Icox

Green transparent, clear transparent hard gelatin capsule size "1" filled with white to off white granular powder.
Each capsule contains: Celecoxib BP 200 mg.

Pharmacology: Pharmacotherapeutic group: Non-steroidal anti-inflammatory and antirheumatic drugs, [NSAIDs], Coxibs, Selective Cox-2 Inhibitor. ATC code: M01AH01.
Pharmacodynamics: Mechanism of action: Celecoxib is an oral, selective, cyclooxygenase-2 (COX-2) inhibitor within the dose range (200-400 mg daily). No statistically significant inhibition of COX-1 was observed in this dose range.
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 human 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 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).
Pharmacokinetics: 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 T_max of about 4 hours and increases bioavailability by about 20%.
Distribution: Plasma protein binding is about 97% at therapeutic plasma concentrations and the drug 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.
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.

Celecoxib 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 individual patient's overall risks.

Posology: 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.
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 (>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.
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.
Mode of Administration: For oral use.
Celecoxib may be taken with or without food.

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 drug removal due to high protein binding.

Hypersensitivity to the active substance or to any of the excipients of this formulation.
Known hypersensitivity to sulphonamides.
Active peptic ulceration or gastrointestinal (GI) bleeding.
Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid (aspirin) or other NSAIDs including COX-2 inhibitors.
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 concomitantly, glucocorticoids, 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).
Concomitant NSAID use: The concomitant use of Celecoxib and a non-aspirin NSAID should be avoided.
Cardiovascular effects: As the cardiovascular risk 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. 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 drugs known to inhibit prostaglandin synthesis, fluid retention and oedema have been observed in patients taking celecoxib. Therefore, celecoxib should be used with caution in patients with history of cardiac failure, left ventricular dysfunction or hypertension, and in patients with pre-existing oedema from any other reason, since prostaglandin inhibition may result in deterioration of renal function and fluid retention. Caution is also required in patients taking diuretic treatment or otherwise at risk of hypovolaemia.
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.
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 drugs 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 sulphonamide allergy or any drug allergy may be at greater risk of serious skin reactions or hypersensitivity reactions. Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
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).
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. Patients at greatest risk to 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.

Pregnancy: The potential for human risk in pregnancy is unknown, but cannot be excluded. Celecoxib, as with other drugs 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. If a woman becomes pregnant during treatment, celecoxib should be discontinued.
Breast-feeding: Administration of celecoxib to a limited number of lactating women has shown a very low transfer of celecoxib into breast milk. Women who take celecoxib should not breastfeed.

The following adverse reactions of Celecoxib reported with frequencies: 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.
Very common: Hypertension (including aggravated hypertension).
Common: Sinusitis, upper respiratory tract infection, pharyngitis, urinary tract infection, hyper-sensitivity, insomnia, dizziness, hypertonia, headache, myocardial infarction, rhinitis, cough, dyspnoea, nausea, abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting, dysphagia, rash, pruritus (includes pruritus generalised), arthralgia, influenza-like illness, oedema peripheral fluid retention, injury (accidental injury).
Uncommon: Anaemia, hyperkalaemia, anxiety, depression, fatigue, cerebral infarction, paraesthesia, somnolence, vision blurred, conjunctivitis, tinnitus, hypoacusis, cardiac failure, palpitations, tachycardia, bronchospasm. Constipation, gastritis, stomatitis, gastrointestinal inflammation (including aggravation of gastrointestinal inflammation eructation, hepatic function abnormal, hepatic enzyme increased (including increased SGOT and SGPT), urticaria, ecchymosis, muscle spasms (leg cramps), blood creatinine increased, blood urea increased, face oedema, chest pain.
Rare: Leukopenia, thrombo-cytopenia, confusional state, hallucinations, ataxia, dysgeusia, eye haemorrhage, arrhythmia, pulmonary embolism, flushing, pneumonitis, gastrointestinal haemorrhage, duodenal ulcer, gastric ulcer, oesophageal ulcer, intestinal ulcer, and large intestinal ulcer, intestinal perforation; oesophagitis, melaena; pancreatitis, colitis, hepatitis, angioedema, alopecia, photosensitivity. Renal failure acute, hyponatraemia, menstrual disorder.
Very Rare: Pancytopenia, anaphylactic shock, anaphylactic reaction, haemorrhage intracranial (including fatal intracranial haemorrhage), meningitis aseptic, epilepsy (including aggravated epilepsy), ageusia, anosmia, retinal artery occlusion, retinal vein occlusion, vasculitis, hepatic failure (sometimes fatal or requiring liver transplant), hepatitis fulminant (some with fatal outcome), hepatic necrosis, cholestasis, hepatitis cholestatic, jaundice, dermatitis exfoliative, erythema multiform, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP), dermatitis bullous, myositis, tubulointerstitial nephritis, nephrolic syndrome, glomerulonephritis minimal lesion.
Not Known: Infertility female (female fertility decreased).

Pharmacodynamic interactions: Anticoagulants: 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. 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.
Antihypertensives: NSAIDs may reduce the effect of anti-hypertensive medicinal products including ACE-inhibitors, angiotensin II receptor antagonists, diuretics and beta-blockers, 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, patients on diuretics, or elderly patients) when ACE inhibitors, angiotensin II receptor antagonists, and/or diuretics 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.
Ciclosporin and Tacrolimus: Coadministration of NSAIDs and ciclosporin or tacrolimus may increase the nephrotoxic effect of ciclosporin or tacrolimus, respectively. Renal function should be monitored when celecoxib and any of these drugs are combined.
Acetylsalicylic acid: Celecoxib can be used with low-dose acetylsalicylic acid but is not a substitute for acetylsalicylic acid for cardiovascular prophylaxis.
Pharmacokinetic interactions: Effects of celecoxib on other drugs: CYP2D6 Inhibition: Celecoxib is an inhibitor of CYP2D6. The plasma concentrations of drugs that are substrates of this enzyme may be increased when celecoxib is used concomitantly. Examples of drugs which are metabolised by CYP2D6 are antidepressants (tricyclics and SSRIs), neuroleptics, anti-arrhythmic drugs, etc. The dose of individually dose-titrated CYP2D6 substrates may need to be reduced when treatment with celecoxib is initiated or increased if treatment with celecoxib is terminated. Concomitant administration of celecoxib 200 mg twice daily resulted in 2.6-fold and 1.5-fold increases in plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates), respectively. These increases are due to celecoxib CYP2D6 inhibition of the CYP2D6 substrate metabolism.
CYP2C19 Inhibition: In vitro studies have shown some potential for celecoxib to inhibit CYP2C19 catalysed metabolism. The clinical significance of this in vitro finding is unknown. Examples of drugs which are metabolised by CYP2C19 are diazepam, citalopram and imipramine.
Methotrexate: In patients with rheumatoid arthritis, celecoxib had no statistically significant effect on the pharmacokinetics (plasma or renal clearance) of methotrexate (in rheumatologic doses).
However, adequate monitoring for methotrexate-related toxicity should be considered when combining these two drugs.
Lithium: Patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn.
Oral contraceptives: Celecoxib had no clinically relevant effects on the pharmacokinetics of oral contraceptives (1 mg norethisterone/35 micrograms ethinylestradiol).
Glibenclamide and tolbutamide: Celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrate), or glibenclamide to a clinically relevant extent.
Effects of other drugs on celecoxib: CYP2C9 Poor Metabolisers: Concomitant treatment with CYP2C9 inhibitors such as fluconazole could result in further increases in celecoxib exposure.
Such combinations should be avoided in known CYP2C9 poor metabolisers.
CYP2C9 Inhibitors and Inducers: 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 C_max 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 and Antacids: Ketoconazole and antacids have not been observed to affect the pharmacokinetics of Celecoxib.
Paediatric population: Interaction studies have only been performed in adults.

Store at temperatures not exceeding 30°C.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AH01 - celecoxib ; Belongs to the class of non-steroidal antiinflammatory and antirheumatic products, coxibs.

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