7.1% in patients receiving celecoxib and 6.1% in patients receiving placebo.
The frequencies used throughout this section are: 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), frequency not known (post marketing experience).
Immune System Disorders: Common: Allergy aggravated. Frequency Not Known: Serious allergic reactions, anaphylactic shock, anaphylaxis.
Infections and Infestations: Common: Sinusitis, upper respiratory tract infection, urinary tract infection.
Blood and Lymphatic System Disorders: Uncommon: Anemia. Rare: Leucopenia, thrombocytopenia. Frequency Not Known: Pancytopenia.
Metabolism and Nutrition Disorders: Uncommon: Hyperkalemia.
Psychiatric Disorders: Common: Insomnia. Uncommon: Anxiety, depression, tiredness. Rare: Confusion. Frequency Not Known: Hallucinations.
Nervous System Disorders: Common: Dizziness, hypertonia. Uncommon: Paresthesia, somnolence, cerebral infarction. Rare: Ataxia, taste alteration. Frequency Not Known: Headache, aggravated epilepsy, meningitis aseptic, ageusia, anosmia, fatal intracranial hemorrhage.
Eye Disorders: Uncommon: Blurred vision. Frequency Not Known: Conjunctivitis, ocular hemorrhage, retinal artery or vein occlusion.
Ear and Labyrinth Disorders: Uncommon: Tinnitus, decreased hearing.
Cardiac Disorders: Common: Myocardial infarction. Uncommon: Heart failure, palpitations, tachycardia. Frequency Not Known: Arrhythmia.
Vascular Disorders: Very Common: Hypertension. Uncommon: Hypotension aggravated. Frequency Not Known: Vasculitis, flushing, pulmonary embolism.
Respiratory, Thoracic and Mediastinal Disorders: Common: Pharyngitis, rhinitis, cough, dyspnea. Frequency Not Known: Bronchospasm.
Gastrointestinal Disorders: Common: Abdominal pain, diarrhea, dyspepsia, flatulence, vomiting, dysphagia. Uncommon: Constipation, eructation, gastritis, stomatitis, aggravation of gastrointestinal inflammation. Rare: Duodenal, gastric, esophageal, intestinal and colonic ulceration, intestinal perforation, esophagitis, melena, pancreatitis. Frequency Not Known: Nausea, gastrointestinal hemorrhage, colitis/colitis aggravated.
Hepatobiliary Disorders: Uncommon: Abnormal hepatic function, increased SGOT and SGPT. Rare: Elevation of hepatic enzymes. Frequency Not Known: Hepatitis, jaundice, hepatic failure (sometimes fatal or requiring liver transplant, fulminant hepatitis (some with fatal outcome), liver necrosis.
Skin and Subcutaneous Tissue Disorders: Common: Rash, pruritus. Uncommon: Urticaria. Rare: Alopecia, photosensitivity. Frequency Not Known: Ecchymosis, bullous eruption, angioedema, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Leg cramps. Frequency Not Known: Myositis, arthralgia.
Renal and Urinary Disorders: Uncommon: Increased creatinine, BUN increased. Frequency Not Known: Acute renal failure, interstitial nephritis, hyponatremia.
Reproductive System and Breast Disorders: Frequency Not Known: Menstrual disorder NOS.
General Disorders and Administration Side Conditions: Common: Peripheral edema/fluid retention, flu-like symptoms. Frequency Not Known: Chest pain.
In a pooled analysis of 20 placebo-controlled studies with duration greater than 2 weeks up to 1 year in patients with OA and RA, the excess rate of myocardial infarction in patients treated with celecoxib 200 or 400 mg daily over placebo was 0.7 events per 1,000 patients (Rare) and there was no excess of strokes.
In preliminary data from two studies in patients with colorectal polyps treated with celecoxib 400 mg daily (see Pharmacology: Pharmacodynamics under Actions) the excess rate over placebo of myocardial infarction over 3 years was 7 events per 1,000 patients (Uncommon). In the same studies, the excess rate for clearly identified ischemic stroke for the 400 mg daily dose (not including events that were hemorrhagic or of unknown etiology) was 0.5 event per 1,000 over 3 years (Rare). For all strokes, there was no increased event rate with celecoxib compared with placebo.
The frequencies used throughout this section are: 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), frequency not known (post marketing experience).
Immune System Disorders: Common: Allergy aggravated. Frequency Not Known: Serious allergic reactions, anaphylactic shock, anaphylaxis.
Infections and Infestations: Common: Sinusitis, upper respiratory tract infection, urinary tract infection.
Blood and Lymphatic System Disorders: Uncommon: Anemia. Rare: Leucopenia, thrombocytopenia. Frequency Not Known: Pancytopenia.
Metabolism and Nutrition Disorders: Uncommon: Hyperkalemia.
Psychiatric Disorders: Common: Insomnia. Uncommon: Anxiety, depression, tiredness. Rare: Confusion. Frequency Not Known: Hallucinations.
Nervous System Disorders: Common: Dizziness, hypertonia. Uncommon: Paresthesia, somnolence, cerebral infarction. Rare: Ataxia, taste alteration. Frequency Not Known: Headache, aggravated epilepsy, meningitis aseptic, ageusia, anosmia, fatal intracranial hemorrhage.
Eye Disorders: Uncommon: Blurred vision. Frequency Not Known: Conjunctivitis, ocular hemorrhage, retinal artery or vein occlusion.
Ear and Labyrinth Disorders: Uncommon: Tinnitus, decreased hearing.
Cardiac Disorders: Common: Myocardial infarction. Uncommon: Heart failure, palpitations, tachycardia. Frequency Not Known: Arrhythmia.
Vascular Disorders: Very Common: Hypertension. Uncommon: Hypotension aggravated. Frequency Not Known: Vasculitis, flushing, pulmonary embolism.
Respiratory, Thoracic and Mediastinal Disorders: Common: Pharyngitis, rhinitis, cough, dyspnea. Frequency Not Known: Bronchospasm.
Gastrointestinal Disorders: Common: Abdominal pain, diarrhea, dyspepsia, flatulence, vomiting, dysphagia. Uncommon: Constipation, eructation, gastritis, stomatitis, aggravation of gastrointestinal inflammation. Rare: Duodenal, gastric, esophageal, intestinal and colonic ulceration, intestinal perforation, esophagitis, melena, pancreatitis. Frequency Not Known: Nausea, gastrointestinal hemorrhage, colitis/colitis aggravated.
Hepatobiliary Disorders: Uncommon: Abnormal hepatic function, increased SGOT and SGPT. Rare: Elevation of hepatic enzymes. Frequency Not Known: Hepatitis, jaundice, hepatic failure (sometimes fatal or requiring liver transplant, fulminant hepatitis (some with fatal outcome), liver necrosis.
Skin and Subcutaneous Tissue Disorders: Common: Rash, pruritus. Uncommon: Urticaria. Rare: Alopecia, photosensitivity. Frequency Not Known: Ecchymosis, bullous eruption, angioedema, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Leg cramps. Frequency Not Known: Myositis, arthralgia.
Renal and Urinary Disorders: Uncommon: Increased creatinine, BUN increased. Frequency Not Known: Acute renal failure, interstitial nephritis, hyponatremia.
Reproductive System and Breast Disorders: Frequency Not Known: Menstrual disorder NOS.
General Disorders and Administration Side Conditions: Common: Peripheral edema/fluid retention, flu-like symptoms. Frequency Not Known: Chest pain.
In a pooled analysis of 20 placebo-controlled studies with duration greater than 2 weeks up to 1 year in patients with OA and RA, the excess rate of myocardial infarction in patients treated with celecoxib 200 or 400 mg daily over placebo was 0.7 events per 1,000 patients (Rare) and there was no excess of strokes.
In preliminary data from two studies in patients with colorectal polyps treated with celecoxib 400 mg daily (see Pharmacology: Pharmacodynamics under Actions) the excess rate over placebo of myocardial infarction over 3 years was 7 events per 1,000 patients (Uncommon). In the same studies, the excess rate for clearly identified ischemic stroke for the 400 mg daily dose (not including events that were hemorrhagic or of unknown etiology) was 0.5 event per 1,000 over 3 years (Rare). For all strokes, there was no increased event rate with celecoxib compared with placebo.
Drug Interactions
Pharmacodynamic Interactions: Anticoagulant 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. (See Precautions.) 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.
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 medicinal products 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 gastrointestinal ulceration or other gastrointestinal complications compared to use of celecoxib alone was shown for concomitant administration of low-dose acetylsalicylic acid. (See Pharmacology: Pharmacodynamics under Actions.)
Pharmacokinetic Interactions: Effects of Celecoxib on Other Drugs: Celecoxib is an inhibitor of CYP2D6. During celecoxib treatment the plasma concentrations of the CYP2D6 substrate dextromethorphan were increased by 136%. The plasma concentrations of active substances that are substrates of this enzyme may be increased when celecoxib is used concomitantly. Examples of active substances which are metabolised by CYP2D6 are antidepressants (tricyclics and SSRIs), neuroleptics, anti-arrhythmic active substances, 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 active substances 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 mcg 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 active substances.
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 Celecoxib: In 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 (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
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.
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.
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 medicinal products 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 gastrointestinal ulceration or other gastrointestinal complications compared to use of celecoxib alone was shown for concomitant administration of low-dose acetylsalicylic acid. (See Pharmacology: Pharmacodynamics under Actions.)
Pharmacokinetic Interactions: Effects of Celecoxib on Other Drugs: Celecoxib is an inhibitor of CYP2D6. During celecoxib treatment the plasma concentrations of the CYP2D6 substrate dextromethorphan were increased by 136%. The plasma concentrations of active substances that are substrates of this enzyme may be increased when celecoxib is used concomitantly. Examples of active substances which are metabolised by CYP2D6 are antidepressants (tricyclics and SSRIs), neuroleptics, anti-arrhythmic active substances, 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 active substances 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 mcg 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 active substances.
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 Celecoxib: In 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 (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
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.
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacotherapeutic Group: Antiinflammatory and antirheumatic products, non-steroids. ATC Code: M01AH01.
Pharmacology: Pharmacodynamics: Celecoxib is an oral, selective, cyclooxygenase-2 (COX-2) inhibitor within the clinical dose range (200-400 mg daily). No statistically significant inhibition of COX-1 [assessed as ex vivo inhibition of thromboxane 82 (TxB2) formation] was observed in this dose range in healthy volunteers.
Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by pro-inflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function, and central nervous system functions (fever induction. pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in man but its relevance to ulcer healing has not been established.
The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical significance in patients at risk of thrombo-embolic reactions. COX-2 selective inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane.
Celecoxib is a diaryl-substituted pyrazole chemically similar to other non-arylamine sulfonamides (e.g. thiazides, furosemide) but differs from arylamine sulfonamides (e.g. sulfamethoxazole and other sulfonamide antibiotics).
A dose dependent effect on TxB2 formation has been observed after high doses of celecoxib. However, in healthy subjects, in small multiple dose studies with 600 mg twice daily (three times the highest recommended dose) celecoxib had no effect on platelet aggregation and bleeding time compared to placebo.
Several clinical studies have been performed confirming efficacy and safety in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Celecoxib was evaluated for the treatment of the inflammation and pain of OA of the knee and hip in approximately 4,200 patients in placebo and active controlled trials of up to 12 weeks duration. It was also evaluated for treatment of the inflammation and pain of RA in approximately 2,100 patients in placebo and active controlled trials of up to 24 weeks duration. Celecoxib at daily doses of 200 mg-400 mg provided pain relief within 24 hours of dosing. Celecoxib was evaluated for the symptomatic treatment of ankylosing spondylitis in 896 patients in placebo and active controlled trials of up to 12 weeks duration. Celecoxib at doses of 100 mg twice daily, 200 mg once daily, 200 mg twice daily and 400 mg once daily in these studies demonstrated significant improvement in pain, global disease activity and function in ankylosing spondylitis.
Five randomised double-blind controlled studies have been conducted including scheduled upper gastrointestinal endoscopy in approximately 4,500 patients free from initial ulceration (celecoxib doses from 50 mg-400 mg BID). In twelve week endoscopy studies celecoxib (100-800 mg per day) was associated with a significantly lower risk of gastroduodenal ulcers compared with naproxen (1,000 mg per day) and ibuprofen (2,400 mg per day). The data were inconsistent in comparison with diclofenac (150 mg per day). In two of the 12-week studies the percentage of patients with endoscopic gastroduodenal ulceration were not significantly different between placebo and celecoxib 200 mg twice daily and 400 mg twice daily.
In a prospective long-term safety outcome study (6 to 15 month duration, CLASS study), 5,800 OA and 2,200 RA patients received celecoxib 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily (both at therapeutic doses). Twenty-two percent of enrolled patients took concomitant low-dose acetylsalicylic acid (325 mg/day), primarily for cardiovascular prophylaxis. For the primary endpoint complicated ulcers (defined as gastrointestinal bleeding, perforation or obstruction) celecoxib was not significantly different than either ibuprofen or diclofenac individually. Also for the combined NSAID group there was no statistically significant difference for complicated ulcers (relative risk 0.77, 95% CI 0.41-1.46, based on entire study duration). For the combined endpoint, complicated and symptomatic ulcers, the incidence was significantly lower in the celecoxib group compared to the NSAID group, relative risk 0.66, 95% CI 0.45-0.97 but not higher rates of complicated ulcers as compared to those on celecoxib alone. The incidence of clinically significant decreases in hemoglobin (>2 g/dL), confirmed by repeat testing, was significantly lower in patients on celecoxib compared to the NSAID group, relative risk 0.2, 95% CI 0.17-0.48. The significantly lower incidence of this event with celecoxib was maintained with or without acetylsalicylic acid use.
Cardiovascular Safety - Long-Term Studies Involving Subjects With Sporadic Adenomatous Polyps: Two studies involving subjects with sporadic adenomatous polyps were conducted with celecoxib i.e., the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint of cardiovascular death, myocardial infarction, or stroke (adjudicated) with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint.
In the APC trial, the relative risks compared to placebo for a composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4-8.5) with celecoxib 400 mg twice daily and 2.8 (95% CI 1.1-7.2) with celecoxib 200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) for placebo. The increases for both celecoxib dose groups versus placebo were mainly due to an increased incidence of myocardial infarction.
In the PreSAP trial, the relative risk compared to placebo for this same composite endpoint (adjudicated) was 1.2 (95% CI 0.6-2.4) with celecoxib 400 mg once daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects), respectively. The incidence of myocardial infarction (adjudicated) was 1.0% (9/933 subjects) with celecoxib 400 mg once daily and 0.6% (4/628 subjects) with placebo.
Data from a third long-term study, ADAPT (The Alzheimer's Disease Anti-inflammatory Prevention Trial), did not show a significantly increased cardiovascular risk with celecoxib 200 mg BID compared to placebo.
The relative risk compared to placebo for a similar composite endpoint (CV death, MI, stroke) was 1.14 (95% CI 0.61-2.12) with celecoxib 200 mg twice daily. The incidence of myocardial infarction was 1.1 % (8/717 patients) with celecoxib 200 mg twice daily and 1.2% (13/1,070 patients) with placebo.
Pharmacokinetics: Celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. Dosing with food (high fat meal) delays absorption by about 1 hour.
Celecoxib is mainly eliminated by metabolism. Less than 1% of the dose is excreted unchanged in urine. The inter-subject variability in the exposure of celecoxib is about 10-fold. Celecoxib exhibits dose- and time-independent pharmacokinetics in the therapeutic dose range. Plasma protein binding is about 97% at therapeutic plasma concentrations and the active substance is not preferentially bound to erythrocytes. Elimination half-life is 8-12 hours. Steady state plasma concentrations are reached within 5 days of treatment. Pharmacological activity resides in the parent active substance. The main metabolites found in the circulation have no detectable COX-1 or COX-2 activity.
Celecoxib is metabolised in the liver by hydroxylation, oxidation and some glucuronidation. The phase I metabolism is mainly catalyzed by CYP2C9. There is a genetic polymorphism of this enzyme. Less than 1% of the population are poor metabolisers and have an enzyme with decreased activity. Plasma concentrations of celecoxib are probably markedly increased in such patients.
Patients known to be CYP2C9 poor metabolisers should be treated with caution.
No clinically significant differences were found in PK parameters of celecoxib between elderly African-Americans and Caucasians.
The plasma concentration of celecoxib is approximately 100% increased in elderly women (>65 years).
Compared to subjects with normal hepatic function, patients with mild hepatic impairment had a mean increase in Cmax of 53% and in AUC of 26% of celecoxib. The corresponding values in patients with moderate hepatic impairment were 41% and 146% respectively. The metabolic capacity in patients with mild to moderate impairment was best correlated to their albumin values. Treatment should be initiated at half the recommended dose in patients with moderate liver impairment (with serum albumin 25-35 g/L). Patients with severe hepatic impairment (serum albumin <25 g/L) have not been studied and celecoxib is contraindicated in this patient group.
There is little experience of celecoxib in renal impairment. The pharmacokinetics of celecoxib has not been studied in patients with renal impairment but is unlikely to be markedly changed in these patients. Thus caution is advised when treating patients with renal impairment. Severe renal impairment is contraindicated.
Toxicology: Preclinical Safety Data: Conventional embryo-fetal toxicity studies resulted in dose dependent occurrences of diaphragmatic hernia in rat fetuses and of cardiovascular malformations in rabbit fetuses at systemic exposures to free active substance approximately 5X (rat) and 3X (rabbit) higher than those achieved at the maximum recommended daily human dose (400 mg). Diaphragmatic hernia was also seen in a peri-post natal toxicity study in rats, which included exposure during the organogenetic period. In the latter study, at the lowest systemic exposure where this anomaly occurred in a single animal, the estimated margin relative to the maximum recommended daily human dose was 3X.
In animals, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses.
These effects are expected following inhibition of prostaglandin synthesis.
Celecoxib was excreted in rat milk. In a peri-post natal study in rats, pup toxicity was observed.
Based on conventional studies, genotoxicity or carcinogenicity, no special hazard for humans was observed, beyond those addressed in other sections of the SmPC. In a two-year toxicity study an increase in nonadrenal thrombosis was observed in male rat at high doses.
Pharmacology: Pharmacodynamics: Celecoxib is an oral, selective, cyclooxygenase-2 (COX-2) inhibitor within the clinical dose range (200-400 mg daily). No statistically significant inhibition of COX-1 [assessed as ex vivo inhibition of thromboxane 82 (TxB2) formation] was observed in this dose range in healthy volunteers.
Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by pro-inflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function, and central nervous system functions (fever induction. pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in man but its relevance to ulcer healing has not been established.
The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical significance in patients at risk of thrombo-embolic reactions. COX-2 selective inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane.
Celecoxib is a diaryl-substituted pyrazole chemically similar to other non-arylamine sulfonamides (e.g. thiazides, furosemide) but differs from arylamine sulfonamides (e.g. sulfamethoxazole and other sulfonamide antibiotics).
A dose dependent effect on TxB2 formation has been observed after high doses of celecoxib. However, in healthy subjects, in small multiple dose studies with 600 mg twice daily (three times the highest recommended dose) celecoxib had no effect on platelet aggregation and bleeding time compared to placebo.
Several clinical studies have been performed confirming efficacy and safety in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Celecoxib was evaluated for the treatment of the inflammation and pain of OA of the knee and hip in approximately 4,200 patients in placebo and active controlled trials of up to 12 weeks duration. It was also evaluated for treatment of the inflammation and pain of RA in approximately 2,100 patients in placebo and active controlled trials of up to 24 weeks duration. Celecoxib at daily doses of 200 mg-400 mg provided pain relief within 24 hours of dosing. Celecoxib was evaluated for the symptomatic treatment of ankylosing spondylitis in 896 patients in placebo and active controlled trials of up to 12 weeks duration. Celecoxib at doses of 100 mg twice daily, 200 mg once daily, 200 mg twice daily and 400 mg once daily in these studies demonstrated significant improvement in pain, global disease activity and function in ankylosing spondylitis.
Five randomised double-blind controlled studies have been conducted including scheduled upper gastrointestinal endoscopy in approximately 4,500 patients free from initial ulceration (celecoxib doses from 50 mg-400 mg BID). In twelve week endoscopy studies celecoxib (100-800 mg per day) was associated with a significantly lower risk of gastroduodenal ulcers compared with naproxen (1,000 mg per day) and ibuprofen (2,400 mg per day). The data were inconsistent in comparison with diclofenac (150 mg per day). In two of the 12-week studies the percentage of patients with endoscopic gastroduodenal ulceration were not significantly different between placebo and celecoxib 200 mg twice daily and 400 mg twice daily.
In a prospective long-term safety outcome study (6 to 15 month duration, CLASS study), 5,800 OA and 2,200 RA patients received celecoxib 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily (both at therapeutic doses). Twenty-two percent of enrolled patients took concomitant low-dose acetylsalicylic acid (325 mg/day), primarily for cardiovascular prophylaxis. For the primary endpoint complicated ulcers (defined as gastrointestinal bleeding, perforation or obstruction) celecoxib was not significantly different than either ibuprofen or diclofenac individually. Also for the combined NSAID group there was no statistically significant difference for complicated ulcers (relative risk 0.77, 95% CI 0.41-1.46, based on entire study duration). For the combined endpoint, complicated and symptomatic ulcers, the incidence was significantly lower in the celecoxib group compared to the NSAID group, relative risk 0.66, 95% CI 0.45-0.97 but not higher rates of complicated ulcers as compared to those on celecoxib alone. The incidence of clinically significant decreases in hemoglobin (>2 g/dL), confirmed by repeat testing, was significantly lower in patients on celecoxib compared to the NSAID group, relative risk 0.2, 95% CI 0.17-0.48. The significantly lower incidence of this event with celecoxib was maintained with or without acetylsalicylic acid use.
Cardiovascular Safety - Long-Term Studies Involving Subjects With Sporadic Adenomatous Polyps: Two studies involving subjects with sporadic adenomatous polyps were conducted with celecoxib i.e., the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint of cardiovascular death, myocardial infarction, or stroke (adjudicated) with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint.
In the APC trial, the relative risks compared to placebo for a composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4-8.5) with celecoxib 400 mg twice daily and 2.8 (95% CI 1.1-7.2) with celecoxib 200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) for placebo. The increases for both celecoxib dose groups versus placebo were mainly due to an increased incidence of myocardial infarction.
In the PreSAP trial, the relative risk compared to placebo for this same composite endpoint (adjudicated) was 1.2 (95% CI 0.6-2.4) with celecoxib 400 mg once daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects), respectively. The incidence of myocardial infarction (adjudicated) was 1.0% (9/933 subjects) with celecoxib 400 mg once daily and 0.6% (4/628 subjects) with placebo.
Data from a third long-term study, ADAPT (The Alzheimer's Disease Anti-inflammatory Prevention Trial), did not show a significantly increased cardiovascular risk with celecoxib 200 mg BID compared to placebo.
The relative risk compared to placebo for a similar composite endpoint (CV death, MI, stroke) was 1.14 (95% CI 0.61-2.12) with celecoxib 200 mg twice daily. The incidence of myocardial infarction was 1.1 % (8/717 patients) with celecoxib 200 mg twice daily and 1.2% (13/1,070 patients) with placebo.
Pharmacokinetics: Celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. Dosing with food (high fat meal) delays absorption by about 1 hour.
Celecoxib is mainly eliminated by metabolism. Less than 1% of the dose is excreted unchanged in urine. The inter-subject variability in the exposure of celecoxib is about 10-fold. Celecoxib exhibits dose- and time-independent pharmacokinetics in the therapeutic dose range. Plasma protein binding is about 97% at therapeutic plasma concentrations and the active substance is not preferentially bound to erythrocytes. Elimination half-life is 8-12 hours. Steady state plasma concentrations are reached within 5 days of treatment. Pharmacological activity resides in the parent active substance. The main metabolites found in the circulation have no detectable COX-1 or COX-2 activity.
Celecoxib is metabolised in the liver by hydroxylation, oxidation and some glucuronidation. The phase I metabolism is mainly catalyzed by CYP2C9. There is a genetic polymorphism of this enzyme. Less than 1% of the population are poor metabolisers and have an enzyme with decreased activity. Plasma concentrations of celecoxib are probably markedly increased in such patients.
Patients known to be CYP2C9 poor metabolisers should be treated with caution.
No clinically significant differences were found in PK parameters of celecoxib between elderly African-Americans and Caucasians.
The plasma concentration of celecoxib is approximately 100% increased in elderly women (>65 years).
Compared to subjects with normal hepatic function, patients with mild hepatic impairment had a mean increase in Cmax of 53% and in AUC of 26% of celecoxib. The corresponding values in patients with moderate hepatic impairment were 41% and 146% respectively. The metabolic capacity in patients with mild to moderate impairment was best correlated to their albumin values. Treatment should be initiated at half the recommended dose in patients with moderate liver impairment (with serum albumin 25-35 g/L). Patients with severe hepatic impairment (serum albumin <25 g/L) have not been studied and celecoxib is contraindicated in this patient group.
There is little experience of celecoxib in renal impairment. The pharmacokinetics of celecoxib has not been studied in patients with renal impairment but is unlikely to be markedly changed in these patients. Thus caution is advised when treating patients with renal impairment. Severe renal impairment is contraindicated.
Toxicology: Preclinical Safety Data: Conventional embryo-fetal toxicity studies resulted in dose dependent occurrences of diaphragmatic hernia in rat fetuses and of cardiovascular malformations in rabbit fetuses at systemic exposures to free active substance approximately 5X (rat) and 3X (rabbit) higher than those achieved at the maximum recommended daily human dose (400 mg). Diaphragmatic hernia was also seen in a peri-post natal toxicity study in rats, which included exposure during the organogenetic period. In the latter study, at the lowest systemic exposure where this anomaly occurred in a single animal, the estimated margin relative to the maximum recommended daily human dose was 3X.
In animals, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses.
These effects are expected following inhibition of prostaglandin synthesis.
Celecoxib was excreted in rat milk. In a peri-post natal study in rats, pup toxicity was observed.
Based on conventional studies, genotoxicity or carcinogenicity, no special hazard for humans was observed, beyond those addressed in other sections of the SmPC. In a two-year toxicity study an increase in nonadrenal thrombosis was observed in male rat at high doses.
MedsGo Class
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Features
Brand
RiteMed
Full Details
Dosage Strength
200mg
Drug Ingredients
- Celecoxib
Drug Packaging
Capsule 1's
Generic Name
Celecoxib
Dosage Form
Capsule
Registration Number
DRP-3857-01
Drug Classification
Prescription Drug (RX)