Components:
Method of action:
Treatment option:
Medically reviewed by Militian Inessa Mesropovna, PharmD. Last updated on 26.06.2023
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B-Nagen is indicated in adults for the symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
The decision to prescribe a selective cyclooxygenase-2 (COX-2) inhibitor should be based on an assessment of the individual patient's overall risks.
Symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
B-Nagen is indicated in adults.
The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks.
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. The patient's need for symptomatic relief and response to therapy should be re-evaluated 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 400 mg once daily or in two divided doses may increase efficacy. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered.
The maximum recommended daily dose is 400 mg for all indications.
Special populations
Elderly
As in younger adults, 200 mg per day should be used initially. The dose may, if needed, later be increased to 200 mg twice daily. Particular caution should be exercised in elderly with a body weight less than 50 kg.
Paediatric population
Celecoxib is not indicated for use in children.
CYP2C9 poor metabolisers
Patients who are known, or suspected to be CYP2C9 poor metabolisers based on genotyping or previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution as the risk of dose-dependent adverse effects is increased. Consider reducing the dose to half the lowest recommended dose.
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.
Method of administration
Oral use
B-Nagen may be taken with or without food. For patients who have difficulty swallowing capsules, the contents of a celecoxib capsule can be added to applesauce, rice gruel, yogurt or mashed banana. To do so, the entire capsule contents must be carefully emptied onto a level teaspoon of cool or room temperature applesauce, rice gruel, yogurt or mashed banana and should be ingested immediately with 240 ml of water. The sprinkled capsule contents on applesauce, rice gruel or yogurt are stable for up to 6 hours under refrigerated conditions (2-8°C). The sprinkled capsule contents on mashed banana should not be stored under refrigerated conditions and should be ingested immediately.
Posology
As the cardiovascular risks of B-Nagen 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.
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.
Elderly patients: (>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..
Patients with 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.
Patients with renal impairment: Experience with B-Nagen in patients with mild or moderate renal impairment is limited; therefore such patients should be treated with caution..
Paediatric population: B-Nagen 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 B-Nagen with caution as the risk of dose- dependent adverse effects is increased. Consider reducing the dose to half the lowest recommended dose.
Method of administration
Oral use
Capsules should be swallowed whole with a drink of water.
B-Nagen may be taken with or without food.
Known hypersensitivity to sulfonamides.
Active peptic ulceration or gastrointestinal (GI) bleeding.
Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid (aspirin) or other non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors.
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.
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. B-Nagen 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.
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 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. NSAIDs + acetylsalicylic acid has not been demonstrated in long-term clinical trials.
Concomitant NSAID use
The concomitant use of celecoxib and a non-aspirin NSAID should be avoided.
Cardiovascular effects
Increased number of serious cardiovascular (CV) 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 BID and 400 mg 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. 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. The patient's need for symptomatic relief and response to therapy should be re-evaluated 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.
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, 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. 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.
CYP2D6 inhibition
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 metabolised by CYP2D6.
CYP2C9 poor metabolisers
Patients known to be CYP2C9 poor metabolisers should be treated with caution.
Skin and systemic hypersensitivity reactions
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 (including anaphylaxis, angioedema and drug rash with eosinophilia and systemic symptoms (DRESS), or hypersensitivity syndrome), have been reported in patients receiving celecoxib. Patients with a history of sulfonamide 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.
General
Celecoxib may mask fever and other signs of inflammation.
Use with oral anticoagulants
In patients on concurrent therapy with warfarin, serious bleeding events, some of them fatal, have been reported. Increased prothrombin time (INR) with concurrent therapy has been reported. Therefore, this should be closely monitored in patients receiving warfarin/coumarin-type oral anticoagulants, particularly when therapy with celecoxib is initiated or celecoxib dose is changed. Concomitant use of anticoagulants with NSAIDS may increase the risk of bleeding. Caution should be exercised when combining celecoxib with warfarin or other oral anticoagulants, including novel anticoagulants (e.g. apixaban, dabigatran, and rivaroxaban).
Excipients
B-Nagen 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.
Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them resulting in fatal outcome, have occurred in patients treated with B-Nagen. 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 B-Nagen (gastrointestinal ulceration or other gastrointestinal complications), when B-Nagen 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 B-Nagen 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 B-Nagen at doses of 200 mg BID and 400mg BID compared to placebo.
As the cardiovascular risks of B-Nagen 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.
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with B-Nagen 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 B-Nagen. Therefore, B-Nagen 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, B-Nagen 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 B-Nagen 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 B-Nagen, may cause renal toxicity. Clinical trials with B-Nagen 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, ACE-inhibitors, angiotensin II receptor antagonists, and the elderly. Such patients should be carefully monitored while receiving treatment with B-Nagen.
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 B-Nagen. Among the cases that reported time to onset, most of the severe adverse hepatic events developed within one month after initiation of B-Nagen treatment.
If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken and discontinuation of B-Nagen therapy should be considered.
B-Nagen 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 B-Nagen. 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 (including anaphylaxis, angioedema and drug rash with eosinophilia and systemic symptoms (DRESS, or hypersensitivity syndrome)) have been reported in patients receiving B-Nagen. Patients with a history of sulphonamide allergy or any drug allergy may be at greater risk of serious skin reactions or hypersensitivity reactions. B-Nagen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
B-Nagen 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 B-Nagen with warfarin and other oral anticoagulants.
B-Nagen contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Patients who experience dizziness, vertigo or somnolence while taking B-Nagen should refrain from driving or operating machinery.
Adverse reactions are listed by system organ class and ranked by frequency in Table 1, 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 in Table 1.
- - 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.
Table 1. Adverse drug reactions in celecoxib clinical trials and surveillance experience (MedDRA preferred terms)1,2
| Adverse Drug Reaction Frequency | ||||||
| System Organ Class | Very Common (>1/10) | Common (>1/100 to <1/10) | Uncommon (>1/1,000 to <1/100) | Rare (>1/10,000 to <1/1,000) | Very Rare (<1/10,000) | Frequency Not Known (cannot be estimated from available data) |
| Infections and infestations | Sinusitis, upper respiratory tract infection, pharyngitis,urinary tract infection | |||||
| Blood and lymphatic system disorders | Anaemia | Leukopenia, thrombo-cytopenia | Pancytopenia4 | |||
| Immune system disorders | Hypersensitivity | Anaphylactic shock4, anaphylactic reaction4) | ||||
| Metabolism and nutrition disorders | Hyperkalaemia | |||||
| Psychiatric disorders | Insomnia | Anxiety, depression, fatigue | Confusional state, hallucinations4 | |||
| Nervous system disorders | Dizziness, hypertonia, headache4 | Cerebral infarction1, paraesthesia, somnolence | Ataxia, dysgeusia | Haemorrhage intracranial (including fatal intracranial haemorrhage)4, meningitis aseptic4, epilepsy (including aggravated epilepsy)4, ageusia4, anosmia4 | ||
| Eye disorders | Vision blurred, conjunctivitis4 | Eye haemorrhage4 | Retinal artery occlusion4, retinal vein occlusion4 | |||
| Ear and labyrinth disorders | Tinnitus, hypoacusis1 | |||||
| Cardiac disorders | Myocardial infarction1 | Cardiac failure, palpitations, tachycardia | Arrhythmia4 | |||
| Vascular disorders | Hyper-tension1 (including aggravated hyper-tension) | Pulmonary embolism4, flushing4 | Vasculitis4 | |||
| Respiratory, thoracic, and mediastinal disorders | Rhinitis, cough, dyspnoea1 | Bronchospasm4 | Pneumonitis4 | |||
| Gastrointestinal disorders | Nausea4, abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting1, dysphagia1 | Constipation, gastritis, stomatitis, gastrointestinal inflammation (including aggravation of gastrointestinal inflammation), eructation | Gastro-intestinal haemorrhage4, duodenal ulcer, gastric ulcer, oesophageal ulcer, intestinal ulcer, large intestinal ulcer, intestinal perforation, oesophagitis, melaena; pancreatitis, colitis4 | |||
| Hepatobiliary disorders | Hepatic function abnormal, hepatic enzyme increased (including increased SGOT and SGPT) | Hepatitis4 | Hepatic failure4 (sometimes fatal or requiring liver transplant), hepatitis fulminant4 (some with fatal outcome), hepatic necrosis4, cholestasis4, hepatitis cholestatic4, jaundice4 | |||
| Skin and subcutaneous tissue disorders | Rash, pruritus (includes pruritus generalised) | Urticaria, ecchymosis4 | Angioedema4, alopecia, photo-sensitivity | Dermatitis exfoliative4, erythema multiforme4, Stevens-Johnson syndrome4, toxic epidermal necrolysis4, drug reaction with eosinophilia and systemic symptoms (DRESS) 4, acute generalised exanthematous pustulosis (AGEP)4, dermatitis bullous4 | ||
| Musculoskeletal and connective tissue disorders | Arthralgia4 | Muscle spasms (leg cramps) | Myositis4 | |||
| Renal and urinary disorders | Blood creatinine increased, blood urea increased | Renal failure acute4, hypo-natraemia4 | Tubulointerstitial nephritis4, nephrotic syndrome4, glomerulonephritis minimal lesion4 | |||
| Reproductive system and breast disorders | Menstrual disorder4 | Infertility female (female fertility decreased)3 | ||||
| General disorders and administrative site conditions | Influenza-like illness, oedema peripheral/ fluid retention | Face oedema, chest pain4 | ||||
| Injury, poisoning and procedural complications | Injury (accidental injury | |||||
| 1 Adverse drug reactions that occurred in polyp prevention trials, representing subjects treated with celecoxib 400 mg daily in 2 clinical trials of duration up to 3 years (the APC and PreSAP trials). 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 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 Women intending to become pregnant are excluded from all trials, thus consultation of the trial database for the frequency of this event was not reasonable. 4 Frequencies are based on cumulative meta-analysis with pooling of trials representing exposure in 38102 patients. | ||||||
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Adverse reactions are listed by system organ class and ranked by frequency in Table, 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 B-Nagen daily doses from 100 mg up to 800 mg.: 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 B-Nagen (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
The following table summarises adverse drug reactions of B-Nagen divided into groups according to MedDRA terminology together with their frequency:
- Very common (> 1/10)
- Common (> 1/100 to < 1/10)
- Uncommon (> 1/1,000 to < 1/100)
- Rare (> 1/10,000 to < 1/1,000)
- Very rare (< 1/10,000)
- Not known (cannot be estimated from the available data)
Table. Adverse Drug Reactions in B-Nagen Clinical Trials and Surveillance Experience (MedDRA Preferred Terms)1,2
| Very Common | Common | Uncommon | Rare | Not known (Post- marketing experience)3 | |
| Infections and infestations | Sinusitis, upper respiratory tract infection, urinary tract infection | ||||
| Blood and lymphatic system disorders | Anemia | Leucopenia, thrombocyto penia | Pancytopenia | ||
| Immune system disorders | Allergy aggravated | Serious allergic reactions, anaphylactic shock, anaphylaxis | |||
| Metabolism and nutrition disorders | Hyperkalaemia | ||||
| Psychiatric disorders | Insomnia | Anxiety, depression, tiredness | Confusion | Hallucinations | |
| Nervous system disorders | Dizziness, hypertonia | Paraesthesia, somnolence, cerebral infarction1 | Ataxia, taste alteration | Headache, aggravated epilepsy, meningitis aseptic, ageusia, anosmia, fatal intracranial haemorrhage | |
| Eye disorders | Blurred vision | Conjunctivitis, ocular haemorrhage, retinal artery or vein occlusion | |||
| Ear and labyrinth disorders | Tinnitus, hypoacusis1 | ||||
| Cardiac disorders | Myocardial infarction1 | Heart failure, palpitations, tachycardia | Arrhythmia | ||
| Vascular disorders | Hypertension1 | Hypertension aggravated | Flushing, vasculitis, pulmonary embolism | ||
| Respiratory, thoracic and mediastinal disorders | Pharyngitis, rhinitis, cough, dyspnoea1 | Bronchospasm | |||
| Gastrointestinal disorders | Abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting1dys phagia1 | Constipation, eructation, gastritis, stomatitis, aggravation of gastrointestinal inflammation | Duodenal, gastric, oesophageal, intestinal, and colonic ulceration; intestinal perforation; oesophagitis, melaena; pancreatitis | Nausea, gastrointestinal haemorrhage, colitis/colitis aggravated | |
| Hepatobiliary disorders | Abnormal hepatic function, increased SGOT and SGPT | Elevation of hepatic enzymes | Hepatic failure (sometimes fatal or requiring liver transplant), fulminant hepatitis (some with fatal outcome), liver necrosis, hepatitis jaundice | ||
| Skin and subcutaneous tissue disorders | Rash, pruritus | Urticaria | Alopecia, photosensitivity | Ecchymosis, bullous eruption, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS) or hypersensitivity syndrome, angioedema, acute generalized exanthematous pustulosis | |
| Musculoskeletal and connective tissue disorders | Leg cramps | Arthralgia, myositis | |||
| Renal and urinary disorders | Increased creatinine, BUN increased | Acute renal failure, interstitial nephritis,hyponatraemia | |||
| Reproductive system and breast disorders | Menstrual disorder NOS | ||||
| General disorders and administration site conditions | Flu-like symptoms, peripheral oedema/ fluid retention | Chest pain | |||
| 1 Adverse drug reactions that occurred in polyp prevention trials, representing subjects treated with B-Nagen 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 recognized 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 B-Nagen 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 B-Nagen (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. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard Overdose
Capsule set; Capsules; Coated tablet Substance-granules; Substance-powder There is no clinical experience of overdose. Single doses up to 1200 mg and multiple doses up to 1200 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 medicinal product removal due to high protein binding. There is no clinical experience of overdose. Single doses up to 1200 mg and multiple doses up to 1200 mg twice daily have been administered to healthy subjects for nine days without clinically significant adverse effects. Management 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 drug removal due to high protein binding. Pharmacodynamic properties
Capsule set; Capsules; Coated tablet Substance-granules; Substance-powder Pharmacotherapeutic group: Non-steroidal anti-inflammatory and antirheumatic drugs, NSAIDs, Coxibs, ATC code: M01AH01. Mechanism of action 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 B2 [TxB2] formation) was observed in this dose range in healthy volunteers. Pharmacodynamic effects 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 humans 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. sulfamethoxizole 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 BID (three times the highest recommended dose) celecoxib had no effect on platelet aggregation and bleeding time compared to placebo. Clinical efficacy and safety 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 osteoarthritis of the knee and hip in approximately 4200 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 rheumatoid arthritis in approximately 2100 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 BID, 200 mg QD, 200 mg BID and 400 mg QD 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 4500 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 (1000 mg per day) and ibuprofen (2400 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 was not significantly different between placebo and celecoxib 200 mg BID and 400 mg BID. In a prospective long-term safety outcome study (6 to 15 month duration, CLASS study), 5,800 osteoarthritis and 2,200 rheumatoid arthritis patients received celecoxib 400 mg BID (4-fold and 2-fold the recommended osteoarthritis and rheumatoid arthritis doses, respectively), ibuprofen 800 mg TID or diclofenac 75 mg BID (both at therapeutic doses). Twenty-two percent of enrolled patients took concomitant low-dose acetylsalicylic acid (≤325 mg/day), primarily for cardiovascular (CV) 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 between celecoxib and diclofenac. Those patients on celecoxib and concomitant low-dose acetylsalicylic acid experienced 4 fold higher rates of complicated ulcers as compared to those on celecoxib alone. The incidence of clinically significant decreases in haemoglobin (>2 g/dL), confirmed by repeat testing, was significantly lower in patients on celecoxib compared to the NSAID group, relative risk 0.29, 95% CI 0.17- 0.48. The significantly lower incidence of this event with celecoxib was maintained with or without acetylsalicylic acid use. In a prospective randomised 24 week safety study in patients who were aged >60 years or had a history of gastroduodenal ulcers (users of ASA excluded), the percentages of patients with decreases in haemoglobin (>2 g/dL) and/or haematocrit (>10%) of defined or presumed GI origin were lower in patients treated with celecoxib 200 mg twice daily (N=2238) compared to patients treated with diclofenac SR 75 mg twice daily plus omeprazole 20 mg once daily (N=2246) (0.2% vs. 1.1% for defined GI origin, p = 0.004; 0.4% vs. 2.4% for presumed GI origin, p = 0.0001). The rates of clinically manifest GI complications such as perforation, obstruction or haemorrhage were very low with no differences between the treatment groups (4-5 per group). 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 CV 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 CV 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 CV risk with celecoxib 200 mg BID compared to placebo. The relative risk compared to placebo for a similar composite endpoint (CV death, myocardial infarction, 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% (13/1070 patients) with placebo. Pharmacotherapeutic group: antiinflammatory and antirheumatic products, non- steroids, coxibs; ATC code: M01AH01. Mechanism of action B-Nagen 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 B2 [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. B-Nagen is a diaryl-substituted pyrazole, chemically similar to other non-arylamine sulfonamides (e.g. thiazides, furosemide) but differs from arylamine sulfonamides (e.g. sulfamethoxizole and other sulfonamide antibiotics). A dose dependent effect on TxB2 formation has been observed after high doses of B-Nagen. However, in healthy subjects, in small multiple dose studies with 600 mg BID (three times the highest recommended dose) B-Nagen 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. B-Nagen was evaluated for the treatment of the inflammation and pain of OA of the knee and hip in approximately 4200 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 2100 patients in placebo and active controlled trials of up to 24 weeks duration. B-Nagen at daily doses of 200 mg - 400 mg provided pain relief within 24 hours of dosing. B-Nagen was evaluated for the symptomatic treatment of ankylosing spondylitis in 896 patients in placebo and active controlled trials of up to 12 weeks duration. B-Nagen at doses of 100 mg BID, 200 mg QD, 200 mg BID and 400 mg QD 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 4500 patients free from initial ulceration (B-Nagen doses from 50 mg-400 mg BID). In twelve week endoscopy studies B-Nagen (100-800 mg per day) was associated with a significantly lower risk of gastroduodenal ulcers compared with naproxen (1000 mg per day) and ibuprofen (2400 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 B-Nagen 200 mg BID and 400 mg BID. In a prospective long-term safety outcome study (6 to 15 month duration, CLASS study), 5,800 OA and 2,200 RA patients received B-Nagen 400 mg BID (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg TID or diclofenac 75 mg BID (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) B-Nagen was not significantly different than either ibuprofen or diclofenac individually. Also for the combined NSAID group there was no statically 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 B-Nagen group compared to the NSAID group, relative risk 0.66, 95% CI 0.45-0.97 but not between B-Nagen and diclofenac. Those patients on B-Nagen and concomitant low-dose acetylsalicylic acid experienced 4 fold higher rates of complicated ulcers as compared to those on B-Nagen alone. The incidence of clinically significant decreases in haemoglobin (>2 g/dL), confirmed by repeat testing, was significantly lower in patients on B-Nagen compared to the NSAID group, relative risk 0.29, 95% CI 0.17- 0.48. The significantly lower incidence of this event with B-Nagen was maintained with or without acetylsalicylic acid use. In a prospective randomised 24 week safety study in patients who were aged >60 years or had a history of gastroduodenal ulcers (users of ASA excluded), the percentages of patients with decreases in haemoglobin (>2 g/dL) and/or haematocrit (>10%) of defined or presumed GI origin were lower in patients treated with B-Nagen 200 mg twice daily (N=2238) compared to patients treated with diclofenac SR 75 mg twice daily plus omeprazole 20 mg once daily (N=2246) (0.2% vs. 1.1% for defined GI origin, p = 0.004; 0.4% vs. 2.4% for presumed GI origin, p = 0.0001). The rates of clinically manifest GI complications such as perforation, obstruction or haemorrhage were very low with no differences between the treatment groups (4-5 per group). Cardiovascular Safety - Long-Term Studies Involving Subjects With Sporadic Adenomatous Polyps Two studies involving subjects with sporadic adenomatous polyps were conducted with B-Nagen i.e., the APC trial (Adenoma Prevention with B-Nagen) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In theAPC trial, there was a dose-related increase in the composite endpoint of cardiovascular death, myocardial infarction, or stroke (adjudicated) with B-Nagen 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 B-Nagen 400 mg twice daily and 2.8 (95% CI 1.1 - 7.2) with B-Nagen 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 B-Nagen 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 B-Nagen 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% with (9/933 subjects) with B-Nagen 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 B-Nagen 200mg 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 B-Nagen 200 mg twice daily. The incidence of myocardial infarction was 1.1% (8/717 patients) with B-Nagen 200 mg twice daily and 1.2% (13/1070 patients) with placebo. Pharmacokinetic properties
Capsule set; Capsules; Coated tablet Substance-granules; Substance-powder Absorption Celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. Dosing with food (high fat meal) delays absorption of celecoxib by about 1 hour resulting in a Tmax of about 4 hours and increases bioavailability by about 20%. In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in Cmax, Tmax or T1/2 after administration of capsule contents on applesauce. Distribution Plasma protein binding is about 97 % at therapeutic plasma concentrations and the medicinal product is not preferentially bound to erythrocytes. Biotransformation Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, inactive as COX-1 or COX-2 inhibitors, have been identified in human plasma i.e., a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate. Cytochrome P450 2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*3 polymorphism. In a pharmacokinetic study of celecoxib 200 mg administered once daily in healthy volunteers, genotyped as either CYP2C9*1/*1, CYP2C9*1/*3, or CYP2C9*3/*3, the median Cmax and AUC0-24 of celecoxib on day 7 were approximately 4-fold and 7-fold, respectively, in subjects genotyped as CYP2C9*3/*3 compared to other genotypes. In three separate single dose studies, involving a total of 5 subjects genotyped as CYP2C9*3/*3, single-dose AUC0-24 increased by approximately 3-fold compared to normal metabolisers. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3-1.0% among different ethnic groups. Patients who are known, or suspected to be CYP2C9 poor metabolisers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib 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. Elimination 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. Elimination half-life is 8-12 hours. Steady state plasma concentrations are reached within 5 days of treatment. Absorption B-Nagen is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. Dosing with food (high fat meal) delays absorption by about 1 hour. Distribution The inter-subject variability in the exposure of B-Nagen is about 10-fold. B-Nagen exhibits dose- and time-independent pharmacokinetics in the therapeutic dose range. Plasma protein binding is about 97% at therapeutic plasma concentrations and the drug 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 drug. The main metabolites found in the circulation have no detectable COX-1 or COX-2 activity. Biotransformation B-Nagen metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, inactive as COX-1 or COX-2 inhibitors, have been identified in human plasma i.e., a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate. Cytochrome P450 2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*3 polymorphism. In a pharmacokinetic study of B-Nagen 200 mg administered once daily in healthy volunteers, genotyped as either CYP2C9*1/*1, CYP2C9*1/*3, or CYP2C9*3/*3, the median Cmax and AUC 0-24 of B-Nagen on day 7 were approximately 4-fold and 7- fold, respectively, in subjects genotyped as CYP2C9*3/*3 compared to other genotypes. In three separate single dose studies, involving a total of 5 subjects genotyped as CYP2C9*3/*3, single-dose AUC 0-24 increased by approximately 3- fold compared to normal metabolizers. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3-1.0% among different ethnic groups. Patients who are known, or suspected to be CYP2C9 poor metabolizers based on previous history/experience with other CYP2C9 substrates should be administered B-Nagen with caution. Elimination B-Nagen is mainly eliminated by metabolism. Less than 1% of the dose is excreted unchanged in urine. Renal impairment There is little experience of B-Nagen in renal impairment. The pharmacokinetics of B-Nagen 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. Hepatic impairment 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 B-Nagen. 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 25-35g/L). Patients with severe hepatic impairment (serum albumin <25 g/l) have not been studied and B-Nagen is contraindicated in this patient group. Elderly No clinically significant differences were found in PK parameters of B-Nagen between elderly African-Americans and Caucasians. The plasma concentration of B-Nagen is approximately 100% increased in elderly women (>65 years). Pharmacotherapeutic group
Capsule set; Capsules; Coated tablet Substance-granules; Substance-powder Non-steroidal anti-inflammatory and antirheumatic drugs, NSAIDs, Coxibs, ATC code: M01AH01. antiinflammatory and antirheumatic products, non- steroids, coxibs; ATC code: M01AH01. Preclinical safety data
Capsule set; Capsules; Coated tablet Substance-granules; Substance-powder <6, and 5.1 of the SmPC. Celecoxib at oral doses >150 mg/kg/day (approximately 2-fold human exposure at 200 mg twice daily as measured by AUC0-24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses >30 mg/kg/day (approximately 6-fold human exposure based on the AUC0-24 at 200 mg twice daily) throughout organogenesis. These effects are expected following inhibition of prostaglandin synthesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses, and reduced embryo/fetal survival. Celecoxib was excreted in rat milk. In a peri-post natal study in rats, pup toxicity was observed. In a 2 year toxicity study an increase in nonadrenal thrombosis was observed in male rat at high doses. 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 drug 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 B-Nagen during early embryonic development resulted in pre-implantation and post-implantation losses. These effects are expected following inhibition of prostaglandin synthesis. B-Nagen 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. Incompatibilities
Not applicable. Special precautions for disposal and other handling
Capsule set; Capsules; Coated tablet Substance-granules; Substance-powder Any unused medicinal product or waste material should be disposed of in accordance with local requirements. No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Available in countries | |||||
