MIMS Classification(s): Non-steroidal Anti-inflammatory Agent (NSAID).
Pharmacology: The mechanism of action of Celecoxib is via inhibition of prostaglandin synthesis primarily by inhibition of COX-2. At therapeutic concentrations in humans, Celecoxib does not inhibit cyclooxygenase 1 (COX-1). COX-2 is induced in response to inflammatory stimuli. This leads to the synthesis and accumulation of inflammatory prostanoids, in particular prostaglandin E2, causing inflammation, edema and pain. Celecoxib acts as an anti-inflammatory, analgesic, and antipyretic agent by blocking the production of inflammatory prostanoids via COX-2 inhibition.
Consequently at therapeutic doses Celecoxib has no effect on prostanoids synthesized by activation of COX-1 thereby not interfering with normal COX-1 related physiological processes in tissues, particularly the stomach, intestine and platelets.
Pharmacokinetics: Absorption: When given under fasting conditions, Celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. Oral bioavailability from capsules is about 99% relative to administration in suspension (optimally available oral dosage form). Under fasting conditions, both peak plasma levels (Cmax) and area under the curve (AUC) are roughly dose proportional up to 200 mg twice daily; at higher doses there are less than proportional increases in Cmax and AUC.
Distribution: Plasma protein binding, which is concentration independent, is about 97% at the therapeutic plasma concentration and Celecoxib is not preferentially bound to erythrocytes in the blood.
Metabolism: 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: 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 reduce enzyme activity, such as those homozygous for the CYP2C9*3 polymorphism.
Patients who are known, or suspected to be CYP2C9 poor metabolizers based on previous history/experience with other CYP2C9 substrates should be administered Celecoxib with caution. Consider starting treatment at half the lowest recommended dose (see Dosage & Administration, and Interactions).
Excretion: Elimination of Celecoxib is mostly by hepatic metabolism with less than 1% of the dose excreted unchanged in urine. After multiple dosing, elimination half-life is 8 to 12 hours and the rate of clearance is about 500 mL/min. With multiple dosing steady-state plasma concentrations are reached before day 5. The intersubject variability on the main pharmacokinetic parameters (AUC, Cmax, elimination half-life) is about 30%. The mean steady-state volume of distribution is about 500 L/70 Kg in young healthy adults indicating wide distribution of Celecoxib into the tissues.
Food effects: Dosing with food (high fat meal) delays absorption of Celecoxib resulting in a Tmax of about 4 hours and increases bioavailability by about 20% (see Dosage & Administration).
Special Populations: Elderly: In the population > 65 years there is a one and a half to two-fold increase in mean Cmax and AUC for Celecoxib. This is a predominantly weight-related rather than age-related change. Celecoxib levels being higher in lower weight individuals and consequently higher in the elderly population who are generally of lower mean weight than the younger population. Therefore, elderly females tend to have higher drug plasma concentrations than elderly males. No dosage adjustment is generally necessary. However, for elderly patients with a lower than average body weight (< 50 Kg), initiate therapy at the lowest recommended dose.
Race: An approximately 40% AUC of Celecoxib is higher in the Black population compared to Caucasians. The cause and clinical significance of this finding is unknown.
Hepatic impairment: Plasma concentrations of Celecoxib in patients with mild hepatic impairment (Child-Pugh Class A) are not significantly different from those of age and sex matched controls. In patients with moderate hepatic impairment (Child-Pugh Class B) Celecoxib plasma concentrations are about twice those of matched controls (see Dosage & Administration).
Renal impairment: In the elderly with age-related reductions in glomerular filtration rate (GFR) (mean GFR > 65 mL/min 1.73 m2) and in patients with chronic stable renal insufficiency (GFR 35-60 mL/min/1.73 m2). Celecoxib pharmacokinetics is comparable to those seen in patients with normal renal function. No significant relationship can be found between serum creatinine (or creatinine clearance) and Celecoxib clearance. Severe renal insufficiency is expected to alter clearance of Celecoxib since the main route of elimination is via hepatic metabolism to inactive metabolites.
Renal effects: The relative roles of COX-1 and COX-2 in renal physiology are not completely understood. Celecoxib reduces the urinary excretion of PGE2 and 6-keto-PGF1 (a prostacyclin metabolite) but leaves serum thromboxane B2 (TXB2) and urinary excretion of 11-dehydro-TXB2, a thromboxane metabolite (both COX-1 products) unaffected. Celecoxib produces no decreases in GFR in the elderly or those with chronic renal insufficiency. It will also show transient reductions in fractional excretion of sodium.
For the management of acute pain in adults and for the treatment of primary dysmenorrhea.
Relief of the acute and chronic pain and inflammation of rheumatoid arthritis and osteoarthritis.
Relief of signs and symptoms of ankylosing spondylitis.
For the management of low back pain (100 mg and 200 mg only).
Oral.
Posology: Celecoxib capsules can be taken with or without food.
*Given the association between cardiovascular (CV) risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment.
Adults: Symptomatic Treatment of Osteoarthritis (OA): The recommended dose of Celecoxib is 200 mg administered as a single dose or as 100 mg twice per day.
Symptomatic Treatment of Rheumatoid Arthritis (RA): The recommended dose of Celecoxib is 100 mg or 200 mg twice per day.
Ankylosing Spondylitis (AS): The recommended dose of Celecoxib is 200 mg administered as a single dose or 100 mg twice per day. Some patients may benefit from a total daily dose of 400 mg.
Management of Acute Pain: The recommended dose of Celecoxib is 400 mg, initially, followed by an additional 200 mg dose, if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily, as needed.
Treatment of Primary Dysmenorrhea: The recommended dose of Celecoxib is 400 mg, initially, followed by an additional 200 mg dose, if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily, as needed.
Low Back Pain (LBP): Usual dosage for adults is 100 mg of Celecoxib orally twice daily, morning and evening, or 200 mg once daily (100 mg and 200 mg only).
Elderly: No dosage adjustment is generally necessary. However, for elderly patients with a lower than average body weight (< 50 Kg), it is advisable to initiate therapy at the lowest recommended dose.
Hepatic impairment: No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A). Introduce Celecoxib at half the recommended dose in arthritis or pain patients with moderate hepatic impairment (Child-Pugh Class B). Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied (see Hepatic effects under Precautions).
Renal impairment: No
dosage adjustment is necessary in patients with mild or moderate renal
impairment. There is no clinical experience in patients with severe renal
impairment (see Renal Effects under Precautions).
Children: Celecoxib is not indicated for use in children.
CYP2C9 Poor Metabolizers: Patients who are known, or suspected to be CYP2C9 poor metabolizers based on genotyping or previous history/experience with other CYP2C9 substrates should be administered Celecoxib with caution as the risk of dose-dependent adverse effects is increased. Consider reducing the dose to half the lowest recommended dose (see Pharmacology: Pharmacokinetics: Metabolism under Actions).
Clinical experience of overdose is limited. Single doses up to 1200 mg and multiple doses up to 1200 mg twice daily have been administered to healthy subjects without clinically significant adverse effects. In the event of suspected overdose, appropriate supportive medical care should be provided. Dialysis is unlikely to be an efficient method of drug removal because of high protein binding of the drug.
Celecoxib is contraindicated in: Patients with known hypersensitivity to Celecoxib or any other ingredient of the product.
Patients with known sulfonamide hypersensitivity.
Patients who have experienced asthma, urticaria or allergic-type reactions after taking Acetylsalicylic acid (ASA [Aspirin]) or other non-steroidal anti-inflammatory drugs (NSAIDs), including other cyclooxygenase-2 (COX-2) specific inhibitors.
Treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see Precautions).
Patients who have established cardiovascular disease (ischemic heart disease and stroke).
Patients who have increased risk of cardiovascular disease (ischemic heart disease and stroke).
Risk of GI ulceration, bleeding and perforation with NSAID: Serious GI toxicity such as bleeding, ulceration and perforation can occur at any time with or without warning symptoms in patients treated with NSAID therapy. Although minor upper GI problems (e.g. dyspepsia) are common, usually developing early in therapy, prescribers should remain alert for ulceration and bleeding in patients treated with NSAIDs even in the absence of previous GI tract symptoms.
Studies to date have not identified any subset of patients not at risk of developing peptic ulceration with bleeding. Patients with prior history of serious GI events and other risk factors associated with peptic ulcer disease (e.g. alcoholism, smoking and corticosteroid therapy) are at increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less than other individuals and account for most spontaneous reports for fatal GI events.
Cardiovascular Effects: Cardiovascular Thrombotic Events: Celecoxib may cause an increased risk of serious CV thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with dose and duration of use. The relative increase of this risk appears to be similar in those with or without known CV disease or CV risk factors. However, patients with CV disease or CV risk factors may be at greater risk in terms of absolute incidence, due to their increased rate at baseline. To minimize the potential risk for an adverse CV event in patients treated with Celecoxib, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and symptoms of serious CV toxicity and the steps to take if they occur (see Pharmacology under Actions).
Celecoxib is not a substitute for Acetylsalicylic acid for prophylaxis of CV thromboembolic diseases because of the lack of effect on platelet function. Because Celecoxib does not inhibit platelet aggregation, anti-platelet therapies (e.g. Acetylsalicylic acid) should not be discontinued.
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 CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, Thiazide diuretics or Loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Celecoxib, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with Celecoxib and throughout the course of therapy (see Pharmacology under Actions).
Fluid Retention and Edema: As with other drugs known to inhibit prostaglandin synthesis, fluid retention and edema have been observed in some patients taking Celecoxib. Therefore, patients with pre-existing congestive heart failure (CHF) or hypertension should be closely monitored. Celecoxib should be used with caution in patients with compromised cardiac function, pre-existing edema, or other conditions predisposing to, or worsened by, fluid retention including those taking diuretic treatment or otherwise at risk of hypovolemia.
Gastrointestinal (GI) Effects: Upper and lower GI perforations, ulcers or bleeds can occur in patients treated with Celecoxib. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with Celecoxib.
Patients most at risk of developing these types of GI complications with NSAIDs are the elderly, patients with CV disease, patients using concomitant glucocorticoids, antiplatelet drugs (such as Aspirin), or other NSAIDs, patients using alcohol or patients with a prior history of, or active, GI disease, such as ulceration, GI bleeding or inflammatory conditions. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as Aspirin), anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most spontaneous reports of fatal GI events have been in elderly or debilitated patients.
Strategies to Minimize the GI Risks in NSAID-treated Patients: Use the lowest effective dosage for the shortest possible duration.
Avoid administration of more than one NSAID at a time.
Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue Celecoxib until a serious GI adverse event is ruled out.
In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding.
Renal Effects: NSAIDs including Celecoxib may cause renal toxicity. 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. Caution should be used when initiating treatment in patients with dehydration. It is advisable to rehydrate patients first and then start therapy with Celecoxib.
Advanced Renal Disease: Renal function should be closely monitored in patients with advance renal disease who are administered Celecoxib (see Dosage & Administration).
Anaphylactoid Reactions: As with NSAIDs in general, anaphylactoid reactions can occur in patients exposed to Celecoxib (see Contraindications).
Serious Skin Reactions: Serious skin reactions, some of them fatal, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), exfoliative dermatitis, Stevens-Johnsons syndrome, and toxic epidermal necrolysis, can be observed very rarely in association with the use of Celecoxib. Patients appear to be at highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within the first month of treatment. Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Hepatic Effects: Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of Celecoxib in patients with severe hepatic impairment is not recommended. Celecoxib should be used with caution when treating patients with moderate hepatic impairment (Child-Pugh Class B), and initiated half the recommended dose (see Dosage & Administration). Rare 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), can be observed with Celecoxib.
A patient with symptoms and/or signs of liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with Celecoxib.
Use with Oral Anticoagulants: The concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding and should be given with caution. Oral anticoagulants include warfarin/coumarin-type and novel oral anticoagulants (e.g. Apixaban, Dabigatran, and Rivaroxaban). In patients on concurrent therapy with warfarin or similar agents, serious bleeding events, some of them fatal, may occur. Because of increase in prothrombin time (INR) have been reported, anticoagulation/INR should be monitored in patients taking a warfarin/coumadin-type anticoagulant after initiating treatment with Celecoxib or changing the dose (see Interactions).
General: By reducing inflammation, Celecoxib may diminish the utility of diagnosis signs, such as fever, in detecting infections. The concomitant use of Celecoxib and a non-Aspiring NSAID should be avoided.
CYP2D6 Inhibition: Celecoxib inhibits CYP2D6. Although it is not a strong inhibitor of the enzyme, a dose reduction may be necessary for individually dose-titrated medicinal products that are metabolized by CYP2D6 (see Interactions).
Warning to prescriber when prescribing COX-2 inhibitors to patients with risk factors of heart disease, hypertension (high blood pressure), hyperlipidemia, diabetes, smoking patients and patient with peripheral arterial disease.
Effects on Ability to Drive and Use Machines: The effect of Celecoxib on ability to drive or use machinery has not been studied, but based on its pharmacodynamic properties and overall safety profile it is unlikely to have an effect.
Fertility: Based on the mechanism of action, the use of NSAIDs, including Celecoxib, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs, including Celecoxib, should be considered.
Pregnancy: There are no studies in pregnant women. The relevance of these data for humans is unknown.
Celecoxib, as with other drugs inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus and should be avoided during the third trimester of pregnancy. Celecoxib should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Inhibition of prostaglandin synthesis might adversely affect pregnancy. If used during second or third trimester of pregnancy, NSAIDs may cause fetal renal dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe cases. Such effects may occur shortly after treatment initiation and are usually reversible. Pregnant women on Celecoxib should be closely monitored for amniotic fluid volume.
Lactation: Administration of Celecoxib to lactating women show very low transfer of Celecoxib into breast milk. Because of the potential for adverse reactions in nursing infants form Celecoxib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the expected benefit of the drug to the mother.
Adverse reactions are listed by system organ class in table. (See table.)
Click on icon to see table/diagram/image
General: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered Celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Consider starting treatment at half the lowest recommended dose (see Dosage & Administration and Pharmacology: Pharmacokinetics: Metabolism under Actions).
Concomitant administration of Celecoxib with inhibitors of CYP2C9 can lead to increases in plasma concentrations of Celecoxib. Therefore, a dose reduction of Celecoxib may be necessary when Celecoxib is co-administered with CYP2C9 inhibitors. Concomitant administration of Celecoxib with inducers of CYP2C9, such as Rifampicin, Carbamazepine and Barbiturates can lead to decreases in plasma concentrations of Celecoxib. Therefore, a dose increase of Celecoxib may be necessary when Celecoxib is co-administered with CYP2C9 inducers.
Drug-specific: Interaction of Celecoxib with Warfarin or similar agents: See Use with Oral Anticoagulants under Precautions.
Lithium: Patients on Lithium treatment should be closely monitored when Celecoxib is introduced or withdrawn.
Aspirin: Celecoxib does not interfere with the anti-platelet effect of low-dose Aspirin (See
Gastrointestinal (GI) Effects
under Precautions). Because of its lack of platelet effects, Celecoxib is not a substitute for Aspirin in the prophylactic treatment of CV disease.
Antihypertensives including Angiotensin-converting enzyme inhibitors (ACEIs), Angiotensin II antagonists (also known as angiotensin receptor blockers, [ARBs]), diuretics and beta-blockers: Inhibition of prostaglandins may diminish the effect of antihypertensives including ACEIs and/or ARBs, diuretics and beta-blockers. This interaction should be given consideration in patients taking Celecoxib concomitantly with ACEIs and/or ARBs, diuretics and beta-blockers.
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, angiotensin II antagonists or diuretics, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the concomitant administration of these drugs should be done with caution.
Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.
Cyclosporine: Because of their effect on renal prostaglandins, NSAIDs may increase the risk of nephrotoxicity with Cyclosporine.
Fluconazole and Ketoconazole: Since Celecoxib is predominantly metabolized 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, may result in a mean increase in Celecoxib Cmax of 60% and in AUC of 130%. Ketoconazole, a CYP3A4 inhibitor, shows no clinically relevant inhibition in the metabolism of Celecoxib.
Dextromethorphan and Metoprolol: Concomitant administration of Celecoxib 200 mg twice daily resulted in a 2.6-fold and a 1.5-fold increases in plasma concentrations of Dextromethorphan and Metoprolol (CYP2D6 substrates), respectively. These increases are due to Celecoxib inhibition to the CYP2D6 substrate metabolism via CYP2D6. Therefore, the dose of drugs as CYP2D6 substrate may need to be reduced when treatment with Celecoxib is initiated or increased when treatment with Celecoxib is terminated (see Use with Oral Anticoagulants under Precautions).
Diuretics: NSAIDs in some patients can reduce the natriuretic effect of Furosemide and Thiazides by inhibition of renal prostaglandin synthesis.
Methotrexate: No pharmacokinetic and clinically important interactions can be observed in Celecoxib and Methotrexate.
Oral contraceptives: Celecoxib have no clinically relevant effects on the pharmacokinetics of a prototype combination oral contraceptive (1 mg Norethindrone/0.035 mg Ethinyl estradiol).
Other drugs: No clinically important interactions can be observed with Celecoxib and antacids (Aluminum and Magnesium), Omeprazole, Glibenclamide (Glyburide), Phenytoin or Tolbutamide.
Store at temperature of not more than 30°C.
M01AH01 - celecoxib ; Belongs to the class of non-steroidal antiinflammatory and antirheumatic products, coxibs.
Celxib 200 cap 200 mg
10 × 10's
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