Celebrex (celecoxib)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Celecoxib is a nonsteroidal anti-inflammatory agent (NSAIA) that is a selective inhibitor of cyclooxygenase-2 (COX-2).
Celecoxib is a selective inhibitor of the cyclooxygenase-2 (COX-2) isoform of prostaglandin endoperoxide synthase (prostaglandin G/H synthase, PGHS) and exhibits many of the pharmacologic actions of nonselective NSAIAs, including anti-inflammatory, analgesic, and antipyretic activity. NSAIAs appear to inhibit prostaglandin synthesis via inhibition of cyclooxygenase (COX); at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as PGHS-1 and -2, respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway. Although the exact mechanisms have not been clearly established, NSAIAs appear to exert anti-inflammatory, analgesic, and antipyretic activity principally through inhibition of the COX-2 isoenzyme; COX-1 inhibition presumably is responsible for the drugs' unwanted effects on GI mucosa.
The precise mechanism of action by which celecoxib exerts therapeutic effects in the acute treatment of migraine attacks is not fully understood but may involve inhibition of prostaglandin synthesis, primarily via inhibition of COX-2. While most NSAIAs are nonselective, inhibiting both COX-1 and COX-2 to varying degrees, celecoxib's highly selective inhibition of COX-2 potentially may be associated with a decreased risk of certain adverse effects (e.g., on GI mucosa); however, additional experience is needed to evaluate fully the adverse effect profile of the drug.
When celecoxib is administered in the management of osteoarthritis and rheumatoid arthritis, the principal physiologic action of the drug is inhibition of COX-2; celecoxib does not inhibit COX-1 when given in recommended dosages.
Certain pharmacokinetic parameters of celecoxib (i.e., peak plasma concentration, AUC) are approximately dose proportional when the drug is administered in capsule form to fasting adults in dosages up to 200 mg twice daily. However, there is a less-than-proportional increase in peak plasma concentration and AUC when the drug is administered to fasting adults in dosages exceeding 200 mg twice daily; this effect has been attributed to the low aqueous solubility of celecoxib. Limited data indicate that the pharmacokinetics of celecoxib are affected by advanced age, renal and/or hepatic function, and race.
Celecoxib is well absorbed from the GI tract, and peak plasma concentrations of the drug generally are attained within 3 hours after dosing as capsules in fasting individuals. Absolute bioavailability of celecoxib has not been determined. Following administration of single doses of celecoxib, the onset of analgesia occurred within 60 minutes.
Bioavailability (AUC) was increased 10-20% and time to reach peak plasma concentrations of celecoxib was delayed by 1-2 hours when the commercially available capsules were administered with a high-fat meal. When a celecoxib capsule is opened and the contents sprinkled over applesauce prior to administration, the pharmacokinetic profile of the drug (i.e., AUC, peak plasma concentration, time to peak plasma concentration, plasma elimination half-life) is similar to that following oral administration of the intact capsule. Following oral administration of celecoxib at recommended dosages (200-400 mg daily), steady-state plasma concentrations are achieved within 5 days.
After once daily oral administration of 120 to 240 mg doses (2 times the recommended dosage) of celecoxib as the oral solution, a dose-proportional increase in exposure occurs. Following administration of celecoxib 120 mg as an oral solution in healthy, fasting individuals, the median time to peak plasma concentration was 1 hour. When the oral solution was administered with a high-fat meal, the median time to peak plasma concentration was delayed by 2 hours and peak plasma concentration was decreased by approximately 50% compared with administration under fasting conditions, with no change in total exposure (AUC).
However, in the principal clinical trials establishing efficacy of celecoxib oral solution for acute treatment of migraine, the drug was administered without regard to food.
Following oral administration of celecoxib capsules at recommended dosages in geriatric patients >=65 years of age, peak plasma concentration and AUC were increased 40 and 50%, respectively, compared with younger adults. Peak plasma celecoxib concentration and AUC values were higher in geriatric women than geriatric men, predominantly because of the lower body weight of these women. Analysis of pooled pharmacokinetic data indicates that the AUC of celecoxib, administered as capsules, is about 40% higher in Black patients compared with white patients; the cause and clinical importance of this finding are not known.
At therapeutic plasma concentrations, celecoxib is about 97% bound to plasma proteins, principally albumin and to a lesser extent, alpha1-acid glycoprotein. Celecoxib is not preferentially bound to erythrocytes in blood.
The plasma elimination half-life of celecoxib following oral administration of a single 200-mg dose in capsule form under fasting conditions is about 11 hours; wide intraindividual variability is observed, presumably because the low aqueous solubility of celecoxib prolongs absorption. The mean apparent elimination half-life of celecoxib following administration as an oral solution is approximately 6 hours independent of dosing condition and is similar to that observed for celecoxib capsules administered under fed conditions.
Celecoxib is primarily metabolized in the liver to inactive metabolites by the cytochrome P-450 (CYP) isoenzyme 2C9. In patients with the CYP2C9 poor metabolizer phenotype, the metabolic clearance of celecoxib may be decreased substantially and plasma concentrations may be increased. Metabolism may be moderately or mildly decreased in patients with the CYP2C9 intermediate metabolizer phenotype with a diplotype activity score (AS) of 1 or 1.5, respectively.
Limited data indicate that celecoxib concentrations are increased 3-fold to 7-fold in individuals with the homozygous CYP2C9*3/*3 diplotype compared with individuals with a diplotype of CYP2C9*1/*1 or CYP2C9*1/*3. Data are lacking in individuals with other CYP2C9 polymorphisms, such as *2, *5, *6, *9, and *11.
In pediatric patients, oral clearance of celecoxib appears to increase in a less-than-proportional manner with increasing weight; pediatric patients with juvenile rheumatoid arthritis weighing 10 or 25 kg are predicted to have a 40 or 24% lower clearance, respectively, than a 70-kg adult with rheumatoid arthritis.
Celecoxib is excreted in urine and feces principally as metabolites; less than 3% of the dose is excreted unchanged. Following oral administration of a single dose of radiolabeled celecoxib, approximately 27 and 57% of the dose was excreted in urine and feces, respectively. The principal metabolite in both urine and feces was the carboxylic acid metabolite (73% of the dose); small amounts of the glucuronide metabolite were present in urine.
USES: See also Warning section. This medication is used to treat arthritis, acute pain, and menstrual pain and discomfort. Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID), specifically a COX-2 inhibitor.
It works by blocking your body's production of certain natural substances that cause inflammation. This effect helps to decrease swelling, pain, or fever. If you are treating a chronic condition such as arthritis, ask your doctor about non-drug treatments and/or using other medications to treat your pain.
Generic name: celecoxib
Pronunciation: (SEL-e-KOX-ib)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Celebrex
Indications
The following indications are listed for Celebrex:
- Ankylosing Spondylitis
- Dysmenorrhea
- Juvenile Idiopathic Arthritis
- Osteoarthritis
- Postoperative Acute Pain
- Rheumatoid Arthritis
Also known as: Arthritis Deformans, Arthrosis Deformans, Axial Spondyloarthritis With Radiographic Sacroiliitis, Bekhterev's Arthritis, Bekhterev's Disease, Bekhterev's Spondylitis, Degenerative Arthritis, Degenerative Joint Disease, Degenerative Polyarthritis, Difficult Menses, Difficult Menstruation, Hypertrophic Arthritis, Juvenile Ra, Juvenile Rheumatoid Arthritis, Marie-Strumpell Disease, Marie-Strumpell Spondylitis, Nodose Rheumatism, Osteoarthrosis, Painful Menses, Painful Menstrual Cramps, Post-Op Acute Pain, Rheumatic Arthritis, Rheumatic Gout, Rheumatoid Spondylitis, Rhizomelic Spondylitis, Rhizomelic Spondylosis, Spondylosis Deformans, Strumpell-Marie Disease.
Dosing
No dosing information is available for this tab.
Celecoxib is administered orally. The drug is commercially available as capsules and an oral solution; the oral solution is FDA-labeled for the treatment of migraine only.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Celecoxib is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 2C9. In vitro studies indicate that celecoxib is an inhibitor of CYP2D6, but not an inhibitor of CYP2C9, 2C19, or 3A4.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to the drug, sulfonamides, or any ingredient in the formulation.
*History of asthma, urticaria, or other sensitivity reactions after taking aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs).
*Contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in >2% of adult patients receiving celecoxib for osteoarthritis and rheumatoid arthritis in clinical trials include abdominal pain, diarrhea, dyspepsia, flatulence, peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, and rash. Adverse events reported in adult patients receiving celecoxib for ankylosing spondylitis, analgesia, and dysmenorrhea in clinical trials were similar to those reported in the osteoarthritis and rheumatoid arthritis trials.
In the clinical trial of celecoxib in pediatric patients with juvenile rheumatoid arthritis, the most commonly occurring (>=5%) adverse events in celecoxib-treated patients were headache, pyrexia, upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea, and vomiting.
The most common adverse effect reported in >=3% of adult patients receiving celecoxib for migraine is dysgeusia.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Celecoxib is used for the management of the signs and symptoms of juvenile rheumatoid arthritis in pediatric patients >=2 years of age; safety and efficacy of celecoxib therapy have not been established beyond 6 months in pediatric patients with juvenile rheumatoid arthritis. Celecoxib has been evaluated in pediatric patients 2-17 years of age with pauciarticular course, polyarticular course, or systemic onset juvenile rheumatoid arthritis in one clinical study. Celecoxib has not been studied in pediatric patients younger than 2 years of age, those weighing <10 kg, or those with active systemic disease. Alternative therapies should be considered in pediatric patients known to be CYP2C9 poor metabolizers.
In the pediatric clinical study for juvenile rheumatoid arthritis, patients with systemic onset juvenile rheumatoid arthritis appeared to be at risk for the development of abnormal coagulation test results. Use of NSAIAs, including celecoxib, has been associated with mild prolongation of activated partial thromboplastin time (aPTT) but not prothrombin time in pediatric patients with systemic onset juvenile rheumatoid arthritis. Because of the risk of disseminated intravascular coagulation in pediatric patients with systemic onset juvenile rheumatoid arthritis who are receiving celecoxib, these patients should be monitored for clinical signs or symptoms of abnormal clotting or bleeding and with coagulation tests.
Long-term cardiovascular toxicity has not been evaluated in pediatric patients, and it is not known whether long-term risks may be similar to those observed in adults exposed to celecoxib and other NSAIAs.
Safety and efficacy of celecoxib for the acute treatment of migraine attacks have not been established in pediatric patients.
Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used. Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.
Fetal renal dysfunction has been observed, on average, after days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy. Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy. Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation. A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios. Some cases of neonatal renal dysfunction have required treatment with invasive procedures, such as exchange transfusion or dialysis.
Observational data regarding other embryofetal risks with NSAIAs during the first or second trimester of pregnancy are not conclusive. An increased incidence of fetuses with ventricular septal defects, sternebral fusion or abnormality, and rib fusion was observed in reproduction studies in rabbits receiving oral celecoxib dosages >=150 mg/kg daily throughout organogenesis (exposure approximately twice the usual human dosage of 200 mg twice daily, expressed in terms of AUC (0-24 hours)). A dose-dependent increase in diaphragmatic hernias was observed in rats receiving oral celecoxib dosages >=30 mg/kg daily throughout organogenesis (exposure approximately 6-fold the usual human dosage of 200 mg twice daily, expressed in terms of AUC (0-24 hours)). Reproduction studies in rats using oral dosages up to 100 mg/kg daily (exposure approximately 7-fold the usual human dosage of 200 mg twice daily, expressed in terms of AUC (0-24 hours)) did not reveal evidence of delayed labor or parturition. In rats receiving oral celecoxib dosages >=50 mg/kg daily (exposure approximately 6-fold the usual human dosage of 200 mg twice daily, expressed in terms of AUC (0-24 hours)), pre- and post-implantation losses and reduced embryonic/fetal survival were observed.
Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, inhibitors of prostaglandin synthesis, such as celecoxib, were associated with increased pre- and post-implantation losses. Prostaglandins also have an important role in fetal kidney development. In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.
The effects of celecoxib on labor and delivery are unknown. In animal studies, drugs that inhibit prostaglandin synthesis, including NSAIAs, delayed parturition and increased stillbirth.
Celecoxib is distributed into milk in small amounts. Limited data obtained from nursing women receiving celecoxib indicate that the calculated average infant exposure to the drug is 10-40 mcg/kg daily, which is less than 1% of the weight-based therapeutic dosage for a 2-year-old child. Maternal use of celecoxib was not associated with adverse effects in 2 breast-fed infants 17 and 22 months of age. It is not known whether celecoxib affects milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for celecoxib and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.
Dosage adjustment in geriatric patients based solely on age generally is not required. However, for geriatric patients weighing <50 kg, celecoxib therapy should be initiated at the lowest recommended dosage.
Geriatric patients are at increased risk for NSAIA-associated serious adverse cardiovascular, GI, and renal effects. In clinical trials evaluating celecoxib for acute treatment of migraine attacks, approximately 70 patients were >=65 years of age, while in clinical trials evaluating celecoxib for other indications, more than 3300 patients were 65-74 years of age and about 1300 were >=75 years of age. No overall differences in efficacy of celecoxib were observed between geriatric and younger patients. Although results from clinical studies indicated that renal function (measured by glomerular filtration rate, blood urea nitrogen, and creatinine) and platelet function (measured by bleeding time and platelet aggregation) in geriatric individuals receiving celecoxib did not differ from those in younger individuals, spontaneous postmarketing reports of fatal adverse GI effects and acute renal failure have occurred more often in geriatric individuals than in younger individuals. If it is determined that the anticipated benefits of celecoxib therapy outweigh the potential risks, celecoxib should be initiated at the lower end of the dosing range and patients should be monitored for adverse effects; if used for the acute treatment of migraine attacks, celecoxib should be used for the fewest possible number of days per month.
Peak plasma concentration and AUC of celecoxib (as the oral capsules) were increased 40 and 50%, respectively, in geriatric individuals (i.e., >=65 years of age), but dosage adjustment in this age group based solely on age generally is not required. Peak plasma celecoxib concentration and AUC values were higher in geriatric women than geriatric men, predominantly because of the lower body weight of these women. In geriatric patients weighing <50 kg, celecoxib therapy should be initiated at the lowest recommended dosage.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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