Celecoxib Information

Brand Name: Celebrex
Drug Name: Celecoxib

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,  1-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.

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.

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).

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.

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 follow-up, 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). (See Figure 1.)

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.

Celebrex 50 mg BID 3.4% (8/233) —

Celebrex 400 mg BID — 4.1% (8/197)

*p ¡Ü0.05 vs all other treatments

*p ¡Ü0.05 Celebrex vs. naproxen based on interval and cumulative analyses

†p ¡Ü0.05 Celebrex vs. ibuprofen based on interval and cumulative analyses

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 long-term 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.

3) For the management of acute pain in adults (see CLINICAL STUDIES).

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).

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).

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.

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.

CLASS Study: The estimated cumulative rates at 9 months of complicated and symptomatic ulcers (an adverse event similar but not identical to the "upper GI ulcers, gross bleeding or perforation" described in the preceding paragraphs) for patients treated with CELEBREX 400 mg BID (see Special

Studies – Use with Aspirin) are described in Table 5. Table 5 also displays results for patients less than or greater than or equal to the age of 65 years. The differences in rates between the CELEBREX alone and CELEBREX with ASA groups may be due to the higher risk for GI events in ASA users.

Patients <65 Years

Patients ¡Ý65 Years

In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer rates in patients taking CELEBREX alone or CELEBREX with ASA were, respectively, 2.56% (n =243) and 6.85% (n = 91) at 48 weeks. These results are to be expected in patients with a prior history of ulcer disease (see WARNINGS – Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation).

As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to CELEBREX. In post-marketing 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 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.

No information is available from controlled clinical studies regarding the use of CELEBREX in patients with advanced kidney disease. Therefore, treatment with CELEBREX is not recommended in these patients with advanced kidney disease. If CELEBREX therapy must be initiated, close monitoring of the patient's kidney function is advisable (see PRECAUTIONS – Renal Effects).

In late pregnancy CELEBREX should be avoided because it may cause premature closure of the ductus arteriosus. (See PRECAUTIONS – Pregnancy).

General: CELEBREX 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.

Hepatic Effects: Borderline elevations of one or more liver associated enzymes 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, including CELEBREX (see ADVERSE REACTIONS – post-marketing experience). In controlled clinical trials of CELEBREX, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes 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.

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 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 recommended in patients with pre-existing kidney disease (see WARNINGS – Advanced Renal Disease).

Hematological Effects: Anemia is sometimes seen in patients receiving CELEBREX. 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 thromboplastin time (PTT), and does not inhibit platelet aggregation at indicated dosages (see CLINICAL STUDIES – Special Studies – Platelets).

Fluid Retention, Edema, and Hypertension: Fluid retention and edema have been observed in some patients taking CELEBREX (see ADVERSE REACTIONS). In CLASS study (see Special Studies – Use with Aspirin), the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on 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 and diclofenac 75 mg BID were 4.5%, 6.9% and 4.7%, respectively. The rates of hypertension in the CELEBREX, ibuprofen and diclofenac treated patients were 2.4%, 4.2% and 2.5%, respectively. As with other NSAIDs, CELEBREX 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, CELEBREX 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 Patients: CELEBREX 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 – Gastrointestinal (GI) Effects – Risk of Gastrointestinal Ulceration, Bleeding and Perforation).

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 CELEBREX 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. In controlled clinical trials, elevated BUN occurred more frequently in patients receiving CELEBREX compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established.

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 natriuretic 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 increases the rate of GI ulceration or other complications, compared to use of CELEBREX alone (see CLINICAL STUDIES – Special Studies – Use with Aspirin and WARNINGS – Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation – CLASS Study).

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 fluconazole (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.

Warfarin: 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 anticoagulant 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, serious bleeding events, some of which were fatal, have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving CELEBREX concurrently with warfarin.

Carcinogenesis, mutagenesis, 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 2- to 4-fold 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 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.

Celecoxib 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 AUC0-24).

Teratogenic effects: Pregnancy Category C. Celecoxib at oral doses ¡Ý150 mg/kg/day (approximately 2-fold human exposure at 200 mg BID as measured by AUC0-24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ¡Ý30 mg/kg/day (approximately 6-fold human exposure based on the AUC0-24 at 200 mg BID) throughout organogenesis. 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 pre-implantation and post-implantation losses and reduced embryo/fetal survival in rats at oral dosages ¡Ý50 mg/kg/day (approximately 6-fold 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 CELEBREX 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 7-fold human exposure as measured by the AUC0-24 at 200 mg BID). The effects of CELEBREX 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. Limited data from one subject indicate that celecoxib is also 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.

Of the total number of patients who received CELEBREX in clinical trials, more than 3,300 were 65-74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. 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. However, as with other NSAIDS, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients (see WARNINGS – Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation).

Adverse events from CELEBREX premarketing controlled arthritis trials: Table 6 lists all adverse events, regardless of causality, occurring in ¡Ý2% of patients receiving CELEBREX from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group.

table

Gastrointestinal: Constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, tooth disorder, vomiting

Cardiovascular: Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction

General: Allergy aggravated, allergic reaction, asthenia, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain

Resistance mechanism disorders: Herpes simplex, herpes zoster, infection bacterial, infection fungal, infection soft tissue, infection viral, moniliasis, moniliasis genital, otitis media

Central, peripheral nervous system: Leg cramps, hypertonia, hypoesthesia, migraine, neuralgia, neuropathy, paresthesia, vertigo

Female reproductive: Breast fibroadenosis, breast neoplasm, breast pain, dysmenorrhea, menstrual disorder, vaginal hemorrhage, vaginitis

Male reproductive: Prostatic disorder

Hearing and vestibular: Deafness, ear abnormality, earache, tinnitus

Heart rate and rhythm: Palpitation, tachycardia

Liver and biliary system: Hepatic function abnormal, SGOT increased, SGPT increased

Metabolic and nutritional: BUN increased, CPK increased, diabetes mellitus, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increase, creatinine increased, alkaline phosphatase increased, weight increase

Musculoskeletal: Arthralgia, arthrosis, bone disorder, fracture accidental, myalgia, neck stiffness, synovitis, tendinitis

Platelets (bleeding or clotting): Ecchymosis, epistaxis, thrombocythemia

Psychiatric: Anorexia, anxiety, appetite increased, depression, nervousness, somnolence

Hemic: Anemia

Respiratory: Bronchitis, bronchospasm, bronchospasm aggravated, coughing, dyspnea, laryngitis, pneumonia

Skin and appendages: Alopecia, dermatitis, nail disorder, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria

Application site disorders: Cellulitis, dermatitis contact, injection site reaction, skin nodule

Special senses: Taste perversion

Urinary system: Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus, urinary incontinence, urinary tract infection

Vision: Blurred vision, cataract, conjunctivitis, eye pain, glaucoma

Other serious adverse reactions which occur rarely (estimated <0.1%), regardless of causality: The following serious adverse events have occurred rarely in patients taking CELEBREX. Cases reported only in the post-marketing experience are indicated in italics.

Cardiovascular: Syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis, vasculitis

Gastrointestinal: Intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, ileus

Liver and biliary system: Cholelithiasis, hepatitis, jaundice, liver failure

Hemic and lymphatic: Thrombocytopenia, agranulocytosis, aplastic anemia, pancytopenia, leukopenia

Metabolic: Hypoglycemia, hyponatremia

Nervous system: Aseptic meningitis, ataxia, suicide, fatal intracranial hemorrhage (see

PRECAUTIONS - Drug Interactions – Warfarin)

Renal: Acute renal failure, interstitial nephritis

Skin: Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis

General: Sepsis, sudden death, anaphylactoid reaction, angioedema

During this study (see Special Studies – Use with Aspirin), the incidence of clinically significant decreases in hemoglobin (>2 g/dL) confirmed by repeat testing was lower in patients on CELEBREX 400 mg BID (4-fold and 2-fold the recommended OA and RA doses, respectively, and the approved dose for FAP) compared to patients on either diclofenac 75 mg BID or ibuprofen 800 mg TID: 0.5%, 1.3% and 1.9%, respectively. The lower incidence of events with CELEBREX was maintained with or without ASA use (see CLINICAL STUDIES – Special Studies – Platelets).

Withdrawals/Serious Adverse Events:

Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for CELEBREX, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e. those causing hospitalization or felt to be life threatening or otherwise medically significant) regardless of causality were not different across treatment groups, respectively, 8%, 7%, and 8%. Based on Kaplan-Meier cumulative rates for investigator-reported serious cardiovascular thromboembolic adverse events * , there were no differences between the CELEBREX, diclofenac, or ibuprofen treatment groups. The rates in all patients at 9 months for CELEBREX, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The rates for non-ASA users in each of the three treatment groups were less than 1%. The rates for myocardial infarction in each of the three non-ASA treatment groups were less than 0.2%.

Adverse events from analgesia and dysmenorrhea studies: Approximately 1,700 patients were treated with CELEBREX in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose of study medication. Doses up to 600 mg/day of CELEBREX were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only additional adverse event reported was post-dental extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies.

Adverse events from the controlled trial in familial adenomatous polyposis: The adverse event profile reported for the 83 patients with familial adenomatous polyposis enrolled in the randomized, controlled clinical trial was similar to that reported for patients in the arthritis controlled trials. Intestinal anastomotic ulceration was the only new adverse event reported in the FAP trial, regardless of causality, and was observed in 3 of 58 patients (one at 100 mg BID, and two at 400 mg BID) who had prior intestinal surgery.

No overdoses of CELEBREX were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious toxicity. Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

* includes myocardial infarction, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic attacks or ischemic cerebrovascular accidents.

Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. No information is available regarding the removal of celecoxib by hemodialysis, but based on its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

Osteoarthritis: For relief of the signs and symptoms of osteoarthritis the recommended oral dose is 200 mg per day administered as a single dose or as 100 mg twice per day.

Rheumatoid arthritis: For relief of the signs and symptoms of rheumatoid arthritis the recommended oral dose is 100 to 200 mg twice per day.

Management of Acute Pain and Treatment of Primary Dysmenorrhea: The recommended dose of CELEBREX is 400 mg initially, followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily as needed.

Familial adenomatous polyposis (FAP): Usual medical care for FAP patients should be continued while on CELEBREX. To reduce the number of adenomatous colorectal polyps in patients with FAP, the recommended oral dose is 400 mg twice per day to be taken with food.

Hepatic insufficiency: The daily recommended dose of CELEBREX capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by approximately 50% (see CLINICAL PHARMACOLOGY – Special Populations).

Store at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F) [see USP Controlled Room Temperature]