Mechanism of Action
CELEBREX is a nonsteroidal 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.
Pharmacodynamics
Platelets: In clinical trials using normal volunteers,
CELEBREX at single doses up to 800 mg and multiple doses of 600 mg twice
daily for up to 7 days duration (higher than recommended therapeutic doses)
had no effect on reduction of platelet aggregation or increase in bleeding
time. Because of its lack of platelet effects, CELEBREX is not a substitute
for aspirin for cardiovascular prophylaxis. It is not known if there are
any effects of CELEBREX on platelets that may contribute to the increased
risk of serious cardiovascular 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 antidiuretic 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 increases in Cmax and AUC [see
Food Effects]. 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 3.
Table 3
Summary of Single Dose (200 mg) Disposition
Kinetics of Celecoxib in Healthy Subjects1
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%. Under fasting conditions,
at doses above 200 mg, there is less than a proportional increase in Cmax
and AUC, which is thought to be due to the low solubility of the drug in
aqueous media.
Coadministration 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 twice daily, can be administered without regard to
timing of meals. Higher doses (400 mg twice daily) 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 t1/2 after administration of
capsule contents on applesauce [see Dosage and Administration].
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 CYP2C9. 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.
CYP2C9 activity is reduced in individuals with genetic polymorphisms
that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*2
and CYP2C9*3 polymorphisms. Limited data from 4 published reports that included
a total of 8 subjects with the homozygous CYP2C9*3/*3 genotype showed celecoxib
systemic levels that were 3- to 7-fold higher in these subjects compared
to subjects with CYP2C9*1/*1 or *I/*3 genotypes. The pharmacokinetics of
celecoxib have not been evaluated in subjects with other CYP2C9 polymorphisms,
such as *2, *5, *6, *9 and *11. It is estimated that the frequency of the
homozygous *3/*3 genotype is 0.3% to 1.0% in various ethnic groups. [see
Dosage and Administration, Use in Specific Populations].
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 (t1/2) 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.
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
[see Dosage and Administration and Use in Specific Populations].
Pediatric: The steady state pharmacokinetics of celecoxib
administered as an investigational oral suspension was evaluated in 152
JRA patients 2 years to 17 years of age weighing ≥10 kg with pauciarticular
or polyarticular course JRA and in patients with systemic onset JRA. Population
pharmacokinetic analysis indicated that the oral clearance (unadjusted for
body weight) of celecoxib increases less than proportionally to increasing
weight, with 10 kg and 25 kg patients predicted to have 40% and 24% lower
clearance, respectively, compared with a 70 kg adult RA patient.
Twice-daily administration of 50 mg capsules to JRA patients weighing
≥12 to ≤25 kg and 100 mg capsules to JRA patients weighing >25 kg should
achieve plasma concentrations similar to those observed in a clinical trial
that demonstrated the non-inferiority of celecoxib to naproxen 7.5 mg/kg
twice daily (see Dosage and Administration). Celecoxib has not been
studied in JRA patients under the age of 2 years, in patients with body
weight less than 10 kg (22 lbs), or beyond 24 weeks.
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, the daily recommended dose of 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 and Administration and Use
in Specific Populations).
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 Warnings and Precautions).
Drug Interactions:
In vitro studies indicate that celecoxib is not an inhibitor of
cytochrome P450 2C9, 2C19 or 3A4.
In vivo studies have shown the following:
Lithium: In a study conducted in healthy subjects, mean steady-state
lithium plasma levels increased approximately 17% in subjects receiving
lithium 450 mg twice daily with CELEBREX 200 mg twice daily as compared
to subjects receiving lithium alone [see Drug Interactions].
Fluconazole: Concomitant administration of fluconazole at 200
mg once daily resulted in a two-fold increase in celecoxib plasma concentration.
This increase is due to the inhibition of celecoxib metabolism via P450
2C9 by fluconazole [see Drug Interactions].
Other Drugs: The effects of celecoxib on the pharmacokinetics
and/or pharmacodynamics of glyburide, ketoconazole, methotrexate [see
Drug Interactions], phenytoin, and tolbutamide have been studied in
vivo and clinically important interactions have not been found.