CONTRAINDICATIONS
Celecoxib is contraindicated in patients with known hypersensitivity to celecoxib.
Celecoxib should not be given to patients who have demonstrated allergic-type reactions to
sulfonamides.
Celecoxib 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. 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 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.
It is unclear, at the present time, how the above rates apply to celecoxib (see CLINICAL
STUDIES, Special Studies). Among 5285 patients who received celecoxib in controlled clinical
trials of 1-6 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. Prospective, long-term studies required to compare the incidence of serious,
clinically significant upper GI adverse events in patients taking celecoxib vs. comparator NSAID
products have not been performed.
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 tenfold 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.
Anaphylactoid Reactions
Anaphylactoid reactions were not reported in patients receiving celecoxib in clinical trials. However,
as with NSAIDs in general, anaphylactoid reactions may occur in patients without known prior
exposure to celecoxib. Celecoxib should not be given to patients with the aspirin 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 aspirin or other
NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). 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.
Therefore, treatment with celecoxib is not recommended in these patients. If celecoxib therapy
must be initiated, close monitoring of the patient's kidney function is advisable (see
PRECAUTIONS, Renal Effects).
Pregnancy
In late pregnancy celecoxib should be avoided because it may cause premature closure of the
ductus arteriosus.
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.
The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may
diminish the utility of these diagnostic signs in detecting infectious complications of presumed
noninfectious, painful conditions.
Hepatic Effects
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.
Renal Effects
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 nonsteroidal
anti-inflammatory drug 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.
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. Caution
is also recommended in patients with pre-existing kidney disease (see WARNINGS, Advanced
Renal Disease).
Hematological Effects
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 CLINICAL STUDIES, Special Studies, Platelets).
Fluid Retention and Edema
Fluid retention and edema have been observed in some patients taking celecoxib (see ADVERSE
REACTIONS). Therefore, celecoxib should be used with caution in patients with fluid retention,
hypertension, or heart failure.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with
aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since
cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory
drugs has been reported in such aspirin-sensitive patients, celecoxib should not be administered to
patients with this form of aspirin sensitivity and should be used with caution in patients with
preexisting asthma.
Information for the Patient
Celecoxib can cause discomfort and, rarely, more serious side effects, such as gastrointestinal
bleeding, which may result in hospitalization and even fatal outcomes. Although serious GI tract
ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs
and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any
indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see
WARNINGS, Risk of Gastrointestinal Ulceration, Bleeding, and Perforation).
Patients should promptly report signs or symptoms of gastrointestinal ulceration or bleeding, skin
rash, unexplained weight gain, or edema to their physicians.
Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If
these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
Patients should also be instructed to seek immediate emergency help in the case of an
anaphylactoid reaction (see WARNINGS).
In late pregnancy celecoxib should be avoided because it may cause premature closure of the
ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs or symptoms of GI bleeding.
During the controlled clinical trials, there was an increased incidence of hyperchloremia in patients
receiving celecoxib compared with patients on placebo. Other laboratory abnormalities that
occurred more frequently in the patients receiving celecoxib included hypophosphatemia, and
elevated BUN. These laboratory abnormalities were also seen in patients who received comparator
NSAIDs in these studies. The clinical significance of these abnormalities has not been established.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Celecoxib was not carcinogenic in rats given oral doses up to 200 mg/kg for males and 10 mg/kg for
females (approximately twofold to fourfold the human exposure as measured by the AUC0-24 at
200 mg bid) or in mice given oral doses up to 25 mg/kg for males and 50 mg/kg for females
(approximately equal to human exposure as measured by the AUC0-24 at 200 mg bid) for 2 years.
Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary
(CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo
micronucleus test in rat bone marrow.
Celecoxib did not impair male and female fertility in rats at oral doses up to 600 mg/kg/day
(approximately elevenfold human exposure at 200 mg bid based on the AUC0-24.
Pregnancy Category C
Teratogenic Effects: Celecoxib was not teratogenic in rabbits up to an oral dose of 60 mg/kg/day
(equal to human exposure at 200 mg bid as measured by AUC0-24); however, at oral doses ³150
mg/kg/day (approximately twofold human exposure at 200 mg bid as measured by AUC0-24), an
increased incidence of fetal alterations, such as ribs fused, sternebrae fused, and sternebrae
misshapen, was observed. A dose-dependent increase in diaphragmatic hernias was observed in
one of two rat studies at oral doses ³30 mg/kg/day (approximately sixfold human exposure based on
the AUC0-24 at 200 mg bid). There are no studies in pregnant women. Celecoxib should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: Celecoxib produced pre-implantation and post-implantation losses and
reduced embryo/fetal survival in rats at oral dosages ³50 mg/kg/day (approximately sixfold human
exposure based on the AUC0-24 at 200 mg bid). These changes are expected with inhibition of
prostaglandin synthesis and are not the result of permanent alteration of female reproductive
function, nor are they expected at clinical exposures. No studies have been conducted to evaluate
the effect of celecoxib on the closure of the ductus arteriosus in humans. Therefore, use of
celecoxib during the third trimester of pregnancy should be avoided.
Labor and Delivery
Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats
(approximately sevenfold human exposure as measured by the AUC0-24 at 200 mg bid). The
effects of celecoxib on labor and delivery in pregnant women are unknown.
Nursing Mothers
Celecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. It is
not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk and because of the potential for serious adverse reactions in nursing infants from
celecoxib, a decision should be made whether to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 18 years have not been evaluated.
Geriatric Use
Of the total number of patients who received celecoxib in clinical trials, more than 2100 were 65-74
years of age, while approximately 800 additional patients were 75 years and over. While the
incidence of adverse experiences tended to be higher in elderly patients, no substantial differences
in safety and effectiveness were observed between these subjects and younger subjects. Other
reported clinical experience has not identified differences in response between the elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and
platelet function as measured by bleeding time and platelet aggregation, the results were not
different between elderly and young volunteers.