Singapore Drugs Database

Indication

For the relief and management of osteoarthritis (OA), rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), ankylosing spondylitis, acute pain, primary dysmenorrhea and oral adjunct to usual care for patients with familial adenomatous polyposis [FDA label].

Mechanism of Action

Unlike most NSAIDs, which inhibit both types of cyclooxygenases (COX-1 and COX-2), celecoxib is a selective noncompetitive inhibitor of cyclooxygenase-2 (COX-2) enzyme [FDA label]. The mechanism of action of _celecoxib_ is the inhibition of prostaglandin synthesis through COX-2 inhibition [FDA label]. COX-2 is expressed heavily in inflamed tissues where it is induced by inflammatory mediators. COX-2 also plays physiological roles in a limited number of tissues, including those of the female reproductive tract, the kidney, and possibly the vascular endothelium [L3296].

Pharmacokinetics

Absorption

Easily absorbed in the gastrointestinal tract. When a single dose of 200 mg is given to healthy subjects, peak plasma levels occur 3 hours after an oral dose. The peak plasma level is 705 ng/mL. Absolute bioavailability studies have not been conducted. When multiple doses are given, steady-state is reached on or before Day 5. When taken with a high-fat meal, peak plasma levels are delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20% [FDA label]. A meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC (area under the curve) of celecoxib in black patients compared to Caucasians for unknown reasons [L3296].

Distribution

The apparent volume of distribution at steady state (Vss/F) is about 400 L, suggesting extensive distribution into various tissues. Celecoxib is not preferentially bound to red blood cells [FDA label].

Metabolism

Celecoxib metabolism is primarily mediated via _cytochrome P450 2C9_, in the liver. Three metabolites, a primary alcohol, the corresponding _carboxylic acid_ and its _glucuronide conjugate_, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors. Patients who are known or suspected to be P450 2C9 poor metabolizers, based on a previous history, should be administered celecoxib with caution as they may have abnormally high plasma levels due to their reduced metabolic clearance [FDA label]. When celecoxib capsules were taken with a high-fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20% [FDA label].

Elimination

Clearance

Apparent clearance (CL/F), single oral 200 mg dose, healthy subjects = 27.7 L/hr [FDA label].

Toxicity

LD50 in both the rat and dog is >2000 mg/kg [FDA label]. It is not advisable to administer celecoxib in patients with renal impairment or advanced hepatic impairment [FDA label]. Symptoms of overdose celecoxib include breathing difficulties, coma, drowsiness, gastrointestinal bleeding, high blood pressure, kidney failure, nausea, sluggishness, stomach pain, and vomiting [L3293]. Because serious GI tract ulcerations and bleeding can occur without preceding symptoms, physicians should monitor for signs/symptoms of GI bleeding [FDA label]. Multiple studies have been performed on the coadministration of celecoxib and proton pump inhibitors [A34171], [A34172]. It has been concluded that in patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib in addition to a proton-pump inhibitor is the preferred treatment to reduce the risk of recurrent episodes of upper gastrointestinal bleeding [A34172]. **A note on cardiovascular safety:** The concerns about the cardiovascular thrombotic risk of COX-2 selective NSAIDS emerged in the early 2000’s. Following an FDA Advisory Committee meeting in 2005, in which data from large clinical outcome trials in a wide range of indications and epidemiology studies of several individual NSAIDs were analyzed, the FDA concluded that the risk for cardiovascular thrombotic events was apparent for both COX-2 selective NSAIDs and nonselective NSAIDs [L3293]. Importantly, postmarketing cardiovascular outcomes trial (PRECISION) found that the lowest dose of celecoxib was similar to moderate doses of naproxen and ibuprofen in regards to cardiovascular (CV) safety [L3293]. Patients with recent cardiovascular events such as acute MI, coronary revascularization, or coronary stent placement were not studied in the PRECISION trial. NSAID use is not advisable in these groups of patients [L3293].

Active Ingredient/Synonyms

Celecoxib | Célécoxib | Celecoxibum | P-(5-P-Tolyl-3-(trifluoromethyl)pyrazol-1-yl)benzenesulfonamide | Celecoxib |