Celebrex

Celebrex Mechanism of Action

celecoxib

Manufacturer:

Pfizer
Full Prescribing Info
Action
Pharmacology: Mechanism of Action: CELEBREX is a non-steroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of CELEBREX is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, CELEBREX does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. In animal colon tumor models, celecoxib reduced the incidence and multiplicity of tumors.
Platelets: In clinical trials, CELEBREX at single doses up to 800 mg and multiple doses of 600 mg BID for up to 7 days duration (higher than recommended therapeutic doses) had no effect on platelet aggregation and bleeding time. Because of its lack of platelet effects, CELEBREX is not a substitute for acetyl salicylic acid for CV prophylaxis. It is not known if there are any effects of CELEBREX on platelets that may contribute to the increased risk of serious CV thrombotic adverse events associated with the use of CELEBREX.
Fluid Retention: Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of anti-diuretic hormone.
Pharmacokinetics: Absorption: Peak plasma levels of celecoxib occur approximately 3 hrs after an oral dose. Under fasting conditions, both peak plasma levels (Cmax) and area under the curve (AUC) are roughly dose proportional up to 200 mg BID; at higher doses, there are less than proportional increase in Cmax and AUC (see Food Effects), which is thought to be due to the low solubility of the drug in aqueous media. Absolute bioavailability studies have not been conducted. With multiple dosing, steady-state conditions are reached on or before Day 5.
The pharmacokinetic parameters of celecoxib in a group of healthy subjects are shown in Table 1. (See Table 1.)


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Distribution: In healthy subjects, celecoxib is highly protein bound (~97%) within the clinical dose range. In vitro studies indicate that celecoxib binds primarily to albumin and, to a lesser extent, α1-acid glycoprotein. The apparent volume of distribution at steady-state (Vss/F) is approximately 400 L, suggesting extensive distribution into the tissues. Celecoxib is not preferentially bound to red blood cells.
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 reduced enzyme activity, such as those homozygous for the CYP2C9*3 polymorphism.
In a pharmacokinetic study of celecoxib 200 mg administered once daily in healthy volunteers, genotyped as either CYP2C9*1/*1, CYP2C9*1/*3, or CYP2C9*3/*3, the median Cmax and AUC0-24 of celecoxib on day 7 were approximately 4-fold and 7-fold, respectively, in subjects genotyped as CYP2C9*3/*3 compared to other genotypes. In three separate single dose studies, involving a total of 5 subjects genotyped as CYP2C9*3/*3, single-dose AUC0-24 increased by approximately 3-fold compared to normal metabolizers. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3% - 1.0% among different ethnic groups.
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: Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t½) determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 mL/min.
Food Effects: When CELEBREX 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%. Co-administration of CELEBREX with an aluminum and magnesium-containing antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC. CELEBREX at doses up to 200 mg BID can be administered without regard to the timing of meals. Higher doses (400 mg BID) should be administered with food to improve absorption.
In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in Cmax, Tmax or T½ after administration of capsule contents on applesauce.
Special Populations: Geriatric: At steady-state, elderly subjects (over 65 years old) had a 40% higher Cmax and a 50% higher AUC compared to the young subjects. In elderly females, celecoxib Cmax and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Dose adjustment in the elderly is not generally necessary. However, for patients of less than 50 kg in body weight, initiate therapy at the lowest recommended dose.
Pediatric: CELEBREX capsules have not been investigated in pediatric patients below 18 years of age.
Race: Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in Blacks compared to Caucasians. The cause and clinical significance of this finding is unknown.
Hepatic Insufficiency: A pharmacokinetic study in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment has shown that steady-state celecoxib AUC is increased about 40% and 180%, respectively, above that seen in healthy control subjects. Therefore, CELEBREX capsules should be reduced by approximately 50% in patients with moderate (Child-Pugh Class B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of CELEBREX in patients with severe hepatic impairment is not recommended (see DOSAGE & ADMINISTRATION).
Renal Insufficiency: In a cross-study comparison, celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 35-60 mL/min) than that seen in subjects with normal renal function. No significant relationship was found between GFR and celecoxib clearance. Patients with severe renal insufficiency have not been studied. Similar to other NSAIDs, CELEBREX is not recommended in patients with severe renal insufficiency (see Advanced Renal Disease under WARNINGS).
Drug Interactions: Also see Interactions.
General: Significant interactions may occur when celecoxib is administered together with drugs that inhibit P450 2C9. In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4.
Clinical studies with celecoxib have identified potentially significant interactions with fluconazole and lithium. Experience with non-steroidal anti-inflammatory drugs (NSAIDs) suggests the potential for interactions with furosemide and ACE inhibitors.
Toxicology: Preclinical Safety Data: Non-clinical safety data revealed no special hazard for humans based on conventional studies of repeated dose toxicity, mutagenicity or carcinogenicity.
Celecoxib at oral doses ≥150 mg/kg/day (approximately 2-fold human exposure at 200 mg twice daily as measured by AUC0-24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6-fold human exposure based on the AUC0-24 at 200 mg twice daily) throughout organogenesis. These effects are expected following inhibition of prostaglandin synthesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses, and reduced embryo/fetal survival.
Clinical Studies: Osteoarthritis (OA): CELEBREX has demonstrated significant reduction in joint pain compared to placebo. CELEBREX was evaluated for treatment of the signs and the symptoms of OA of the knee and hip in approximately 4200 patients in placebo- and active-controlled clinical trials of up to 12 weeks duration. In patients with OA, treatment with CELEBREX 100 mg BID or 200 mg QD resulted in improvement in WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness, and functional measures in OA. In three 12-week studies of pain accompanying OA flare, CELEBREX doses of 100 mg BID and 200 mg BID provided significant reduction of pain within 24-48 hours of initiation of dosing. At doses of 100 mg BID or 200 mg BID the efficacy of CELEBREX was shown to be similar to that of naproxen 500 mg BID. Doses of 200 mg BID provided no additional benefit above that seen with 100 mg BID. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100 mg BID or 200 mg QD.
Rheumatoid Arthritis (RA): CELEBREX has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. CELEBREX was evaluated for treatment of the signs and symptoms of RA in approximately 2,100 patients in placebo- and active-controlled clinical trials of up to 24 weeks in duration. CELEBREX was shown to be superior to placebo in these studies, using the American College of Rheumatology 20 (ACR20) Responder Index, a composite of clinical, laboratory, and functional measures in RA. CELEBREX doses of 100 mg BID and 200 mg BID were similar in efficacy and both were comparable to naproxen 500 mg BID.
Although CELEBREX 100 mg BID and 200 mg BID provided similar overall efficacy, some patients derived additional benefit from the 200 mg BID dose. Doses of 400 mg BID provided no additional benefit above that seen with 100-200 mg BID.
Ankylosing Spondylitis (AS): Celecoxib was evaluated in AS patients in two placebo- and active-controlled clinical trials of 6 and 12 weeks duration. Celecoxib at doses of 100 mg twice daily, 200 mg once daily and 400 mg once daily was shown to be statistically superior to placebo in these studies for all three co-primary efficacy measures assessing global pain intensity (Visual Analogue Scale), global disease activity (Visual Analogue Scale) and functional impairment (Bath Ankylosing Spondylitis Functional Index). In the 12-week study, there was no difference in the extent of improvement between the 200 mg and 400 mg celecoxib doses in a comparison of mean change from baseline, but there was a greater percentage of patients who responded to celecoxib 400 mg, 53%, than to celecoxib 200 mg, 44%, using the Assessment in Ankylosing Spondylitis response criteria (ASAS 20). The ASAS 20 defines response as improvement from baseline of at least 20% and an absolute improvement of at least 10 mm, on a 0 to 100 mm scale, in at least three of the four following domains: patient global, pain, Bath Ankylosing Spondylitis Functional Index, and inflammation. The responder analysis also demonstrated no change in the responder rates beyond 6 weeks.
Special Studies: Celecoxib Long-term Arthritis Safety Study (CLASS): The Celecoxib Long-Term Arthritis Safety Study (CLASS) was prospective long-term safety outcome study conducted post-marketing in approximately 5,800 OA patients and 2,200 RA patients. Patients received CELEBREX 400 mg BID (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg TID or diclofenac 75 mg BID (common therapeutic doses). Median exposures for CELEBREX (n = 3,987) and diclofenac (n = 1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. The primary endpoint of this outcome study was the incidence of complicated ulcers (gastrointestinal bleeding, perforation or obstruction). Patients were allowed to take concomitant low-dose (≤325 mg/day) acetyl salicylic acid (ASA) for CV prophylaxis (ASA subgroups: CELEBREX, n = 882; diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of complicated ulcers between CELEBREX and the combined group of ibuprofen and diclofenac were not statistically significant.
Those patients on CELEBREX and concomitant low-dose ASA (N = 882) experienced 4-fold higher rates of complicated ulcers compared to those not on ASA (N = 3105). The Kaplan Meier rate for complicated ulcers at 9 months was 1.12% versus 0.32% for those on low dose ASA and those not on ASA, respectively (see Gastrointestinal (GI) Effects under WARNINGS).
The estimated cumulative rates at 9 months of complicated and symptomatic ulcers for patients treated with CELEBREX 400 mg BID are described in Table 2. Table 2 also displays results for patients less than or greater than 65 years of age. The difference in rates between CELEBREX alone and CELEBREX with ASA groups may be due to the higher risk for GI events in ASA users. (See Table 2.)


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In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer rates in patients taking CELEBREX alone or CELEBREX with ASA were, respectively, 2.56% (n = 243) and 6.85% (n = 91) at 48 weeks. These results are to be expected in patients with a prior history of ulcer disease (see Gastrointestinal (GI) Effects: Risk of GI Ulceration, Bleeding, and Perforation under WARNINGS and Safety Data from CLASS Study: Hematological Events under ADVERSE REACTIONS).
Celecoxib versus Omeprazole and Diclofenac for At-risk Osteoarthritis and Rheumatoid Arthritis Patients (CONDOR) Trial: In this prospective, 24-week study in patients with age ≥60 years or history of gastroduodenal ulcers (users of low-dose aspirin excluded), the percentage of patients with clinically significant GI events (composite primary endpoint) was lower in patients treated with celecoxib 200 mg twice daily compared to patients treated with diclofenac SR 75 mg twice daily plus omeprazole 20 mg once daily. This difference was driven by clinically significant decreases in hemoglobin (≥2 g/dL) and/or hematocrit (≥10%) of defined or presumed GI origin. Results for the individual components of this composite endpoint were as follows: See Table 3.


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CV Safety: CV safety outcomes were also evaluated in the CLASS trial. Kaplan-Meier cumulative rates for investigator-reported serious CV thromboembolic adverse events (including MI, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic attacks, and ischemic cerebrovascular accidents) demonstrated no differences between the CELEBREX, diclofenac, or ibuprofen treatment groups. The cumulative rates in all patients at nine months for CELEBREX, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The cumulative rates in non-ASA users at nine months in each of the three treatment groups were less than 1%. The cumulative rates for myocardial infarction in non-ASA users at nine months in each of the three treatment groups were less than 0.2%. There was no placebo group in the CLASS trial, which limits the ability to determine whether the three drugs tested had no increased risk of CV events or if they all increased the risk to a similar degree.
CV Safety - Long-term Studies Involving Patients With Sporadic Adenomatous Polyps: Two studies involving patients with sporadic adenomatous polyps were conducted with celecoxib i.e., the APC trial (Prevention of Sporadic Colorectal Adenomas with Celecoxib) and the PreSAP trial (Prevention of Colorectal Sporadic Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint of CV death, myocardial infarction, or stroke (adjudicated) with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint.
In the APC trial, the hazard ratios compared to placebo for a composite endpoint of CV death, myocardial infarction, or stroke (adjudicated) were 3.4 (95% CI 1.4 - 8.5) with celecoxib 400 mg twice daily and 2.8 (95% CI 1.1 - 7.2) with celecoxib 200 mg twice daily (cumulative rates for this composite endpoint over 3 years were 20/671 subjects, 3.0%, and 17/685 subjects, 2.5%, respectively, compared to 6/679 subjects, 0.9%, for placebo).The increases for both celecoxib dose groups versus placebo were mainly driven by myocardial infarction.
In the PreSAP trial, the hazard ratios compared to placebo for this same composite endpoint was 1.2 (95% CI 0.6 - 2.4) with celecoxib 400 mg once daily (cumulative rates for this composite endpoint over 3 years were 21/933 subjects, 2.3%, compared to 12/628 subjects, 1.9%, for placebo).
CV Safety - Long-term Study of Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT): Data from the ADAPT study did not show a significantly increased CV risk with celecoxib 200 mg twice daily compared to placebo. The relative risk compared to placebo for a similar composite endpoint (CV death, MI, stroke) was 1.14 (95% CI 0.61 - 2.12) with celecoxib 200 mg twice daily.
CV Safety - Meta-analysis from Chronic Usage Studies: No long-term controlled clinical study specifically designed to assess the CV safety of chronic celecoxib dosing of any duration has been conducted. However, a meta-analysis of safety data (adjudicated, investigator-reported serious adverse events) from 39 completed celecoxib clinical studies of up to 65 weeks duration has been conducted, representing 41,077 patients: [23,030 (56.1%) patients exposed to celecoxib 200 mg - 800 mg total daily dose (TDD); 13,990 (34.1%) patients exposed to non-selective NSAIDs; and 4,057 (9.9%) patients exposed to placebo].
In this analysis, the adjudicated event rate for the composite endpoint of CV death, non-fatal myocardial infarction and non-fatal stroke was similar between celecoxib (N = 19,773; 0.96 events/100 patient-years) and non-selective NSAIDs (N = 13,990; 1.12 events/100 patient-years) treatment (RR = 0.90, 95% CI 0.60 - 1.33). This pattern of effect was maintained with or without ASA use (≤325 mg). The adjudicated event rate of non-fatal myocardial infarction trended higher (RR = 1.76, 95% CI 0.93 - 3.35); however, that of non-fatal stroke trended lower (RR = 0.51, 95% CI 0.23 - 1.10), and that of CV death was comparable (RR = 0.57, 95% CI 0.28 - 1.14) for celecoxib compared to combined non-selective NSAIDs.
In this analysis, the adjudicated event rate for the composite endpoint of CV death, non-fatal myocardial infarction and non-fatal stroke was 1.42/100 patient-years for celecoxib (N = 7,462) and 1.20/100 patient-years for placebo (N = 4,057) treatment (RR = 1.11, 95% CI 0.47 - 2.67). This pattern of effect was maintained with or without ASA use (≤325 mg). The incidence of non-fatal myocardial infarction trended higher (RR = 1.56, 95% CI 0.21 - 11.90), as did that of CV death (RR = 1.26, 95% CI 0.33 - 4.77), and that of non-fatal stroke was similar (RR = 0.80, 95% CI 0.19 - 3.31) for celecoxib compared to placebo.
Endoscopic Studies: The correlation between findings of short-term endoscopic studies with CELEBREX and the relative incidence of clinically significant serious upper GI events with long-term use has not been established.
Figure 1 and Table 4 summarize the incidence of endoscopic ulcers in two 12-week studies that enrolled patients in whom baseline endoscopies revealed no ulcer. (See Figure 1 and Table 4.)


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Figure 2 and Table 5 summarize data from two 12-week studies that enrolled patients in whom baseline endoscopies revealed no ulcers. Patients underwent interval endoscopies every 4 weeks to give information on ulcer risk over time. (See Figure 2 and Table 5.)


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One randomized and double-blinded 6-month study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months. The results are shown in Figure 3. (See Figure 3.)


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Gastrointestinal Safety Meta-analysis from Osteoarthritis and Rheumatoid Arthritis Studies: An analysis of 31 randomized controlled clinical studies in OA and RA, involving 39,605 patients with OA (N = 25,903), RA (N = 3,232), or patients with either condition (N = 10,470) compared the incidence of GI adverse events in celecoxib-treated patients to the incidence in patients administered placebo or NSAIDs (including naproxen, diclofenac and ibuprofen). The incidence of clinical ulcers and ulcer bleeds with celecoxib 200 mg - 400 mg total daily dose was 0.2% compared to an incidence of 0.6% with NSAIDs (RR = 0.35; 95% CI 0.22-0.56).
Use with acetyl salicylic acid: Approximately 11% of patients (440/4,000) enrolled in 4 of the 5 endoscopic studies were taking acetyl salicylic acid (≤325 mg/day). In the CELEBREX groups, the endoscopic ulcer rate appeared to be higher in acetyl salicylic acid users than in non-users. However, the increased rate of ulcers in these acetyl salicylic acid users was less than the endoscopic ulcer rates observed in the active comparator groups, with or without acetyl salicylic acid.
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