Celebrex Medicine Labels

The following is information on the labels from the medicine Celebrex.

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Application #(s): NDA 20-998/S-010

Document Type: Supplement Letter

Document Group: Approval Letters

Document Name: Approval letter based on enclosed/submitted labeling text

Letter Code: SNDA-I1

COMIS Decision: AP: APPROVAL

Drafted by: bjg/October 10, 2001

Revised by:

Initialed by: JSchiffenbauer/12-Oct-01 SChoi/11-Oct-01 StLin/12-Oct-01

Finalized: LGoldkind/

Filename: C:\MY DOCUMENTS\NDAs\SEARLE\N20998

CELECOXIB\MISCELLANEOUS\011010APS010.doc

DFS Key Words:

Notes:

Linking Instructions: If this is the first action on the application, link the outgoing letter to the initial submission, RS, AR, or FO coded incoming document for the supplement being acted on, as appropriate. Otherwise, the outgoing letter must be linked to the major amendment submitted in response to the previous action letter.

In addition, the outgoing document should also be linked to all associated amendments and correspondences included in the action.

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

Food and Drug Administration

Rockville MD 20857

NDA 20-998/S-010

G.D. Searle & Co.

Attention: Winifred M. Begley

Senior Director, Worldwide Regulatory Affairs

4901 Searle Parkway

Skokie, IL 60077

Dear Dr. Begley:

Please refer to your supplemental new drug application dated December 18, 2000, received December 19, 2000, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for CelebrexTM (celecoxib capsule) Capsules 100 mg, and 200 mg.

We acknowledge receipt of your submissions dated June 14, September 24, and October 03, 2001.

This supplemental new drug application provides for the use of CelebrexTM (celecoxib capsule) Capsules 100 mg, and 200 mg for the management of acute pain in adults and the treatment of primary dysmenorrhea.

We have completed the review of this supplemental application, as amended, and have concluded that adequate information has been presented to demonstrate that the drug product is safe and effective for use as recommended in the agreed upon enclosed labeling text. Accordingly, the supplemental application is approved effective on the date of this letter.

The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert).

Please submit the copies of final printed labeling (FPL) electronically according to the guidance for industry itled Providing Regulions in Electronic Format - N ssscDA (January 1999). Alternatively, you may submit 20 paper copies of the FPL as soon as it is available but no more than 30 days after it is printed. Please individually mount ten of the copies on heavy-weight paper or similar material. For administrative purposes, this submission should be designated "FPL for approved supplement NDA 20-998/S-010." Approval of this submission by FDA is not required before the labeling is used.

Be advised that, as of April 1, 1999, all applications for new active ingredients, new dosage forms, new indications, new routes of administration, and new dosing regimens are required to contain an assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is waived or deferred (63 FR 66632). We are waiving the pediatric study requirement for this action on this application.

In addition, please submit three copies of the introductory promotional materials that you propose to

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use for this product. All proposed materials should be submitted in draft or mock-up form, not final print. Please submit one copy to this Division and two copies of both the promotional materials and the package insert directly to:

Division of Drug Marketing, Advertising, and Communications, HFD-42

Food and Drug Administration

5600 Fishers Lane

Rockville, Maryland 20857

If a letter communicating important information about this drug product (i.e., a "Dear Health Care Professional" letter) is issued to physicians and others responsible for patient care, we request that you submit a copy of the letter to this NDA and a copy to the following address:

MEDWATCH, HF-2

FDA

5600 Fishers Lane

Rockville, MD 20857

Please submit one market package of the drug product when it is available.

We remind you that you must comply with the requirements for an approved NDA set forth under 21 CFR 314.80 and 314.81.

If you have any questions, call Barbara Gould, Project Manager, at (301) 827-2090.

Sincerely,

{See appended electronic signature page}

Larry Goldkind, M.D.

Deputy Division Director

Division of Anti-Inflammatory, Analgesic &

Ophthalmic Drug Products

Office of Drug Evaluation V

Center for Drug Evaluation and Research

Enclosure

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CELEBREX®
celecoxib capsules

CELEBREX (celecoxib) is chemically designated as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1Hpyrazol- 1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. It has the following chemical structure:

The empirical formula for celecoxib is C₁₇H₁₄F₃N₃O₂S, and the molecular weight is 381.38. CELEBREX oral capsules contain 100 mg and 200 mg of celecoxib.

The inactive ingredients in CELEBREX capsules include: croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone, sodium lauryl sulfate and titanium dioxide.

CLINICAL PHARMACOLOGY

Mechanism of Action: CELEBREX is a nonsteroidal anti-inflammatory drug that exhibits antiinflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of CELEBREX is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, CELEBREX does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. In animal colon tumor models, celecoxib reduced the incidence and multiplicity of tumors.

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Pharmacokinetics:

Peak plasma levels of celecoxib occur approximately 3 hrs after an oral dose. Under fasting conditions, both peak plasma levels (Cmax) and area under the curve (AUC) are roughly dose proportional up to 200 mg BID; at higher doses there are less than proportional increases in Cmax and AUC (see Food Effects). Absolute bioavailability studies have not been conducted. With multiple dosing, steady state conditions are reached on or before day 5. The pharmacokinetic parameters of celecoxib in a group of healthy subjects are shown in Table 1.

Food Effects

When CELEBREX capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media. Coadministration of CELEBREX with an aluminum- and magnesium-containing antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC. CELEBREX, at doses up to 200 mg BID can be administered without regard to timing of meals. Higher doses (400 mg BID) should be administered with food to improve absorption.

Distribution

In healthy subjects, celecoxib is highly protein bound (~97%) within the clinical dose range. In vitro studies indicate that celecoxib binds primarily to albumin and, to a lesser extent, a₁-acid glycoprotein. The apparent volume of distribution at steady state (V_ss/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

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Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t1/2) determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 mL/min.

Special Populations
Geriatric: At steady state, elderly subjects (over 65 years old) had a 40% higher Cmax and a 50% higher AUC compared to the young subjects. In elderly females, celecoxib Cmax and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Dose adjustment in the elderly is not generally necessary. However, for patients of less than 50 kg in body weight, initiate therapy at the lowest recommended dose.

Pediatric: CELEBREX capsules have not been investigated in pediatric patients below 18 years of age.

Race: Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in Blacks compared to Caucasians. The cause and clinical significance of this finding is unknown.

Hepatic Insufficiency: A pharmacokinetic study in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment has shown that steady-state celecoxib AUC is increased about 40% and 180%, respectively, above that seen in healthy control subjects. Therefore, the daily recommended dose of CELEBREX capsules should be reduced by approximately 50% in patients with moderate (Child-Pugh Class B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of CELEBREX in patients with severe hepatic impairment is not recommended.

Renal Insufficiency: In a cross-study comparison, celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 35-60 mL/min) than that seen in subjects with normal renal function. No significant relationship was found between GFR and celecoxib clearance. Patients with severe renal insufficiency have not been studied.

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Also see PRECAUTIONS - Drug Interactions.

General: Significant interactions may occur when celecoxib is administered together with drugs that inhibit P450 2C9. In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4.

Clinical studies with celecoxib have identified potentially significant interactions with fluconazole and lithium. Experience with nonsteroidal anti-inflammatory drugs (NSAIDs) suggests the potential for interactions with furosemide and ACE inhibitors. The effects of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, methotrexate, phenytoin, and tolbutamide have been studied in vivo and clinically important interactions have not been found.

CLINICAL STUDIES
Osteoarthritis (OA): CELEBREX has demonstrated significant reduction in joint pain compared to placebo. CELEBREX was evaluated for treatment of the signs and the symptoms of OA of the knee and hip in approximately 4,200 patients in placebo- and active-controlled clinical trials of up to 12 weeks duration. In patients with OA, treatment with CELEBREX 100 mg BID or 200 mg QD resulted in improvement in WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness, and functional measures in OA. In three 12-week studies of pain accompanying OA flare, CELEBREX doses of 100 mg BID and 200 mg BID provided significant reduction of pain within 24¡V48 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

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adenomatous colorectal polyps. A randomized double-blind placebo-controlled study was conducted in 83 patients with FAP. The study population included 58 patients with a prior subtotal or total colectomy and 25 patients with an intact colon. Thirteen patients had the attenuated FAP phenotype.

One area in the rectum and up to four areas in the colon were identified at baseline for specific followup, and polyps were counted at baseline and following six months of treatment. The mean reduction in the number of colorectal polyps was 28% for CELEBREX 400 mg BID, 12% for CELEBREX 100 mg BID and 5% for placebo. The reduction in polyps observed with CELEBREX 400 mg BID was statistically superior to placebo at the six-month timepoint (p=0.003). (See Figure 1.)

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Special Studies

Endoscopic Studies: Scheduled upper GI endoscopic evaluations were performed in over 4,500 arthritis patients who were enrolled in five controlled randomized 12-24 week trials using active comparators, two of which also included placebo controls. There was no consistent relationship between the incidence of gastroduodenal ulcers and the dose of CELEBREX over the range studied.

Figure 2 and Table 2 summarize the incidence of endoscopic ulcers in two 12-week studies that enrolled patients in whom baseline endoscopies revealed no ulcers.

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Figure 3 and Table 3 summarize 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.

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* p<0.05 Celebrex vs. naproxen based on interval and cumulative analyses

W p<0.05 Celebrex vs. ibuprofen based on interval and cumulative analyses

One randomized and double-blind 6-month study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months. The results are shown in Figure 4.

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The correlation between findings of endoscopic studies, and the relative incidence of clinically serious upper GR events that may be observed with different products, has not ben fully established. Serious clinically significant upper GI bleeding has been obsered in patients receiving CELEBREX in controlled and open-labeled trials, albeit infrequently (see WARNINGS-Gastrointenstinal [GI] Effects). Prospective, long-term studies required to compare the incidence of serious, clinically significant upper GI adverse events in parients taking CELEBREX vs. comparator NSAID products have not been performed.

Use with Aspirin: Approximately 11% of patients (440/4,000) enrolled in 4 of the 5 endoscopic studies were taking aspirin (< 325 mg/day). In the CELEBREX groups, the endoscopic ulcer rate appeared to be higher in aspirin users than in non-users. However, the increased rate of ulcers in these asourub ysers was less than the endoscopic ulcer rates observed in the active comparator groups, with or without aspirin.

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.

CELEBREX is indicated:

1. For relief of the signs and symptoms of osteoarthritis.
2. For relief of the signs and symptoms of rheumatoid arthritis in adults.
3. For the management of acute pain in adults (see CLINICAL STUDIES).
4. For the treatment of primary dysmenorrhea.
5. To reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis (FAP), as an adjunct to usual care (e.g., endoscopic surveillance, surgery). It is not known whether there is a clinical benefit from a reduction in the number of colorectal polyps in FAP patients. It is also not known whether the effects of CELEBREX treatment will persist after CELEBREX is discontinued. The efficacy and safety of CELEBREX treatment in patients with FAP beyond six months have not been studied (see CLINICAL STUDIES, WARNINGS and PRECAUTIONS sections).

CELEBREX is contraindicated in patients with known hypersensitivity to celecoxib.

CELEBREX should not be given to patients who have demonstrated allergic-type reactions to sulfonamides.

CELEBREX should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS - Anaphylactoid Reactions, and PRECAUTIONS - Preexisting Asthma).

Gastrointestinal (GI) Effects-Risk of GI Ulceration, Bleeding, and Perforation:

Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms (see PRECAUTIONS - Hematological Effects).

Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3¡V6 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) 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 14 and 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.

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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.

Anaphylactoid Reactions
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.

Advanced Renal Disease
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).

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

Familial Adenomatous Polyposis (FAP): Treatment with CELEBREX in FAP has not been shown to reduce the risk of gastrointestinal cancer or the need for prophylactic colectomy or other FAP-related surgeries. Therefore, the usual care of FAP patients should not be altered because of the concurrent administration of CELEBREX. In particular, the frequency of routine endoscopic surveillance should not be decreased and prophylactic colectomy or other FAP-related surgeries should not be delayed.

PRECAUTIONS

General: CELEBREX cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroidresponsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

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 conditions.

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 ¡V 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.

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 CELEBREX. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), CELEBREX 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 CELEBREX have shown renal effects similar to those observed with comparator NSAIDs.

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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 ¡V Special Studies - Platelets).

Fluid Retention and Edema: Fluid retention and edema have been observed in some patients taking CELEBREX (see ADVERSE REACTIONS). Therefore, 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 antiinflammatory 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, Rist 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 CELEBREX should be avoided because it may cause premature closure of the ductus arteriosus.

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Patients with familial adenomatous polyposis (FAP) should be informed that CELEBREX has not been shown to reduce colorectal, duodenal or other FAP-related cancers, or the need for endoscopic surveillance, prophylactic or other FAP-related surgery. Therefore, all patients with FAP should be instructed to continue their usual care while receiving CELEBREX.

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 the 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 this abnormality 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 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 - Gastrointestinal). Because of its lack of platelet effects, CELEBREX is not a substitute for aspirin for cardiovascular 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 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.

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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, bleeding events 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 AUC_0-24 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 AUC_0-24 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 AUC_0-24).

Teratogenic effects: Pregnancy Category C. Celecoxib at oral doses .150 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 > 30 mg/kg/day (approximately 6-fold human exposure based on the AUC_0-24 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 .50 mg/kg/day (approximately 6-fold human exposure based on the AUC_0-24 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 AUC_0-24 at 200 mg BID). The effects of CELEBREX on labor and delivery in pregnant women are unknown.

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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. 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.

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 CELEBREX in clinical trials, more than 2,100 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 effectiveness were observed between these subjects and younger subjects. Other reported clinical experiences had 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.

ADVERSE REACTIONS

Of the CELEBREX treated patients in controlled trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients have received a total daily dose of CELEBREX of 200 mg (100 mg BID or 200 mg QD) or more, including more than 400 treated at 800 mg (400 mg BID). Approximately 3,900 patients have received CELEBREX at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more.

Adverse events from CELEBREX premarketing controlled arthritis trials: Table 6 lists all adverse events, regardless of causality, occurring in .2% 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.

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In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving CELEBREX and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the CELEBREX treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of CELEBREX patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain.

The following adverse events occurred in 0.1 - 1.9% of patients regardless of causality.

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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.

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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.

In approximately 700 patients treated with CELEBREX in the post-general and orthopedic surgery pain studies, the most commonly reported adverse events were nausea, vomiting, headache, dizziness and fever.

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.

OVERDOSAGE

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.

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.

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DOSAGE AND ADMINISTRATION

For osteoarthritis and rheumatoid arthritis, the lowest dose of CELEBREX should be sought for each patient. These doses can be given without regard to timing of meals.

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.

Special Populations

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).

HOW SUPPLIED

CELEBREX 100-mg capsules are white, reverse printed white on blue band of body and cap with markings of 7767 on the cap and 100 on the body, supplied as:

CELEBREX 200-mg capsules are white, with reverse printed white on gold band with markings of 7767 on the cap and 200 on the body, supplied as:

Store at 25^OXC (77^OXF); excursions permitted to 15-30^OXC (59-86^OXF) [see USP Controlled Room Temperature]

Rx only Revised: 10/10/01

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Manufactured for:

by:

Searle Ltd. Caguas, PR 00725

©2001, G.D. Searle & Co. Printed in USA

Searle Pfizer
CELEBREX®
A05624-)

Weitz & Luxenberg is no longer accepting Celebrex cases.

see also:

Label: 12/23/1999 Celebrex Labeling Description December 23, 1999
Official FDA labeling description of Celebrex from December 23, 1999

Warfarin FAQ Celebrex Label Changes
Q&A summary of the Celebrex label changes - Read before you take

Labeling Celebrex Medication Labeling Information
Celebrex Medication Information on Past and Present Label Descriptions