Celebrex®
Celecoxib
Anti-inflammatory Agent--Analgesic
Pfizer
http://www.pfizer.com/pfizer/main.jsp
Celebrex Monograph PDF download here.
CPS:PIS_m113500
Pharmacology
Celecoxib is a nonsteroidal anti-inflammatory
drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in
animals. The mechanism of action of celecoxib is believed to be related to
inhibition of cyclooxygenase-2 (COX-2). COX-2 is expressed at high levels in
inflamed tissues where it is induced by mediators of inflammation. COX-2 also
plays physiological roles in a limited number of tissues, including those of
the female reproductive tract, the kidney and possibly the vascular
endothelium. COX-2 has the same catalytic activity as COX-1. COX-1 is expressed
constitutively in most tissues including the gastrointestinal tract, kidney,
lungs, brain, and platelets. The prostaglandins produced by COX-1 play key
roles in the maintenance of physiological functions such as platelet
aggregation and are among the factors that maintain the GI mucosal barrier. At
therapeutic concentrations (see Dosage) celecoxib inhibits COX-2 and does not inhibit
COX-1.
Pharmacokinetics
The pharmacokinetics of celecoxib have been
evaluated in approximately 1500 individuals. In addition to healthy, young and
elderly volunteers (male and female), pharmacokinetic measurements have been
done in patients and also in special populations including individuals with
hepatic or renal impairment.
Absorption: Peak plasma levels of celecoxib
occur approximately 3 hours after an oral dose. Both peak plasma levels (Cmax)
and area under the curve (AUC) are roughly dose proportional across the
clinical dose range of 100 to 200 mg studied. Under fasting conditions, at
higher doses, there is a less than proportional increase in Cmax and
AUC which is thought to be due to the low solubility of the drug in aqueous
media. Because of the low solubility, 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.
CPS:Celebrex_t1Click here for Table 1
Table 1: Celebrex
Summary of Single Dose (200 mg) Disposition
Kinetics of Celecoxib in Healthy Subjectsa
|
Mean (% CV)
Pharmacokinetic (PK) Parameter Values (95% Confidence Interval)
|
|
Cmax (ng/mL)
|
Tmax (h)
|
Effective t1/2
(h)
|
Vss/F (L)
|
CL/F (L/h)
|
|
|
705 (38)
(484.2–925.0)
|
2.8 (37)
(1.95–3.71)
|
11.2 (31)
(8.3–14.0)
|
429 (34)
(307.2–551.5)
|
27.7 (28)
(21.3–34.1)
|
|
a Subjects under fasting conditions
(n=36, 19 to 52 years).
Food Effects: When celecoxib 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%. Coadministration of
celecoxib 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. Celecoxib capsules can be administered without regard to the
timing of meals.
Distribution: In healthy subjects, celecoxib is
highly protein bound (approximately 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: Geriatrics: 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 elderly
patients of less than 50 kg in body weight, initiate therapy at the lowest
recommended dose, and as with all other NSAIDs, exercise caution in the use of
higher doses.
Race: Meta-analysis of pharmacokinetic studies
has suggested an approximately 40% higher AUC of celecoxib in black patients
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 I) and moderate (Child-Pugh Class II)
hepatic impairment has shown that steady-state celecoxib AUC is increased about
40% and 180%, respectively, above that seen in healthy control subjects.
Therefore, celecoxib capsules should be introduced at a reduced dose in
patients with moderate hepatic impairment. Patients with severe hepatic
impairment have not been studied. The use of celecoxib in patients with severe
hepatic impairment is not recommended (see Contraindications).
Renal Insufficiency: In a cross-study
comparison, celecoxib AUC was approximately 40% lower in patients with chronic
renal insufficiency (GFR 35 to 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 (see Contraindications).
Clinical Studies
Osteoarthritis (OA): The clinical effectiveness
of celecoxib in the treatment of the signs and the symptoms of OA of the knee
and hip was demonstrated in placebo- and active-controlled clinical trials of
up to 12 weeks duration, involving approximately 4200 patients. Celecoxib
demonstrated significant reductions in joint pain and disease activity, and
also improvement in patient functional activity and health-related quality of
life compared to placebo. Clinically significant effects on joint pain were
seen as early as 24 hours after the first dose of celecoxib. Doses of
200 mg b.i.d. provided no additional efficacy above that seen with
100 mg b.i.d. In the repeated dose OA studies with 100 mg b.i.d. of
celecoxib, pain was significantly decreased by the end of the first day of
dosing, continued to be significantly less than placebo and was comparable to
naproxen 500 mg b.i.d., diclofenac 75 mg b.i.d., and ibuprofen 800 mg
t.i.d.
A total daily dose of
200 mg has been shown to be equally effective when administered as 100 mg
b.i.d. or 200 mg once daily. Response to celecoxib was independent of age,
gender, severity, or duration of OA. Celecoxib has shown continued
efficacy at doses of up to 400 mg a day in a long-term (up to 12 months) open
label study of 2500 patients.
In patients with OA,
treatment with celecoxib 100 mg b.i.d. or 200 mg once daily resulted in
improvement in functional activity as demonstrated by an improvement in pain,
stiffness, function and total WOMAC (Western Ontario and McMaster Universities Osteoarthritis
Index) scores. Improvement in quality of life, as measured by the MOS-SF-36
(Short Form 36 Item Health Survey) has been shown by improvements in Physical
Function, Role Physical, Bodily Pain, Vitality and Social Functioning domains.
Rheumatoid Arthritis (RA): The clinical
effectiveness of celecoxib in the treatment of the signs and the symptoms of RA
was demonstrated in placebo- and active-controlled clinical trials of up to 24
weeks in duration, involving approximately 2100 patients. Celecoxib
demonstrated significant reductions in joint tenderness and pain, joint
swelling, disease activity, and morning stiffness compared to placebo.
Improvements were demonstrated in the ACR20 Index for RA (American College of Rheumatology 20%
Responder Index), patient functional activity, and health-related quality of
life compared to placebo. Celecoxib doses of 100 mg b.i.d. and 200 mg b.i.d.
were similar in efficacy and both were comparable to naproxen 500 mg b.i.d.
Although celecoxib 100 mg b.i.d. and 200 mg b.i.d. provided similar efficacy
overall, some patients derive additional benefit from the 200 mg b.i.d.
dose. Doses of 400 mg b.i.d. provided no additional efficacy above that seen
with 100 to 200 mg b.i.d.
Additional studies
demonstrated that celecoxib 200 mg b.i.d. was comparable to diclofenac 75 mg
b.i.d. and ibuprofen 800 mg t.i.d. Response to celecoxib was independent of
age, gender, severity, or duration of RA. In an open label study of up to
12 months in approximately 1900 RA patients, celecoxib has shown continued
efficacy.
In patients with RA,
treatment with celecoxib 200 mg b.i.d. resulted in improvement in functioning
as shown by an improvement in the Health Assessment Questionnaire (HAQ)
functional disability index. Improvement in quality of life as measured by the
MOS-SF-36 has been shown by improvements in Physical Function, Role Physical
Bodily Pain, Vitality and Social Functioning domains. Compared to celecoxib 100
mg b.i.d., celecoxib 200 mg b.i.d. resulted in greater improvement in the HAQ
disability index and the MOS-SF-36 domains of Physical Function and Bodily
Pain.
Special Studies: Clinical Experience with
Higher-than-therapeutic Dose for OA and RA (800 mg/day) in the presence of
concomitant ASA: Celecoxib Long-term Arthritis Safety Study (CLASS): Study
Design: A prospective long-term outcome study was conducted in approximately
5800 OA and 2200 RA patients. Patients received celecoxib 400 mg b.i.d. (4-fold
and 2-fold greater than the daily recommended 200 mg OA and 400 mg RA doses,
respectively), ibuprofen 800 mg t.i.d. or diclofenac 75 mg b.i.d. (common
therapeutic doses for OA and RA) for a median exposure of 9 months for
celecoxib and diclofenac, and 6 months for ibuprofen. The primary endpoint of
this outcome study was the incidence of complicated ulcers (GI bleeding,
perforation or obstruction). Additional protocol specified endpoints included
the incidence of symptomatic ulcers (gastroduodenal ulcers identified based on
UGI symptoms such as abdominal pain, dyspepsia, nausea, diarrhea or vomiting)
and clinically relevant decreases in hemoglobin (>2 g/dl) and/or hematocrit
(≥ 10 points). Patients were allowed to take concomitant low-dose ASA
(≤ 325 mg), mostly for cardiovascular prophylaxis.
Study Results: No statistically significant
differences were demonstrated for the incidence of complicated ulcers at the
doses studied among the three treatment groups in all patients. Study results
for the complete study duration are presented in Table 2.
Secondary analysis
showed that the incidence of complicated and symptomatic ulcers was lower for
celecoxib than for ibuprofen in all patients and in those patients not taking
ASA. Approximately 22% of patients were taking low-dose ASA.
Concomitant low-dose
ASA use increased the rates of complicated and symptomatic ulcers to 4 times
that of patients not taking ASA (see Precautions, Drug Interactions—Use With
ASA or other NSAIDs).
Celecoxib at the doses
studied had a significantly lower incidence of GI intolerability compared to
diclofenac, but not ibuprofen (see Adverse Effects).
CPS:Celebrex_t2Click here for Table 2
Table 2: Celebrex
Complicated and Symptomatic Ulcers in OA and RA
Patients (Incidence rates at 12 months [%], events/patients)
|
|
Higher-than-therapeutic
Dose (4X OA; 2X RA) Celebrex 400 mg b.i.d.
|
Common Therapeutic
Dose
|
|
Ibuprofen
800 mg t.i.d.
|
Diclofenac
75 mg b.i.d.
|
|
|
All Patients (Exposure)
|
2320 Pt-years
|
1112 Pt-years
|
1081 Pt-years
|
|
|
Complicated ulcers
|
0.43
(17/3987)
|
0.55
(11/1985)
|
0.50
(10/1996)
|
|
|
Complicated and symptomatic ulcers
|
1.05a
(42/3987)
|
1.76
(35/1985)
|
1.30
(26/1996)
|
|
|
Patients without ASA (Exposure)
|
1803 Pt-years
|
874 Pt-years
|
841 Pt-years
|
|
|
Complicated ulcers
|
0.26b
(8/3105)
|
0.64
(10/1573)
|
0.26
(4/1551)
|
|
|
Complicated and symptomatic ulcers
|
0.68c
(21/3105)
|
1.72
(27/1573)
|
0.64
(10/1551)
|
|
|
Patients with ASA (Exposure)
|
517 Pt-years
|
248 Pt-years
|
240 Pt-years
|
|
|
Complicated ulcers
|
1.02
(9/882)
|
0.24
(1/412)
|
1.35
(6/445)
|
|
|
Complicated and symptomatic ulcers
|
2.38
(21/882)
|
1.94
(8/412)
|
3.60
(16/445)
|
|
a p=0.017 vs ibuprofen.
b p=0.037 vs ibuprofen.
c p=<0.001 vs ibuprofen.
In a prospective
long-term outcome study, celecoxib (4-fold and 2-fold greater than the
recommended OA and RA doses, respectively) also demonstrated a significantly
lower incidence of clinically relevant decreases in hemoglobin (>2 g/dL) or
hematocrit (≥ 10points) than ibuprofen and diclofenac ( Figure 1)
regardless of ASA use. The corresponding incidence rates from the controlled
arthritis trials (1 to 6 months duration, most of 3 months duration) were 0.4%
in placebo, 0.9% in celecoxib, and 1.7%, 3.3%, 5.2% for naproxen, diclofenac,
and ibuprofen respectively. In the controlled arthritis trials celecoxib was
studied at doses up to 400 mg b.i.d. Similar significant differences were seen
in the absence of bleeding ulcers, in patients not on ASA, and in OA and RA
patients.
Figure 1:
Celebrex
Incidence of Clinically Relevant Decreases in
Hemoglobin and/or Hematocrit (Incidence rates at 12 months [%] events/patients)
p<0.05 vs ibuprofen and diclofenac.
Endoscopic Studies: Scheduled upper GI
endoscopic evaluations were performed in over 4500 arthritis patients who were
enrolled in 5 controlled randomized 12-to 24-week trials using active
comparators, 2 of which also included placebo controls. Twelve-week endoscopic
ulcer data are available on approximately 1400 patients and 24-week endoscopic
ulcer data are available on 184 patients on celecoxib at doses ranging from 50
to 400 mg b.i.d. NSAID comparators included naproxen 500 mg b.i.d., diclofenac
75 mg b.i.d., and ibuprofen 800 mg t.i.d.
In active-controlled
studies, the endoscopic gastroduodenal ulceration rate observed with all doses
of celecoxib was less than what was seen with the NSAID comparator (see Table
3 to Table 5) and, in placebo-controlled studies, was similar to that seen
with placebo (see Table 3). Studies were designed to detect differences
between celecoxib and the NSAID comparator, therefore were not powered to detect
small differences relative to placebo. Moreover, celecoxib doses above the
highest recommended therapeutic dose of 200 mg b.i.d. were evaluated, and
demonstrated that with supratherapeutic doses (2 to 4 times the recommended
dose), the incidence of endoscopic ulcers was similar to placebo. Duration of
observation had no impact on the celecoxib gastroduodenal ulcer rate, as shown
in a 24-week trial in which the celecoxib endoscopic ulcer rate was
significantly lower than diclofenac SR and comparable to ulcer rates observed
with placebo in other studies.
In all 3 studies that
included naproxen 500 mg b.i.d., and in the study that included ibuprofen 800
mg t.i.d., celecoxib was associated with a statistically significantly lower
incidence of endoscopic ulcers over the study period. Two studies compared
celecoxib with diclofenac 75 mg b.i.d.; one study revealed a statistically
significantly higher prevalence of endoscopic ulcers in the diclofenac group at
the study endpoint (6 months on treatment), and 1 study revealed no
statistically significant difference between cumulative endoscopic ulcer
incidence rates in the diclofenac and celecoxib groups after 1, 2, and 3 months
of treatment. There was no consistent relationship between the incidence of
gastroduodenal ulcers and the dose of celecoxib over the range studied.
Table 3 summarizes the
incidence of endoscopic ulcers in two 12-week studies that enrolled patients in
whom baseline endoscopies revealed no ulcers.
CPS:Celebrex_t3Click here for Table 3
Table 3: Celebrex
Incidence of Gastroduodenal Ulcers from
Endoscopic Studies in OA and RA Patients
|
|
3-month Studies
|
|
Study 1
(n=1108)
|
Study 2
(n=1049)
|
|
|
Placebo
|
2.3% (5/217)
|
2.0% (4/200)
|
|
|
Celebrex 50 mg b.i.d.
|
3.4% (8/233)
|
—
|
|
|
Celebrex 100 mg b.i.d.
|
3.1% (7/227)
|
4.0% (9/223)
|
|
|
Celebrex 200 mg b.i.d.
|
5.9% (13/221)
|
2.7% (6/219)
|
|
|
Celebrex 400 mg b.i.d.
|
—
|
4.1% (8/197)
|
|
|
Naproxen 500 mg b.i.d.
|
16.2% (34/210)a
|
17.6% (37/210)a
|
|
a p≤ 0.05 vs all other
treatments.
Note: Studies were designed to detect
differences between celecoxib and NSAID comparator, therefore were not powered
to detect small differences relative to placebo.
Table 4 summarizes
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.
CPS:Celebrex_t4Click here for Table 4
Table 4: Celebrex
Incidence of Gastroduodenal Ulcers from 3-month
Serial Endoscopy Studies in OA and RA Patients
|
|
Week 4
|
Week 8
|
Week 12
|
Final
|
|
|
Study 3 (n=523)
|
|
Celebrex 200 mg b.i.d.
|
4.0% (10/252)a
|
2.2% (5/227)a
|
1.5% (3/196)a
|
7.5% (20/266)a
|
|
|
Naproxen 500 mg b.i.d.
|
19.0% (47/247)
|
14.2% (26/182)
|
9.9% (14/141)
|
34.6% (89/257)
|
|
|
Study 4 (n=1062)
|
|
Celebrex 200 mg b.i.d.
|
3.9% (13/337)b
|
2.4% (7/296)b
|
1.8% (5/274)b
|
7.0% (25/356)b
|
|
|
Diclofenac 75 mg b.i.d.
|
5.1% (18/350)
|
3.3% (10/306)
|
2.9% (8/278)
|
9.7% (36/372)
|
|
|
Ibuprofen 800 mg t.i.d.
|
13.0% (42/323)
|
6.2% (15/241)
|
9.6% (21/219)
|
23.3% (78/334)
|
|
a p≤ 0.05 Celebrex vs naproxen
based on interval and cumulative analyses.
b p≤ 0.05 Celebrex vs
ibuprofen based on interval and cumulative analyses.
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
Table 5.
CPS:Celebrex_t5Click here for Table 5
Table 5: Celebrex
Incidence of Gastroduodenal Ulcers from a
6-month Endoscopy Study in RA Patients
|
Study 5 (n=430)
|
6 months
|
|
Celecoxib 200 mg b.i.d.
|
4% (8/212)
|
|
Diclofenac 75 mg b.i.d.
|
15% (33/218)a
|
a Significantly different from
Celebrex; p<0.001.
The correlation between
findings of endoscopic studies, and the relative incidence of clinically
serious upper GI events that may be observed with different products, has not
been fully established. (see Warnings, Gastrointestinal).
Use with ASA: Patients with cardiovascular risk
factors, including those with a recent history of myocardial infarction or
stroke and patients deemed to require low-dose ASA for cardiovascular
prophylaxis were included in the long-term outcome study (see Adverse Effects).
As a result, approximately 22% of patients enrolled in the long-term outcome
study were taking ASA (≤ 325 mg/day). As with the NSAID comparators,
the incidence rate of ulcers and ulcer complications (perforations,
obstructions and bleeds) in celecoxib patients was higher in ASA users as
opposed to non-ASA users (see Special Studies—Long-term Outcome Study).
Approximately 11% of
patients (440/4000) enrolled in 4 of the 5 endoscopic studies were taking ASA
(≤ 325 mg/day). In the celecoxib groups, the endoscopic ulcer rate
appeared to be higher in subjects taking both celecoxib and ASA than in
subjects taking only celecoxib. However, the increased rate of ulcers in these
ASA users was less than the endoscopic ulcer rates observed in the active
comparator groups, with or without ASA.
Platelets: In 4 clinical trials involving 118
subjects, celecoxib did not affect platelet function. Celecoxib at single doses
up to 800 mg and multiple doses of 600 mg b.i.d. for up to 7 days duration
(i.e., 3 times the highest recommended therapeutic dose), had no effect on
platelet aggregation and bleeding time compared to placebo. In contrast, the
NSAIDs naproxen 500 mg b.i.d., ibuprofen 800 mg t.i.d., and diclofenac 75 mg
b.i.d. significantly reduced platelet aggregation and prolonged bleeding time.
Indications
For acute and chronic use in the relief of the
signs and symptoms of osteoarthritis and rheumatoid arthritis in adults.
Contraindications
In patients with known hypersensitivity to
celecoxib.
In patients who have
demonstrated allergic-type reactions to sulfonamides.
In patients who have
experienced asthma, urticaria, or allergic-type reactions after taking ASA or
other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have
been reported in such patients (see Warnings, Anaphylactoid Reactions, and
Precautions, Hypersensitivity Reactions).
In patients with active
peptic ulcer, active GI bleeding, or active inflammatory disease of the bowel.
In patients with
significant liver impairment or active liver disease.
In patients with severe
renal impairment (creatinine clearance <0.5 mL/s: 30 mL/min) or
deteriorating renal disease (individuals with lesser degrees of renal
impairment are at risk of deterioration of their renal function when prescribed
NSAIDs and must be monitored).
Celecoxib is not
recommended for use with other NSAIDs because of the absence of any evidence
demonstrating synergistic benefits and the potential for additive side effects.
Warnings
GI: Celecoxib exhibited a low incidence of
gastroduodenal ulceration and serious clinically significant GI events within clinical
trials. Among 5285 patients who received celecoxib in controlled clinical
trials of 1 to 6 months duration (most were 3 month studies) at a daily dose of
200 mg or more, 2 (0.04%) experienced significant upper GI bleeding, at 14 and
22 days after initiation of dosing. Approximately 40% of these 5285 patients
were in studies that required them to be free of ulcers by endoscopy at study
entry. Thus it is unclear if this study population is representative of the
general population.
In a prospective
randomized controlled long-term outcome trial in 8000 OA and RA patients in
which low-dose ASA (≤ 325 mg/day) use was allowed, approximately 0.43% of
patients on higher-than-recommended dose of celecoxib (400 mg b.i.d.)
demonstrated ulcer complications (perforation, obstruction, or bleeding) over
12 months. In the absence of low-dose ASA use the rate was 0.26% (see
Pharmacology, Clinical Studies—Special Studies—Long-term Outcome Study).
The following general
warnings for NSAIDs should be borne in mind.
Serious GI toxicity,
such as peptic ulceration, perforation and bleeding, sometimes severe and
occasionally fatal, can occur at any time, with or without warning symptoms, in
patients treated with NSAIDs. Minor upper GI problems, such as dyspepsia, are
common, and may also occur at any time during NSAID therapy. Therefore,
physicians should remain alert for ulceration and bleeding in patients treated
with NSAIDs, even in the absence of previous GI tract symptoms. 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 1 in 5
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 to 6 months, and in about 2 to 4% of patients treated for 1 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 GI 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 (see Contraindications).
For elderly patients of
less than 50 kg body weight, initiate therapy at the lowest recommended
dose for arthritis and, as with all other NSAIDs, exercise caution in the use
of higher doses.
Studies have shown that
patients with a prior history of peptic ulcer disease and/or GI 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 cotherapies or comorbid 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.
Anaphylactoid Reactions: As with NSAIDs in
general, anaphylactoid reactions may occur in patients without known prior
exposure to celecoxib. In postmarketing experience, very rare cases of
anaphylactic reactions and angioedema have been reported in patients receiving
celecoxib.
Celecoxib should not be
given to patients with the ASA triad. This symptom complex typically occurs in
asthmatic patients who experience rhinitis with or without nasal polyps, or who
exhibit severe, potentially fatal bronchospasm after taking ASA or other NSAIDs
(see Contraindications and Precautions, Hypersensitivity Reactions). Emergency
help should be sought in cases where an anaphylactoid reaction occurs.
Advanced Renal Disease: No information is
available regarding the use of celecoxib in patients with advanced kidney
disease. In postmarketing experience, serious renal failure, including the need
for dialysis, and fatalities have been reported in patients with impaired renal
function. Therefore, treatment with celecoxib, as with NSAIDs, is not recommended
in these patients with advanced renal disease. Kidney function should be
monitored, especially in high-risk populations, such as the elderly, patients
with cardiovascular disease and diabetes mellitus, as well as in the setting of
concomitant use of diuretics and ACE inhibitors (see Contraindications).
Cross-sensitivity: Patients sensitive to any one
of the NSAIDs may be sensitive to any of the other NSAIDs also.
Allergies to Sulfonamides: See
Contraindications.
Aseptic Meningitis: In occasional cases, with
some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches,
nausea and vomiting, fever or clouding of consciousness) have been observed.
Patients with autoimmune disorders (systemic lupus erythematosus, mixed
connective tissues diseases, etc.) seem to be predisposed. Therefore, in such
patients, the physician must be vigilant to the development of this
complication.
Pregnancy
There are no studies in pregnant women.
Celecoxib should be used during pregnancy only if the potential benefit
outweighs the potential risk to the fetus. No studies to evaluate the effect of
celecoxib on the closure of the ductus arteriosus in humans have been carried
out, therefore use of celecoxib during the third trimester of pregnancy should
be avoided.
Lactation
Celecoxib is excreted in the milk of lactating
rats at concentrations similar to those in plasma. Studies of celecoxib
excretion in human milk have not been conducted, therefore, the benefit of
celecoxib treatment in nursing mothers should be weighed against the potential
risk to the newborn.
Children
Safety and effectiveness in pediatric patients
below the age of 18 years have not been evaluated.
Precautions
General
Celecoxib cannot be expected to substitute for
corticosteroids or to treat corticosteroid insufficiency. Abrupt
discontinuation of corticosteroids may lead to exacerbation of
corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy
should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
Gastrointestinal: There is no definitive
evidence that the concomitant administration of histamine H2-receptor
antagonists and/or antacids will either prevent the occurrence of GI side
effects or allow the continuation of celecoxib when and if these adverse
reactions appear.
Renal Function: Long-term administration of
NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal
toxicity has also been seen in patients in whom renal prostaglandins have a
compensatory role in the maintenance of renal perfusion. In these patients,
administration of a NSAID may cause a dose-dependent reduction in prostaglandin
formation and, secondarily, in renal blood flow, which may precipitate overt
renal decompensation. Patients at greatest risk of this reaction are those with
impaired renal function, heart failure, liver dysfunction, those taking
diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy
is usually followed by recovery to the pretreatment state. Clinical trials with
celecoxib have shown renal effects similar to those observed with comparator
NSAIDs (see Contraindications and Warnings, Advanced Renal Disease).
Caution should be used
when initiating treatment with celecoxib in patients with considerable dehydration.
It is advisable to rehydrate patients first and then start therapy with
celecoxib.
Genitourinary Tract: Some NSAIDs are known to
cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency),
hematuria or cystitis. The onset of these symptoms may occur at any time after
the initiation of therapy with an NSAID. Some cases have become severe on
continued treatment. Should urinary symptoms occur, treatment with celecoxib
must be stopped immediately to obtain recovery. This should be done before any
urological investigations or treatments are carried out.
Hepatic Function: Borderline elevations of one
or more liver tests may occur in up to 15% of patients taking NSAIDs, and
notable elevations of ALT or AST (approximately 3 or more times the upper limit
of normal) have been reported in approximately 1% of patients in clinical
trials with NSAIDs. These laboratory abnormalities may progress, may remain
unchanged, or may be transient with continuing therapy. Rare cases of severe
hepatic reactions, including jaundice and fatal fulminant hepatitis, liver
necrosis and hepatic failure (some with fatal outcome) have been reported with
NSAIDs. In controlled clinical trials of celecoxib, the incidence of borderline
elevations of liver tests was 6% for celecoxib and 5% for placebo, and
approximately 0.2% of patients taking celecoxib and 0.3% of patients taking
placebo had notable elevations of ALT and AST.
A patient with symptoms
and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be monitored carefully for evidence of the development of
a more severe hepatic reaction while on therapy with celecoxib. If clinical
signs and symptoms consistent with liver disease develop, or if systemic
manifestations occur (e.g., eosinophilia, rash, etc.), celecoxib should be
discontinued (see Contraindications).
Fluid and Electrolyte Balance: Fluid retention
and edema have been observed in some patients taking celecoxib (see Adverse
Effects). In the CLASS study, the rates of hypertension in patients on
celecoxib 400 mg b.i.d. (4-fold and 2-fold the recommended doses for OA
and RA respectively), and common therapeutic doses of ibuprofen (800 mg t.i.d.)
and diclofenac (75 mg b.i.d.) were 2.0%, 3.1% and 2.0%, respectively. The
corresponding rates for edema were: 3.7%, 5.2% and 3.5%, respectively.
Therefore, as with other NSAIDs known to inhibit prostaglandin synthesis, the
possibility of precipitating CHF in elderly patients or those with compromised
cardiac function should be borne in mind. Celecoxib should be used with caution
in patients with heart failure, left ventricular dysfunction, hypertension,
edema from any cause or other conditions predisposing to fluid retention.
With nonsteroidal
anti-inflammatory treatment there is a potential risk of hyperkalemia,
particularly in patients with conditions such as diabetes mellitus or renal
failure, elderly patients, or in patients receiving concomitant therapy with β
-adrenergic blockers, angiotensin converting enzyme inhibitors or some
diuretics. Serum electrolytes should be monitored periodically during long-term
therapy, especially in those patients who are at risk.
Hematology: Anemia is sometimes seen in patients
receiving celecoxib. In controlled clinical trials the incidence of anemia was
0.6% with celecoxib and 0.4% with placebo. Patients on long-term treatment with
celecoxib should have their hemoglobin or hematocrit checked if they exhibit
any signs or symptoms of anemia or blood loss. Celecoxib does not generally
affect platelet counts, prothrombin time (PT), or partial thromboplastin time
(PTT), and does not appear to inhibit platelet aggregation at indicated dosages
(see Pharmacology, Clinical Studies—Special Studies—Long-term Outcome Study and
Platelets).
Blood dyscrasias (such
as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and
agranulocytosis) associated with the use of NSAIDs are rare, but could occur
with severe consequences.
Infection: In common with other
anti-inflammatory drugs, celecoxib may mask the usual signs of infection.
Ophthalmology: Blurred and/or diminished vision
has been reported with the use of NSAIDs. If such symptoms develop, celecoxib
should be discontinued and an ophthalmologic examination performed;
ophthalmologic examination should be carried out at periodic intervals in any
patient receiving celecoxib for an extended period of time.
Occupational Hazards
CNS: Some patients may experience drowsiness,
dizziness, vertigo, insomnia or depression with the use of NSAIDs. If patients
experience these side effects, they should exercise caution in carrying out
activities that require alertness.
Hypersensitivity Reactions
Patients with asthma may have ASA-sensitive
asthma. The use of ASA in patients with ASA-sensitive asthma has been
associated with severe bronchospasm which can be fatal. Since cross reactivity,
including bronchospasm, between ASA and other NSAIDs has been reported in such
ASA-sensitive patients, celecoxib should not be administered to patients with
this form of ASA sensitivity and should be used with caution in patients with
pre-existing asthma.
