National Geographic : 2001 Jul
BRIEF SUMMARY-CELEBREX® (celecoxib capsules) Before prescribing, please consult complete prescribing information. INDICATIONS AND USAGE For relief of the signs and symptoms of OA, and of RA in adults. 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 PRE CAUTIONS - Preexisting Asthma). WARNINGS Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and Perforation: Serious GI 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 NSAIDs. Minor upper GI 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. Only 1/5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. 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. It is unclear, at the present time, how the above rates apply to CELEBREX (see CLINICAL STUDIES - Special Studies in the complete prescrib ing information). Among 5,285 patients who received CELEBREX 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 14and 22 days after initiation of dosing. Approximately 40% of these 5,285 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 CELEBREX vs. comparator NSAID products have not been performed. NSAIDs should be pre scribed 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 debili tated patients and therefore special care should be taken in treating this popula tion. 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 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 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: As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to CELEBREX. In post-mar keting experience, rare cases of anaphylactic reactions and angioedema have been reported in patients receiving CELEBREX. CELEBREX should not be given to patients with the aspirin triad. This symptom complex typically occurs in asth matic patients who experience rhinitis with or without nasalpolyps, 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: Treatment with CELEBREX is not recommended. Pregnancy: In late pregnancy CELEBREX should be avoided because it may cause premature closure of the ductus arteriosus. PRECAUTIONS General: CELEBREX cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency.The pharmacological activity of CELEBREX in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful condi tions. 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 (approx imately three or more times the upper limit of normal) have been reported in approximately 1%of patients in clinical trials with NSAIDs. These laboratory abnor malities may progress, may remain unchanged, or may be transient with contin uing 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, including CELEBREX. (See ADVERSE REAC TIONS - post-marketing experience.) Incontrolled clinical trials of CELEBREX, the incidence of borderline elevations of liver tests was 6%for CELEBREX and 5% for placebo, and approximately 0.2% of patients taking CELEBREX 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 devel opment of a more severe hepatic reaction while on therapy with CELEBREX. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g ., eosinophilia, rash, etc.), CELEBREX should be discon tinued. 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 an 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, or liver dys function, those taking diuretics and ACE inhibitors, and the elderly. Discontinua tion of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical trials with CELEBREX have shown renal effects similar to those observed with comparator NSAIDs. Caution should be used when initiating treatment with CELEBREX in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with CELEBREX. Caution is also recom mended in patients with pre-existing kidney disease (see WARNINGS - Advanced Renal Disease). Hematological Effects: Anemia may occur. In controlled clinical trials the incidence of anemia was 0.6% with CELEBREX and 0.4% with placebo. Patients on long term treatment with CELEBREX should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. CELEBREX does not generally affect platelet counts, prothrombin time (PT), or partial throm boplastin time (PTT), and does not appear to inhibit platelet aggregation at indicated dosages (See CLINICAL STUDIES - Special Studies - Platelets in the complete prescribing information). Fluid Retention and Edema: Fluid retention and edema may occur (see ADVERSE REACTIONS). Therefore, CELEBREX should be used with caution in patients with fluid retention, hypertension, or heart failure. Preexisting Asthma: Do not use in patients with aspirin-sensitive asthma because of the risk of severe bronchospasm. Use with caution in patients with preexist ing asthma. 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 com parator NSAIDs in these studies. The clinical significance of these abnormalities has not been established, Drug Interactions: General: Celecoxib metabolism is predominantly mediated via cytochrome P450 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit 2C9 should be done with caution. In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of cytochrome P450 2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by P450 2D6. ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking CELEBREX concomitantly with ACE-inhibitors. Furosemide: Clinical studies, as well as post marketing observations, have shown that NSAIDs can reduce the natri uretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. Aspirin: CELEBREX can be used with low dose aspirin. However, concomitant administration of aspirin with CELEBREX may result in an increased rate of GI ulceration or other compli cations, compared to use of CELEBREX alone (see CLINICAL STUDIES - Special Studies - Gastrointestinal in the complete prescribing information). Because of its lack of platelet effects, CELEBREX is not a substitute for aspirin for cardio vascular prophylaxis. Fluconazole: Concomitant administration of fluconazole at 200 mg QD resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by flu conazole (see Pharmacokinetics - Metabolism). CELEBREX should be introduced at the lowest recommended dose in patients receiving fluconazole. Lithium: In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg BID with CELEBREX 200 mg BID as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when CELEBREX is introduced or withdrawn. Methotrexate: In an interaction study of rheumatoid arthritis patients taking methotrexate, CELEBREX did not have a significant effect on the pharmacokinetics of methotrexate. Warferin: Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing CELEBREX therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. The effect of celecoxib on the anti coagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of 2-5 mg of warfarin. In these subjects, celecoxib did not alter the anticoagulant effect of warfarin as determined by prothrombin time. However, in post-marketing experience, bleeding events have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiv ing CELEBREX concurrently with warfarin. Carcinogenesis, mutagenesis, impair ment 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 2- to 4-fold the human exposure as measured by the AUCo0 24at 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 AUCo-24at 200 mg BID) for two 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. Cele coxib did not impair male and female fertility in rats at oral doses up to 600 mg/kg/day (approximately 11-fold human exposure at 200 mg BID based on the AUCo-24). Pregnancy: Teratogenic effects: Pregnancy Category C. Celecoxib was not ter atogenic in rabbits up to an oral dose of 60 mg/kg/day (equal to human exposure at 200 mg BIDas measured by AUCo-24);however, at oral doses 0 150 mg/kg/day (approximately 2-fold human exposure at 200 mg BID as measured by AUCo_24), an increased incidence of fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen, was observed. A dose-dependent increase in diaphrag matic hernias was observed in one of two rat studies at oral doses 30 mg/kg/day (approximately 6-fold human exposure based on the AUCo-24at 200 mg BID).There are no studies in pregnant women. CELEBREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic effects: Celecoxib produced preimplantation and post-implantation losses and reduced embryo/fetal survival in rats at oral dosages > 50 mg/kg/day (approxi mately 6-fold human exposure based on the AUCo0 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 CELEBREXduring 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 7-fold human exposure as measured by the AUCo24 at 200 mg BID). The effects of CELEBREX on labor and delivery in pregnant women are unknown. Nursing mothers: 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 CELEBREX, 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.