Celecoxib
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DESCRIPTION
Celecoxib (CELEBREX) is chemically designated as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole.
It has the following chemical structure:
The empirical formula for celecoxib is C17H14F3N3O2S, and the molecular weight is 381.38. CELEBREX oral capsules contain either
100 mg, 200 mg or 400 mg of celecoxib.
The inactive ingredients in CELEBREX capsules include: croscarmellose sodium, edible inks, gelatin,lactose monohydrate, magnesium
stearate, povidone, sodium lauryl sulfate and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action:
CELEBREX is a nonsteroidal anti-inflammatory drug that exhibits antiinflammatory,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.
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.
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 BID can be administered without regard to timing of
meals. Higher doses (400 mg BID) should be administered with food to improve absorption.
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, 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 reduced metabolic clearance.
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.
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, 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.
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 – Advanced Renal Disease).
Drug Interactions
Also see PRECAUTIONS – Drug 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 nonsteroidal anti-inflammatory
drugs (NSAIDs) suggests the potential for interactions with furosemide and ACE inhibitors. The effects of celecoxib on the
pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, methotrexate, phenytoin, and tolbutamide have been studied
in vivo and clinically important interactions have not been found.
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 4,200 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 effectiveness 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 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 effectiveness and both were comparable to naproxen 500 mg BID. Although
CELEBREX 100 mg BID and 200 mg BID provided similar overall effectiveness, 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.
Analgesia, including primary dysmenorrhea: In acute analgesic models of post-oral surgery pain, post-orthopedic
surgical pain, and primary dysmenorrhea, CELEBREX relieved pain that was rated by patients as moderate to severe. Single doses
(see DOSAGE AND ADMINISTRATION) of CELEBREX provided pain relief within 60 minutes.
Familial Adenomatous Polyposis (FAP): CELEBREX was evaluated to reduce the number of adenomatous colorectal polyps. A
randomized double-blind placebo-controlled study was conducted in 83 patients with FAP. The study population included 58 patients
with a prior subtotal or total colectomy and 25 patients with an intact colon. Thirteen patients had the attenuated FAP
phenotype. One area in the rectum and up to four areas in the colon were identified at baseline for specific followup, and polyps
were counted at baseline and following six months of treatment. The mean reduction in the number of colorectal polyps was 28% for
CELEBREX 400 mg BID, 12% for CELEBREX 100 mg BID and 5% for placebo. The reduction in polyps observed with CELEBREX 400 mg BID
was statistically superior to placebo at the six-month timepoint (p=0.003).
Special Studies
Endoscopic Studies: Scheduled upper GI endoscopic evaluations were performed in over 4,500 arthritis patients who were enrolled
in five controlled randomized 12-24 week trials using active comparators, two of which also included placebo controls. There was
no consistent relationship between the incidence of gastroduodenal ulcers and the dose of CELEBREX over the range studied.
One randomized and double-blind 6-month study in 430 RA patients was conducted in which an endoscopic examination was performed
at 6 months. The incidence of endoscopic ulcers in patients taking CELEBREX 200 mg BID was 4% vs 15% for patients taking
diclofenac SR 75 mg BID (p<0.001). In 4 of the 5 endoscopic studies, approximately 11% of patients (440/4,000) were taking
aspirin (≤ 325 mg/day). In the CELEBREX groups, the endoscopic ulcer rate appeared to be higher in aspirin users than in
non-users. However, the increased rate of ulcers in these aspirin users was less than the endoscopic ulcer rates observed in the
active comparator groups, with or without aspirin. The correlation between findings of endoscopic studies, and the relative
incidence of clinically significant serious upper GI events has not been established. Serious clinically significant upper GI
bleeding has been observed in patients receiving CELEBREX in controlled and open-labeled trials, albeit infrequently (see Use
with Aspirin and WARNINGS – Gastrointestinal (GI) Effects).
Use with Aspirin: The Celecoxib Long-Term Arthritis Safety Study (CLASS) was a prospective longterm safety outcome study
conducted postmarketing 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, and the approved dose for FAP), 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 Kaplan-Meier cumulative rates at 9 months are provided for all analyses. 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) aspirin (ASA) for cardiovascular 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 experienced 4-fold higher rates of complicated ulcers compared to those not on ASA (see WARNINGS – Gastrointestinal
(GI) Effects). The results for CELEBREX are displayed in Table 4. For complicated and symptomatic ulcer rates, see WARNINGS –
Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation.
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. Comparators
(naproxen 500 mg BID, ibuprofen 800 mg TID, diclofenac 75 mg BID) significantly reduced platelet aggregation and prolonged
bleeding time. Because of its lack of platelet effects, CELEBREX is not a substitute for aspirin for cardiovascular
prophylaxis.
INDICATIONS AND USAGE
CELEBREX is indicated: 1) For relief of the signs and symptoms of osteoarthritis.
2) For relief of the signs and symptoms of rheumatoid arthritis in adults.
3) For the management of acute pain in adults (see CLINICAL STUDIES).
4) For the treatment of primary dysmenorrhea.
5) To reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis (FAP), as an adjunct to usual care
(e.g., endoscopic surveillance, surgery). It is not known whether there is a clinical benefit from a reduction in the number of
colorectal polyps in FAP patients. It is also not known whether the effects of CELEBREX treatment will persist after CELEBREX is
discontinued. The efficacy and safety of CELEBREX treatment in patients with FAP beyond six months have not been studied (see
CLINICAL STUDIES, WARNINGS and PRECAUTIONS sections).
CONTRAINDICATIONS
CELEBREX is contraindicated in patients with known hypersensitivity to celecoxib. CELEBREX should not be given to patients who have demonstrated allergic-type reactions to sulfonamides. CELEBREX should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS – Anaphylactoid Reactions, and PRECAUTIONS – Preexisting Asthma).
WARNINGS
Gastrointestinal (GI) Effects–Risk of GI Ulceration, Bleeding, and Perforation Serious gastrointestinal toxicity such as
bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without
warning symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor upper gastrointestinal problems,
such as dyspepsia, are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should
remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms (see PRECAUTIONS – Hematological
Effects). Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur.
The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five
patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI
ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3–6 months,
and in about 2–4% of patients treated for one year. These trends continue thus, increasing the likelihood of developing a serious
GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding.
Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in
treating this population. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for
the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be
considered.
Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use
NSAIDs, have a greater than 10-fold higher risk for developing a GI bleed than patients with neither of these risk factors. In
addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other co-therapies or
co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with
anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status.
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