Celecoxib

Table: Clinically Significant Drug Interactions with Celecoxib [Table#6655]

Metabolism of celecoxib is mediated by the cytochrome P-450 (CYP) isoenzyme 2C9, and the possibility exists that drugs that inhibit this enzyme (e.g., fluconazole, fluvastatin, zafirlukast) may affect the pharmacokinetics of celecoxib. Therefore, celecoxib and drugs that inhibit the CYP2C9 isoenzyme should be administered concomitantly with caution. In addition, celecoxib inhibits CYP2D6, and the possibility exists that celecoxib may alter the pharmacokinetics of drugs metabolized by this isoenzyme, including various beta-adrenergic blocking agents, many tricyclic and other antidepressants, various antipsychotic agents, and some antiarrhythmics (e.g., encainide, flecainide). Results of in vitro studies indicate that celecoxib is not a substrate for CYP2D6, and the drug does not inhibit the CYP2C9, CYP2C19, or CYP3A4 isoenzymes.

Administration of an antacid containing magnesium or aluminum with celecoxib decreased peak plasma concentrations of celecoxib by 37% and the area under the plasma concentration-time curve (AUC) by 10% in clinical studies. However, the manufacturer makes no specific recommendation for administration of the drug with regard to antacids because these effects are not considered clinically important.

Results of clinical studies indicate that clinically important drug interactions may occur if celecoxib is administered with fluconazole. Concomitant administration of celecoxib with fluconazole can result in substantially increased plasma concentrations of celecoxib. This pharmacokinetic interaction appears to occur because fluconazole inhibits the CYP2C9 isoenzyme involved in celecoxib metabolism. In one study, concomitant administration of fluconazole (200 mg daily) and celecoxib (a single 200-mg dose) increased plasma concentrations of celecoxib twofold. The manufacturer of celecoxib states that celecoxib therapy should be initiated at the lowest recommended dosage in patients receiving fluconazole concomitantly.

For more Interactions (Complete) data for Celecoxib (12 total), please visit the HSDB record page.

In clinical studies involving several thousand patients treated for at least 3 months, the rate of serum aminotransferase enzyme elevations above three times the upper limit of the normal range was 1.1% in celecoxib treated compared to 0.9% in placebo treated patients. The ALT elevations that occurred during celecoxib therapy were usually transient and benign, resolving even with continuation of the medication. It is unclear whether such elevations are due to the medication since similar rates of abnormalities are identified in patients with arthritis receiving placebo.

EC50; Species: Ceriodaphnia dubia (Water Flea) age <24 hr; Conditions: freshwater, renewal, pH 7.6-8.8, dissolved oxygen 6.8-9.5 mg/L; Concentration: >1600 ug/L for 7 days; Effect: intoxication, immobilization />98% purity/

EC50; Species: Daphnia magna (Water Flea) age <24 hr; Conditions: freshwater, renewal, pH 7.6-8.8, dissolved oxygen 6.8-9.5 mg/L; Concentration: >890 ug/L for 7 days; Effect: intoxication, immobilization />98% purity/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 9.7X10+4(SRC), determined from a structure estimation method(2), indicates that celecoxib is expected to be immobile in soil(SRC). Volatilization of celecoxib from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.8X10-13 atm-cu m/mole(SRC), estimated using a fragment constant estimation method(3). Celecoxib is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-9 mm Hg(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 9.7X10+4(SRC), determined from a structure estimation method(2), indicates that celecoxib is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.8X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 90(SRC), from an estimated log Kow of 3.47(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2018).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), celecoxib, which has an estimated vapor pressure of 1.2X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase celecoxib may be removed from the air by wet and dry deposition(SRC). Celecoxib contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Well 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%.

IDENTIFICATION AND USE: Celecoxib is a pale yellow solid. It is a cyclooxygenase-2 (COX-2) inhibitor used in the management of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, pain, ankylosing spondylitis, and dysmenorrhea. HUMAN STUDIES: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. Allergic reactions, aggravated allergy, bronchospasm, or generalized or facial edema has been reported in 0.1-1.9% of patients receiving celecoxib. Anaphylactoid reactions and angioedema have occurred in patients receiving celecoxib. As with other NSAIDs, anaphylactic reactions have been reported rarely in patients with no previous exposure to the drug. Erythema multiforme, exfoliative dermatitis, Sweet's syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely in patients receiving celecoxib. Hepatitis, jaundice, or liver failure has been reported in patients receiving celecoxib during postmarketing surveillance. Celecoxib may cause premature closure of the ductus arteriosus. ANIMAL STUDIES: Celecoxib was not carcinogenic in rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females, or in mice given oral doses up to 25 mg/kg for males and 50 mg/kg for females for two years. An increased incidence of fetuses with ventricular septal defects, sternebral fusion, rib fusion, and sternebrae abnormality was observed in reproduction studies in rabbits receiving oral celecoxib dosages of 150 mg/kg daily or more throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed in rats receiving oral celecoxib dosages of 30 mg/kg or more daily throughout organogenesis. Celecoxib had no effect on male or female fertility or male reproductive function in rats at oral doses up to 600 mg/kg/day. Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow.

Unfortunately, no antidote is available for celecoxib overdose. However, celecoxib is a relatively safe medication. There were no reported overdoses of celecoxib during FDA trials, and doses up to 2400 mg per day for 10 days did not result in severe toxicity.

The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis. 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. It binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site. Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of March 27, 2018: http://actor.epa.gov/dashboard/]

Using a structure estimation method based on molecular connectivity indices(1), the Koc for celecoxib can be estimated to be 9.7X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that celecoxib is expected to be immobile in soil.

/SIGNS AND SYMPTOMS/ Celecoxib may cause premature closure of the ductus arteriosus. Avoid use of nonsteroidal anti-inflammatory drugs (NSAIDs), including Celebrex, in pregnant women starting at 30 weeks of gestation (third trimester).

/SIGNS AND SYMPTOMS/ A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, celebrex is contraindicated in patients with this form of aspirin sensitivity. When celebrex is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

/SIGNS AND SYMPTOMS/ Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

/SIGNS AND SYMPTOMS/ Allergic reactions, aggravated allergy, bronchospasm, or generalized or facial edema has been reported in 0.1-1.9% of patients receiving celecoxib. Anaphylactoid reactions and angioedema have occurred in patients receiving celecoxib. As with other nonsteroidal anti-inflammatory drugs (NSAIDs), anaphylactic reactions have been reported rarely in patients with no previous exposure to the drug. Erythema multiforme, exfoliative dermatitis, Sweet's syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely in patients receiving celecoxib.

For more Human Toxicity Excerpts (Complete) data for Celecoxib (36 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including celecoxib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Cyclooxygenase 2 Inhibitors

MEDICATION

Use (kg; approx.) in Germany (2009): >5000

For 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

Condensation of 4-methylacetophenone with ethyl trifluoroacetate in refluxing methanol using sodium methoxide as catalyst gives 4,4,4-trifluoro-1-(4-methylphenyl)butane1,3-dione, which is cyclized with 4-hydrazinophenylsulfonamide in refluxing ethanol.

Methyl trifluoroacetate and 4-methylbenzophenone are refluxed with sodium methoxide in methanol to yield 1-(p-tolyl)-4,4,4-trifluoro-1,3-butanedione. The latter compound is heated with p-hydrazinobenzenesulfonamide, closing the pyrazole ring forming the product.

Preparation: J. J. Talley et al., World Intellectual Property Organization patent 9515316; eidem, United States of America patent 5466823 (both 1995 to Searle) ... .

Information available in 2005 indicated that Celecoxib was used in the manufacture of pharmaceutical preparations in the following countries: Algeria, Argentina, Australia, Austria, Bahrain, Belgium, Brazil, Canada, Chile, Colombia, Costa Rica, Croatia, Cyprus, Czech Republic, Denmark, Egypt, El Salvador, Finland, France, Germany, Guatemala, Honduras, Hong Kong, Hungary, India, Indonesia, Ireland, Israel, Italy, Jordan, Kuwait, Lebanon, Malaysia, Mexico, Netherlands, New Zealand, Nicaragua, Norway, Oman, Panama, Poland, Portugal, Romania, Russian Federation, Saudi Arabia, Singapore, Slovenia, South Africa, Spain, Sweden, Switzerland, Thailand, Turkey, United Arab Emirates, United Kingdom, United States, Yugoslavia (1,2)