Celecoxib by RxChange Co. CELECOXIB capsule

Celecoxib by

Drug Labeling and Warnings

Celecoxib by is a Prescription medication manufactured, distributed, or labeled by RxChange Co.. Drug facts, warnings, and ingredients follow.

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  • BOXED WARNING (What is this?)

    WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS

    Cardiovascular Thrombotic Events

    • Nonsteroidal anti-inflammatory drugs (NSAIDS) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see Warnings and Precautions ( 5.1).
    • Celecoxib is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see Contraindications, Warnings and Precautions( 4, 5.1)

    Gastrointestinal Risk

    • NSAIDs, including celecoxib, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. ( 5.4)
  • 1. INDICATIONS AND USAGE

    Carefully consider the potential benefits and risks of celecoxib and other treatment options before deciding to use celecoxib capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5)]

    1.1 Osteoarthritis (OA)

    Celecoxib capsules are indicated for relief of the signs and symptoms of OA [ see Clinical Studies (14.1)]

    1.2 Rheumatoid Arthritis (RA)

    Celecoxib capsules are indicated for relief of the signs and symptoms of RA [ see Clinical Studies (14.2)]

    1.3 Juvenile Rheumatoid Arthritis (JRA)

    Celecoxib capsules are indicated for relief of the signs and symptoms of JRA in patients 2 years and older [ see Clinical Studies (14.3)]

    1.4 Ankylosing Spondylitis (AS)

    Celecoxib capsules are indicated for the relief of signs and symptoms of AS [ see Clinical Studies (14.4)]

    1.5 Acute Pain (AP)

    Celecoxib capsules are indicated for the management of AP in adults [ see Clinical Studies (14.5)]

    1.6 Primary Dysmenorrhea (PD)

    Celecoxib capsules are indicated for the treatment of PD [ see Clinical Studies (14.5)]

  • 2. DOSAGE AND ADMINISTRATION

    Use lowest effective dose for the shortest duration consistent with treatment goals for the individual patient.

    These doses can be given without regard to timing of meals.

    2.1 Osteoarthritis

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

    2.2 Rheumatoid Arthritis

    For relief of the signs and symptoms of RA the recommended oral dose is 100 to 200 mg twice daily.

    2.3 Juvenile Rheumatoid Arthritis

    For the relief of the signs and symptoms of JRA the recommended oral dose for pediatric patients (age 2 years and older) is based on weight. For patients ≥10 kg to ≤25 kg the recommended dose is 50 mg twice daily. For patients >25 kg the recommended dose is 100 mg twice daily.

    For patients who have difficulty swallowing capsules, the contents of a celecoxib capsule can be added to applesauce. The entire capsule contents are carefully emptied onto a level teaspoon of cool or room temperature applesauce and ingested immediately with water. The sprinkled capsule contents on applesauce are stable for up to 6 hours under refrigerated conditions (2 to 8° C/ 35 to 45° F).

    2.4 Ankylosing Spondylitis

    For the management of the signs and symptoms of AS, the recommended dose of celecoxib capsules is 200 mg daily in single (once per day) or divided (twice per day) doses. If no effect is observed after 6 weeks, a trial of 400 mg daily may be worthwhile. If no effect is observed after 6 weeks on 400 mg daily, a response is not likely and consideration should be given to alternate treatment options.

    2.5 Management of Acute Pain and Treatment of Primary Dysmenorrhea

    The recommended dose of celecoxib capsules 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.

    2.6 Special Populations

    Hepatic insufficiency: The daily recommended dose of celecoxib capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. The use of celecoxib capsules in patients with severe hepatic impairment is not recommended [ see Warnings and Precautions (5.5), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

    Poor Metabolizers of CYP2C9 Substrates: Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) should be administered celecoxib with caution. Consider starting treatment at half the lowest recommended dose in poor metabolizers (i.e. CYP2C9*3/*3). Consider using alternative management in JRA patients who are poor metabolizers. [ see Use in Specific populations (8.8), and Clinical Pharmacology (12.5)] .

  • 3. DOSAGE FORMS AND STRENGTHS

    Capsules: 50 mg, 100 mg and 200 mg

  • 4. CONTRAINDICATIONS

    Celecoxib capsules are contraindicated:

    • In patients with known hypersensitivity to celecoxib, aspirin, or other NSAIDs.
    • In patients who have demonstrated allergic-type reactions to sulfonamides.
    • In patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe anaphylactoid reactions to NSAIDs, some of them fatal, have been reported in such patients [ see Warnings and Precautions (5.7, 5.13)].
    • For the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions (5.1)].
  • 5. WARNINGS AND PRECAUTIONS

    5.1 Cardiovascular Thrombotic Events

    Clinical trials of several COX-2 selective and nonselective NSAIDS of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses [ see Clinical Studies (14.6)].

    To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as celecoxib increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions ( 5.4) ].

    Status Post Coronary Artery Bypass Graft (CABG) Surgery

    Two large, controlled, clinical trials of a different COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see  Contraindications ( 4) ].

    Post-MI Patients

    Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

    Avoid the use of celecoxib in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If celecoxib is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

    5.2 Hypertension

    As with all NSAIDs, celecoxib can lead to the onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including celecoxib, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with celecoxib and throughout the course of therapy. The rates of hypertension from the CLASS trial in the celecoxib, ibuprofen and diclofenac-treated patients were 2.4%, 4.2% and 2.5%, respectively [ see Clinical Studies (14.6)].

    5.3 Congestive Heart Failure and Edema

    The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

    Additionally, fluid retention and edema have been observed in some patients treated NSAIDs. Use of [active moiety] may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor clockers (ARBs)] (see Drug Interactions). Avoid the use of celecoxib in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If celecoxib is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

    5.4 Gastrointestinal (GI) Effects

    Risk of GI Ulceration, Bleeding, and Perforation

    NSAIDs, including celecoxib, can cause serious gastrointestinal events including bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA. Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA [ see Clinical Studies (14.6)]. With longer duration of use of NSAIDs, there is a trend for increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.

    NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. 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 duration consistent with individual patient treatment goals. Physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during celecoxib therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

    5.5 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 celecoxib [ see Adverse Reactions (6.1)]. In controlled clinical trials of celecoxib, 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 celecoxib and 5% for placebo, and approximately 0.2% of patients taking celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST.

    A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with celecoxib. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), celecoxib should be discontinued.

    5.6 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, liver dysfunction, those taking diuretics, ACE-inhibitors, angiotensin II receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical trials with celecoxib have shown renal effects similar to those observed with comparator NSAIDs.

    No information is available from controlled clinical studies regarding the use of celecoxib in patients with advanced renal disease. Therefore, treatment with celecoxib is not recommended in these patients with advanced renal disease. If celecoxib therapy must be initiated, close monitoring of the patient's renal function is advisable.

    5.7 Anaphylactoid Reactions

    As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to celecoxib. In post-marketing experience, rare cases of anaphylactic reactions and angioedema have been reported in patients receiving celecoxib. Celecoxib should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [ see Contraindications (4), Warnings and Precautions (5.7)]. Emergency help should be sought in cases where an anaphylactoid reaction occurs.

    5.8 Skin Reactions

    Celecoxib is a sulfonamide and can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events can occur without warning and in patients without prior known sulfa allergy. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

    5.9 Pregnancy

    In late pregnancy, starting at 30 weeks gestation, celecoxib should be avoided because it may cause premature closure of the ductus arteriosus [ see Use in Specific Populations (8.1)].

    5.10 Corticosteroid Treatment

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

    5.11 Hematological Effects

    Anemia is sometimes seen in patients receiving celecoxib. In controlled clinical trials the incidence of anemia was 0.6% with celecoxib and 0.4% with placebo. Patients on long-term treatment with celecoxib should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. Celecoxib does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not inhibit platelet aggregation at indicated dosages [ see Clinical Pharmacology (12.2)].

    5.12 Disseminated Intravascular Coagulation (DIC)

    Celecoxib should be used only with caution in pediatric patients with systemic onset JRA due to the risk of disseminated intravascular coagulation.

    5.13 Preexisting Asthma

    Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, celecoxib should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

    5.14 Laboratory Tests

    Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have a CBC and a chemistry profile checked periodically. If abnormal liver tests or renal tests persist or worsen, celecoxib should be discontinued.

    In controlled clinical trials, elevated BUN occurred more frequently in patients receiving celecoxib 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.

    5.15 Inflammation

    The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions.

    5.16 Concomitant NSAID Use

    The concomitant use of celecoxib with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.

  • 6. ADVERSE REACTIONS

    Of the celecoxib-treated patients in the pre-marketing controlled clinical 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 received a total daily dose of celecoxib of 200 mg (100 mg twice daily or 200 mg once daily) or more, including more than 400 treated at 800 mg (400 mg twice daily). Approximately 3,900 patients received celecoxib 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.

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

    6.1 Pre-marketing Controlled Arthritis Trials

    Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving celecoxib from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence.

    Table 1: Adverse Events Occurring in ≥2% of Celecoxib Patients from Pre-marketing Controlled Arthritis Trials
    CXB
    N=4146     		Placebo
    N=1864     		NAP
    N=1366     		DCF
    N=387     		IBU
    N=345
    CXB = celecoxib 100 to 200 mg twice daily or 200 mg once daily;
    NAP = Naproxen 500 mg twice daily;
    DCF = Diclofenac 75 mg twice daily;
    IBU = Ibuprofen 800 mg three times daily.
    Gastrointestinal
      Abdominal Pain4.1%2.8%7.7%9.0%9.0%
      Diarrhea5.6%3.8%5.3%9.3%5.8%
      Dyspepsia8.8%6.2%12.2%10.9%12.8%
      Flatulence2.2%1.0%3.6%4.1%3.5%
      Nausea3.5%4.2%6.0%3.4%6.7%
    Body as a whole
      Back Pain2.8%3.6%2.2%2.6%0.9%
      Peripheral Edema2.1%1.1%2.1%1.0%3.5%
      Injury-Accidental2.9%2.3%3.0%2.6%3.2%
    Central, Peripheral Nervous system
      Dizziness2.0%1.7%2.6%1.3%2.3%
      Headache15.8%20.2%14.5%15.5%15.4%
    Psychiatric
      Insomnia2.3%2.3%2.9%1.3%1.4%
    Respiratory
      Pharyngitis2.3%1.1%1.7%1.6%2.6%
      Rhinitis2.0%1.3%2.4%2.3%0.6%
      Sinusitis5.0%4.3%4.0%5.4%5.8%
      Upper Respiratory Infection8.1%6.7%9.9%9.8%9.9%
    Skin
      Rash2.2%2.1%2.1%1.3%1.2%

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

    The following adverse reactions occurred in 0.1 to 1.9% of patients treated with celecoxib (100 to 200 mg twice daily or 200 mg once daily):

    Gastrointestinal:Constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, vomiting
    Cardiovascular:Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction
    General:Allergy aggravated, allergic reaction, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain
    Central, peripheral nervous system:Leg cramps, hypertonia, hypoesthesia, migraine, paresthesia, vertigo
    Hearing and vestibular:Deafness, tinnitus
    Heart rate and rhythm:Palpitation, tachycardia
    Liver and biliary:Hepatic function abnormal, SGOT increased, SGPT increased
    Metabolic and nutritional:BUN increased, CPK increased, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increased, creatinine increased, alkaline phosphatase increased, weight increased
    Musculoskeletal:Arthralgia, arthrosis, myalgia, 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, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria
    Application site disorders:Cellulitis, dermatitis contact
    Urinary:Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus

    The following serious adverse events (causality not evaluated) occurred in <0.1% of patients (cases reported only in post-marketing experience are indicated in italics):

    Cardiovascular:Syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis, vasculitis, deep venous thrombosis
    Gastrointestinal:Intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, ileus
    Liver and biliary:Cholelithiasis, hepatitis, jaundice, liver failure
    Hemic and lymphatic:Thrombocytopenia, agranulocytosis, aplastic anemia, pancytopenia, leucopenia
    Metabolic:Hypoglycemia, hyponatremia
    Nervous:Ataxia, suicide, aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage [see Drug Interactions (7.1)]
    Renal:Acute renal failure, interstitial nephritis
    Skin:Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis
    General:Sepsis, sudden death, anaphylactoid reaction, angioedema

    6.2 The Celecoxib Long-Term Arthritis Safety Study

    [see Special Studies (14.6)]

    Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on celecoxib 400 mg twice daily (0.5%) compared to patients on either diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower incidence of events with celecoxib was maintained with or without ASA use [ see Clinical Pharmacology (12.2)].

    Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for celecoxib, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., causing hospitalization or felt to be life-threatening or otherwise medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and 8%, respectively).

    6.3 Juvenile Rheumatoid Arthritis Study

    In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were treated with celecoxib or naproxen; 77 JRA patients were treated with celecoxib 3 mg/kg BID, 82 patients were treated with celecoxib 6 mg/kg BID, and 83 patients were treated with naproxen 7.5 mg/kg BID. The most commonly occurring (≥5%) adverse events in celecoxib treated patients were headache, fever (pyrexia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea and vomiting. The most commonly occurring (≥5%) adverse experiences for naproxen-treated patients were headache, nausea, vomiting, fever, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 2). Compared with naproxen, celecoxib at doses of 3 and 6 mg/kg BID had no observable deleterious effect on growth and development during the course of the 12-week double-blind study. There was no substantial difference in the number of clinical exacerbations of uveitis or systemic features of JRA among treatment groups.

    In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were treated with celecoxib 6 mg/kg BID. The incidence of adverse events was similar to that observed during the double-blind study; no unexpected adverse events of clinical importance emerged.

    Table 2: Adverse Events Occurring in ≥5% of JRA Patients in Any Treatment Group, by System Organ Class (% of patients with events)
    All Doses Twice Daily
    System Organ Class
      Preferred Term     		Celecoxib
    3 mg/kg
    N=77     		Celecoxib
    6 mg/kg
    N=82     		Naproxen
    7.5 mg/kg
    N=83
  • * Abnormal laboratory tests, which include: Prolonged activated partial thromboplastin time, Bacteriuria NOS present, Blood creatine phosphokinase increased, Blood culture positive, Blood glucose increased, Blood pressure increased, Blood uric acid increased, Hematocrit decreased, Hematuria present, Hemoglobin decreased, Liver function tests NOS abnormal, Proteinuria present, Transaminase NOS increased, Urine analysis abnormal NOS
    		•
    Any Event647072
    Eye Disorders555
    Gastrointestinal262436
      Abdominal pain NOS477
      Abdominal pain upper8610
      Vomiting NOS3611
      Diarrhea NOS548
      Nausea7411
    General131118
      Pyrexia8911
    Infections 252027
      Nasopharyngitis565
    Injury and Poisoning 465
    Investigations *3117
    Musculoskeletal 81017
      Arthralgia374
    Nervous System171121
      Headache NOS131016
      Dizziness (excl vertigo) 117
    Respiratory81515
      Cough778
    Skin & Subcutaneous10718

    6.4 Other Pre-Approval Studies

    Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with celecoxib in placebo- and active-controlled AS studies. Doses up to 400 mg once daily were studied. The types of adverse events reported in the AS studies were similar to those reported in the OA/RAstudies.

    Adverse Events from Analgesia and Dysmenorrhea Studies: Approximately 1,700 patients were treated with celecoxib 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 celecoxib 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.

    6.5 The APC and PreSAP Trials

    Adverse reactions from long-term, placebo-controlled polyp prevention studies: Exposure to celecoxib in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years [ see Special Studies Adenomatous Polyp Prevention Studies (14.6)].

    Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing trials (treatment durations up to 12 weeks; see Adverse events from celecoxib pre-marketing controlled arthritis trials, above). The adverse reactions for which these differences in patients treated with celecoxib were greater as compared to the arthritis pre-marketing trials were as follows:

    Celecoxib
    (400 to 800 mg daily)
    N = 2285     		Placebo
    N=1303
    Diarrhea10.5%7.0%
    Gastroesophageal reflux disease4.7%3.1%
    Nausea6.8%5.3%
    Vomiting3.2%2.1%
    Dyspnea2.8%1.6%
    Hypertension12.5%9.8%

    The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking celecoxib, at an incidence greater than placebo in the long-term polyp prevention studies, and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in the long-term, placebo-controlled polyp prevention studies:

    Nervous system disorders:Cerebral infarction
    Eye disorders:Vitreous floaters, conjunctival hemorrhage
    Ear and labyrinth:Labyrinthitis
    Cardiac disorders:Angina unstable, aortic valve incompetence, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy
    Vascular disorders:Deep vein thrombosis
    Reproductive system and breast disorders:Ovarian cyst
    Investigations:Blood potassium increased, blood sodium increased, blood testosterone decreased
    Injury, poisoning and procedural complications:Epicondylitis, tendon rupture
  • 7. DRUG INTERACTIONS

    General: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 should be done with caution. Significant interactions may occur when celecoxib is administered together with drugs that inhibit CYP2C9.

    In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6.

    7.1 Warfarin

    Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing celecoxib 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 2 to 5 mg doses 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 celecoxib concurrently with warfarin.

    7.2 Lithium

    In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with celecoxib 200 mg twice daily as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn.

    7.3 Aspirin

    Celecoxib can be used with low-dose aspirin. However, concomitant administration of aspirin with celecoxib increases the rate of GI ulceration or other complications, compared to use of celecoxib alone [ see Warnings and Precautions (5.1, 5.4) and Clinical Studies (14.6)]. Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis [ see Clinical Pharmacology (12.2)].

    7.4 ACE-Inhibitors and Angiotensin II Antagonists

    Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors and angiotensin II antagonists. This interaction should be given consideration in patients taking celecoxib capsules concomitantly with ACE-inhibitors and angiotensin II antagonists [ see Clinical Pharmacology (12.2].

    7.5 Fluconazole

    Concomitant administration of fluconazole at 200 mg once daily 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 Clinical Pharmacology (12.3)]. Celecoxib should be introduced at the lowest recommended dose in patients receiving fluconazole.

    7.6 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.

    7.7 Methotrexate

    In an interaction study of rheumatoid arthritis patients taking methotrexate, celecoxib did not have an effect on the pharmacokinetics of methotrexate [ see Clinical Pharmacology (12.3)].

    7.8 Concomitant NSAID Use

    The concomitant use of celecoxib with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.

  • 8. USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category C. Pregnancy category D from 30 weeks of gestation onward.

    Teratogenic effects: Celecoxib at oral doses ≥150 mg/kg/day (approximately 2-fold human exposure at 200 mg twice daily as measured by AUC 0–24), 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 twice daily) throughout organogenesis. There are no studies in pregnant women. Celecoxib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Nonteratogenic effects: Celecoxib produced pre implantation and post-implantation losses and reduced embryo/fetal survival in rats at oral dosages ≥50 mg/kg/day (approximately 6-fold human exposure based on the AUC 0–24 at 200 mg twice daily). These changes are expected with inhibition of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function, nor are they expected at clinical exposures. No studies have been conducted to evaluate the effect of celecoxib on the closure of the ductus arteriosus in humans. Therefore, use of celecoxib during the third trimester of pregnancy should be avoided.

    8.2 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 celecoxib on labor and delivery in pregnant women are unknown.

    8.3 Nursing Mothers

    Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of celecoxib in breast milk. The calculated average daily infant dose was 10 to 40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants 17 and 22 months of age did not show any adverse events. Caution should be exercised when celecoxib is administered to a nursing woman.

    8.4 Pediatric Use

    Celecoxib is approved for relief of the signs and symptoms of Juvenile Rheumatoid Arthritis in patients 2 years and older. Safety and efficacy have not been studied beyond six months in children. The long-term cardiovascular toxicity in children exposed to celecoxib has not been evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to celecoxib or other COX-2 selective and non-selective NSAIDs [ (see Boxed Warning, Warnings and Precautions (5.12), and Clinical Studies (14.3)].

    The use of celecoxib in patients 2 years to 17 years of age with pauciarticular, polyarticular course JRA or in patients with systemic onset JRA was studied in a 12-week, double-blind, active controlled, pharmacokinetic, safety and efficacy study, with a 12-week open-label extension. Celecoxib has not been studied in patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), and in patients with active systemic features. Patients with systemic onset JRA (without active systemic features) appear to be at risk for the development of abnormal coagulation laboratory tests. In some patients with systemic onset JRA, both celecoxib and naproxen were associated with mild prolongation of activated partial thromboplastin time (APTT) but not prothrombin time (PT). NSAIDs including celecoxib should be used only with caution in patients with systemic onset JRA, due to the risk of disseminated intravascular coagulation. Patients with systemic onset JRA should be monitored for the development of abnormal coagulation tests [see Dosage and Administration (2.3), Warnings and Precautions (5.12), Adverse Reactions (6.3), Animal Toxicology (13.2), Clinical Studies (14.3)].

    Alternative therapies for treatment of JRA should be considered in pediatric patients identified to be CYP2C9 poor metabolizers [see Poor Metabolizers of CYP2C9 substrates (8.8)].

    8.5 Geriatric Use

    Of the total number of patients who received celecoxib in pre-approval clinical trials, more than 3,300 were 65 to 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 and Precautions (5.4, 5.6) ].

    8.6 Hepatic Insufficiency

    The daily recommended dose of celecoxib capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. The use of celecoxib capsules in patients with severe hepatic impairment is not recommended [ see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

    8.7 Renal Insufficiency

    Celecoxib is not recommended in patients with severe renal insufficiency [ see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

    8.8 Poor Metabolizers of CYP2C9 Substrates

    Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) should be administered celecoxib with caution. Consider starting treatment at half the lowest recommended dose in poor metabolizers (i.e., CYP2C9*3/*3). Alternative management should be considered in JRA patients identified to be CYP2C9 poor metabolizers. [ see Dosage and Administration (2.6) and Clinical Pharmacology (12.5)].

  • 10. OVERDOSAGE

    No overdoses of celecoxib 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.

    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.

  • 11. DESCRIPTION

    Celecoxib is chemically designated as 4-[5-(4-methylphenyl)- 3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. The empirical formula is C 17H 14F 3N 3O 2S, and the molecular weight is 381.38; the chemical structure is as follows:

    Chemical Structure

    Celecoxib capsules for oral administration contain either 50 mg, 100 mg, or 200 mg of celecoxib, together with inactive ingredients including: crospovidone, sodium lauryl sulphate, povidone, magnesium stearate.  The capsule shell contains gelatin and titanium dioxide.  The capsule imprinting ink for the 50 mg strength contains shellac, ethyl alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, sodium hydroxide, titanium dioxide, povidone and FD&C Red #40 Aluminum Lake.  The capsule imprinting ink for the 100 mg strength contains shellac, ethyl alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, and FD&C Blue #2 Aluminum Lake.  The capsule imprinting ink for the 200 mg strength contains shellac, ethyl alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, iron oxide yellow, and dimethicone.

  • 12. CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

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

    12.2 Pharmacodynamics

    Platelets: In clinical trials using normal volunteers, celecoxib at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration (higher than recommended therapeutic doses) had no effect on reduction of platelet aggregation or increase in bleeding time. Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of celecoxib on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of celecoxib.

    Fluid Retention: Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone.

    12.3 Pharmacokinetics

    Absorption: Peak plasma levels of celecoxib occur approximately 3 hrs after an oral dose. Under fasting conditions, both peak plasma levels (C max) 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 C max 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 3.

    Table 3 Summary of Single Dose (200 mg) Disposition Kinetics of Celecoxib in Healthy Subjects *
    Mean (%CV) PK Parameter Values
    C max, ng/mL T max, hr Effective t 1/2, hr V ss/F, L CL/F, L/hr
  • * Subjects under fasting conditions (n=36, 19–52 yrs.)
    		•
    705 (38)2.8 (37)11.2 (31)429 (34)27.7 (28)

    Food Effects: When celecoxib capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in C max and AUC, which is thought to be due to the low solubility of the drug in aqueous media.

    Coadministration of celecoxib with an aluminum- and magnesium-containing antacids resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in C max and 10% in AUC. Celecoxib, at doses up to 200 mg twice daily, can be administered without regard to timing of meals. Higher doses (400 mg twice daily) should be administered with food to improve absorption.

    In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in Cmax, Tmax or t 1/2 after administration of capsule contents on applesauce [ see Dosage and Administration (2)].

    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, α 1-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 CYP2C9. 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.

    Excretion: Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t 1/2) 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 C max and a 50% higher AUC compared to the young subjects. In elderly females, celecoxib C max 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 [ see Dosage and Administration (2.6) and Use in Specific Populations (8.5)].

    Pediatric: The steady state pharmacokinetics of celecoxib administered as an investigational oral suspension was evaluated in 152 JRA patients 2 years to 17 years of age weighing ≥10 kg with pauciarticular or polyarticular course JRA and in patients with systemic onset JRA. Population pharmacokinetic analysis indicated that the oral clearance (unadjusted for body weight) of celecoxib increases less than proportionally to increasing weight, with 10 kg and 25 kg patients predicted to have 40% and 24% lower clearance, respectively, compared with a 70 kg adult RA patient.

    Twice-daily administration of 50 mg capsules to JRA patients weighing ≥12 to ≤25 kg and 100 mg capsules to JRA patients weighing >25 kg should achieve plasma concentrations similar to those observed in a clinical trial that demonstrated the non-inferiority of celecoxib to naproxen 7.5 mg/kg twice daily ( see Dosage and Administration (2.3). Celecoxib has not been studied in JRA patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), or beyond 24 weeks.

    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 celecoxib 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 celecoxib in patients with severe hepatic impairment is not recommended [ see Dosage and Administration (2.6) and Use in Specific Populations (8.6)].

    Renal Insufficiency: In a cross-study comparison, celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 35 to 60 mL/min) than that seen in subjects with normal renal function. No significant relationship was found between GFR and celecoxib clearance. Patients with severe renal insufficiency have not been studied. Similar to other NSAIDs, celecoxib is not recommended in patients with severe renal insufficiency [ see Warnings and Precautions (5.6)].

    Drug interactions:

    In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4.

    In vivo studies have shown the following:

    Lithium: In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with celecoxib 200 mg twice daily as compared to subjects receiving lithium alone [ see Drug Interactions (7.2)].

    Fluconazole: Concomitant administration of fluconazole at 200 mg once daily 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 Drug Interactions (7.5)].

    Other Drugs:The effects of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, methotrexate [ see Drug Interactions (7.7)], phenytoin, and tolbutamide have been studied in vivo and clinically important interactions have not been found.

    12.5 Pharmacogenomics

    CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from 4 published reports that included a total of 8 subjects with the homozygous CYP2C9*3/*3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to subjects with CYP2C9*1/*1 or *I/*3 genotypes. The pharmacokinetics of celecoxib have not been evaluated in subjects with other CYP2C9 polymorphisms, such as *2, *5, *6, *9 and *11. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3% to 1.0% in various ethnic groups [ see Dosage and Administration (2.6), Use in Specific Populations (8.8)].

  • 13. NONCLINICAL TOXICOLOGY

    13.1 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 twice daily) 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 twice daily) 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 twice daily based on the AUC 0–24).

    13.2 Animal Toxicology

    An increase in the incidence of background findings of spermatocele with or without secondary changes such as epididymal hypospermia as well as minimal to slight dilation of the seminiferous tubules was seen in the juvenile rat. These reproductive findings while apparently treatment-related did not increase in incidence or severity with dose and may indicate an exacerbation of a spontaneous condition. Similar reproductive findings were not observed in studies of juvenile or adult dogs or in adult rats treated with celecoxib. The clinical significance of this observation is unknown.

  • 14. CLINICAL STUDIES

    14.1 Osteoarthritis

    Celecoxib has demonstrated significant reduction in joint pain compared to placebo. Celecoxib was evaluated for treatment of the signs and the symptoms of OA of the knee and hip in placebo- and active-controlled clinical trials of up to 12 weeks duration. In patients with OA, treatment with celecoxib 100 mg twice daily or 200 mg once daily 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, celecoxib doses of 100 mg twice daily and 200 mg twice daily provided significant reduction of pain within 24 to 48 hours of initiation of dosing. At doses of 100 mg twice daily or 200 mg twice daily the effectiveness of celecoxib was shown to be similar to that of naproxen 500 mg twice daily. Doses of 200 mg twice daily provided no additional benefit above that seen with 100 mg twice daily. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100 mg twice daily or 200 mg once daily.

    14.2 Rheumatoid Arthritis

    Celecoxib has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. Celecoxib was evaluated for treatment of the signs and symptoms of RA in placebo- and active-controlled clinical trials of up to 24 weeks in duration. Celecoxib 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. Celecoxib doses of 100 mg twice daily and 200 mg twice daily were similar in effectiveness and both were comparable to naproxen 500 mg twice daily.

    Although celecoxib 100 mg twice daily and 200 mg twice daily provided similar overall effectiveness, some patients derived additional benefit from the 200 mg twice daily dose. Doses of 400 mg twice daily provided no additional benefit above that seen with 100 to 200 mg twice daily.

    14.3 Juvenile Rheumatoid Arthritis

    In a 12-week, randomized, double-blind active-controlled, parallel-group, multicenter, non-inferiority study, patients from 2 years to 17 years of age with pauciarticular, polyarticular course JRA or systemic onset JRA (with currently inactive systemic features), received one of the following treatments: celecoxib 3 mg/kg (to a maximum of 150 mg) twice daily; celecoxib 6 mg/kg (to a maximum of 300 mg) twice daily; or naproxen 7.5 mg/kg (to a maximum of 500 mg) twice daily. The response rates were based upon the JRA Definition of Improvement greater than or equal to 30% (JRA DOI 30) criterion, which is a composite of clinical, laboratory, and functional measures of JRA. The JRA DOI 30 response rates at week 12 were 69%, 80% and 67% in the celecoxib 3 mg/kg BID, celecoxib 6 mg/kg BID, and naproxen 7.5 mg/kg BID treatment groups, respectively.

    The efficacy and safety of celecoxib for JRA have not been studied beyond six months. The long-term cardiovascular toxicity in children exposed to celecoxib has not been evaluated and it is unknown if the long-term risk may be similar to that seen in adults exposed to celecoxib or other COX-2 selective and non-selective NSAIDs [( see Boxed Warning, Warnings and Precautions (5.12)].

    14.4 Ankylosing Spondylitis

    Celecoxib was evaluated in AS patients in two placebo- and active-controlled clinical trials of 6 and 12 weeks duration. Celecoxib at doses of 100 mg twice daily, 200 mg once daily and 400 mg once daily was shown to be statistically superior to placebo in these studies for all three co-primary efficacy measures assessing global pain intensity (Visual Analogue Scale), global disease activity (Visual Analogue Scale) and functional impairment (Bath Ankylosing Spondylitis Functional Index). In the 12-week study, there was no difference in the extent of improvement between the 200 mg and 400 mg celecoxib doses in a comparison of mean change from baseline, but there was a greater percentage of patients who responded to celecoxib 400 mg, 53%, than to celecoxib 200 mg, 44%, using the Assessment in Ankylosing Spondylitis response criteria (ASAS 20). The ASAS 20 defines a responder as improvement from baseline of at least 20% and an absolute improvement of at least 10 mm, on a 0 to 100 mm scale, in at least three of the four following domains: patient global pain, Bath Ankylosing Spondylitis Functional Index, and inflammation. The responder analysis also demonstrated no change in the responder rates beyond 6 weeks.

    14.5 Analgesia, Including Primary Dysmenorrhea

    In acute analgesic models of post-oral surgery pain, post-orthopedic surgical pain, and primary dysmenorrhea, celecoxib relieved pain that was rated by patients as moderate to severe. Single doses [ see Dosage and Administration (2.5)] of celecoxib provided pain relief within 60 minutes.

    14.6 Special Studies

    Adenomatous Polyp Prevention Studies:

    Cardiovascular safety was evaluated in two randomized, double-blind, placebo-controlled, three year studies involving patients with Sporadic Adenomatous Polyps treated with celecoxib: the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint (adjudicated):

    • In the APC trial, the hazard ratios compared to placebo for a composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4 – 8.5) with celecoxib 400 mg twice daily and 2.8 (95% CI 1.1 – 7.2) with celecoxib 200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction.
    • In the PreSAP trial, the hazard ratio for this same composite endpoint (adjudicated) was 1.2 (95% CI 0.6 – 2.4) with celecoxib 400 mg once daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects), respectively.

    Clinical trials of other COX-2 selective and non-selective NSAIDs of up to three-years duration have shown an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. As a result, all NSAIDs are considered potentially associated with this risk.

    Celecoxib Long-Term Arthritis Safety Study (CLASS):

    This was a prospective, long-term, safety outcome study conducted post-marketing in approximately 5,800 OA patients and 2,200 RA patients. Patients received celecoxib 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily (common therapeutic doses). Median exposures for celecoxib (n = 3,987) and diclofenac (n = 1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. 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: celecoxib, n = 882; diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of complicated ulcers between celecoxib and the combined group of ibuprofen and diclofenac were not statistically significant.

    Patients on celecoxib and concomitant low-dose ASA (N=882) experienced 4-fold higher rates of complicated ulcers compared to those not on ASA (N=3105). The Kaplan-Meier rate for complicated ulcers at 9 months was 1.12% versus 0.32% for those on low-dose ASA and those not on ASA, respectively [ see Warnings and Precautions (5.4)].

    The estimated cumulative rates at 9 months of complicated and symptomatic ulcers for patients treated with celecoxib 400 mg twice daily are described in Table 4. Table 4 also displays results for patients less than or greater than 65 years of age. The difference in rates between celecoxib alone and celecoxib with ASA groups may be due to the higher risk for GI events in ASA users.

    Table 4: Complicated and Symptomatic Ulcer Rates in Patients Taking Celecoxib 400 mg Twice Daily (Kaplan-Meier Rates at 9 months [%]) Based on Risk Factors
    All Patients
      celecoxib alone (n=3105)0.78
      celecoxib with ASA (n=882)2.19
    Patients <65 Years
      celecoxib alone (n=2025)0.47
      celecoxib with ASA (n=403)1.26
    Patients ≥65 Years
      celecoxib alone (n=1080)1.40
      celecoxib with ASA (n=479)3.06

    In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer rates in patients taking celecoxib alone or celecoxib 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 and Precautions (5.4) and Adverse Reactions (6.1)].

    Cardiovascular safety outcomes were also evaluated in the CLASS trial. Kaplan-Meier cumulative rates for investigator-reported serious cardiovascular thromboembolic adverse events (including MI, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic attacks, and ischemic cerebrovascular accidents) demonstrated no differences between the celecoxib, diclofenac, or ibuprofen treatment groups. The cumulative rates in all patients at nine months for celecoxib, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The cumulative rates in non-ASA users at nine months in each of the three treatment groups were less than 1%. The cumulative rates for myocardial infarction in non-ASA users at nine months in each of the three treatment groups were less than 0.2%. There was no placebo group in the CLASS trial, which limits the ability to determine whether the three drugs tested had no increased risk of CV events or if they all increased the risk to a similar degree.

    Endoscopic Studies: The correlation between findings of short-term endoscopic studies with celecoxib and the relative incidence of clinically significant serious upper GI events with long-term use has not been established. Serious clinically significant upper GI bleeding has been observed in patients receiving celecoxib in controlled and open-labeled trials [ see Warnings and Precautions (5.4) and Clinical Studies (14.6)]

    A randomized, double-blind study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months. The incidence of endoscopic ulcers in patients taking celecoxib 200 mg twice daily was 4% vs. 15% for patients taking diclofenac SR 75 mg twice daily. However, celecoxib was not statistically different than diclofenac for clinically relevant GI outcomes in the CLASS trial [ see Clinical Studies (14.6)].

    The incidence of endoscopic ulcers was studied in two 12-week, placebo-controlled studies in 2157 OA and RA patients in whom baseline endoscopies revealed no ulcers. There was no dose relationship for the incidence of gastroduodenal ulcers and the dose of celecoxib (50 mg to 400 mg twice daily). The incidence for naproxen 500 mg twice daily was 16.2 and 17.6% in the two studies, for placebo was 2.0 and 2.3%, and for all doses of celecoxib the incidence ranged between 2.7% to 5.9%. There have been no large, clinical outcome studies to compare clinically relevant GI outcomes with celecoxib and naproxen.

    In the endoscopic studies, approximately 11% of patients were taking aspirin (≤ 325 mg/day). In the celecoxib groups, the endoscopic ulcer rate appeared to be higher in aspirin users than in non-users. However, the increased rate of ulcers in these aspirin users was less than the endoscopic ulcer rates observed in the active comparator groups, with or without aspirin.

  • 16. HOW SUPPLIED/STORAGE AND HANDLING

    Celecoxib capsules 50 mg are available for oral administration as hard gelatin capsules with a white opaque body and a white opaque cap. “APO C50” is imprinted on each capsule in red ink. They are supplied as follows:

    Bottles of 30s                      NDC: 60505-3847-3

    Bottles of 60s                      NDC: 60505-3847-6

    Bottles of 100s                    NDC: 60505-3847-1  

    Bottles of 1000                    NDC: 60505-3847-8                         

    Unit Dose Blisters of 100      NDC: 60505-3847-0                            

    Celecoxib capsules 100 mg are available for oral administration as hard gelatin capsules with a white opaque body and a white opaque cap. “APO C100” is imprinted on each capsule in blue ink.  They are supplied as follows:

    Bottles of 30s                      NDC: 60505-3848-3

    Bottles of 100s                    NDC: 60505-3848-1     

    Bottles of 500s                    NDC: 60505-3848-5                         

    Bottles of 1000                    NDC: 60505-3848-8                         

    Unit Dose Blisters of 100      NDC: 60505-3848-0                           

    Celecoxib capsules 200 mg are available for oral administration as hard gelatin capsules with a white opaque body and a white opaque cap. “APO C200” is imprinted on each capsule in yellow ink.  They are supplied as follows:

    Bottles of 30s                      NDC: 60505-3849-3

    Bottles of 100s                    NDC: 60505-3849-1  

    Bottles of 500s                    NDC: 60505-3849-5                        

    Bottles of 1000                    NDC: 60505-3849-8                         

    Unit Dose Blisters of 100      NDC: 60505-3849-0                         

    Storage: Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

  • 17. PATIENT COUNSELING INFORMATION

    Patients should be informed of the following information before initiating therapy with celecoxib capsules and periodically during the course of ongoing therapy.

    17.1 Medication Guide

    Patients should be informed of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and should be instructed to read the Medication Guide prior to using celecoxib capsules.

    17.2 Cardiovascular Effects

    Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [ see Warnings and Precautions (5.1)].

    Patients should be informed that celecoxib can lead to the onset of new hypertension or worsening of preexisting hypertension, and that celecoxib may impair the response of some antihypertensive agents. Patients should be instructed on the proper follow up for monitoring of blood pressure. [ see Warnings and Precautions (5.2) and Drug Interactions (7.4)].

    17.3 Gastrointestinal Effects

    Patients should be informed that celecoxib capsules can cause gastrointestinal discomfort and more serious side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Patients should be informed of the signs and symptoms of ulcerations and bleeding, and to seek immediate medical advice if they observe any signs or symptoms that are indicative of these disorders, including epigastric pain, dyspepsia, melena, and hematemesis [ see Warnings and Precautions (5.4)].

    17.4 Hepatic Effects

    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). Patients should be instructed that they should stop therapy and seek immediate medical therapy if these signs and symptoms occur [ see Warnings and Precautions (5.5), Use in Specific Populations (8.6)].

    17.5 Adverse Skin Reactions

    Patients should be informed that celecoxib is a sulfonamide and can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be informed of the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and seek immediate medical advice when observing any indicative signs or symptoms.

    Patients should be advised to stop celecoxib capsules immediately if they develop any type of rash and contact their physician as soon as possible.

    Patients with prior history of sulfa allergy should not take celecoxib capsules [ see Warnings and Precautions (5.8)].

    17.6 Weight Gain and Edema

    Long-term administration of NSAIDs including celecoxib has resulted in renal injury. Patients at greatest risk are those taking diuretics, ACE-inhibitors, angiotensin II antagonists, or with renal or liver dysfunction, heart failure, and the elderly [ see Warnings and Precautions (5.3, 5.6), Use in Specific Populations (8)].

    Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see Warnings and Precautions (5.3)].

    17.7 Anaphylactoid Reactions

    Patients should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Patients should be instructed to seek immediate emergency assistance if they develop any of these signs and symptoms [ see Warnings and Precautions (5.7)].

    17.8 Effects During Pregnancy

    Patients should be informed that in late pregnancy celecoxib capsules should be avoided because it may cause premature closure of the ductus arteriosus [ see Warnings and Precautions (5.9), Use in Specific Populations (8.1)].

    17.9 Preexisting Asthma

    Patients should be instructed to tell their physicians if they have a history of asthma or aspirin-sensitive asthma because the use of NSAIDs in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Patients with this form of aspirin sensitivity should be instructed not to take celecoxib capsules. Patients with preexisting asthma should be instructed to seek immediate medical attention if their asthma worsens after taking celecoxib capsules [ see Warnings and Precautions (5.13)].

  • SPL UNCLASSIFIED SECTION

    APOTEX INC.

    CELECOXIB CAPSULES

    50 mg, 100 mg and 200 mg

    Manufactured by:                         Manufactured for:

    Apotex Inc                                   Apotex Corp.

    Toronto, Ontario                           Weston, Florida

    Canada M9L 1T9                          USA 33326 

    Revised: November 2015

    Rev. 4

  • MEDICATION GUIDE

                                                                                     Medication Guide for
                                                                Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

    What is the most important information I should know about medicines called Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)?

    NSAIDs can cause serious side effects, including:

    Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase:

    • with increasing doses of NSAIDs
    • with longer use of NSAIDs

    Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)."

    Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.

    Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:

    • anytime during use
    • without warning symptoms
    • that may cause death

    The risk of getting an ulcer or bleeding increases with:

    • past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs
    • taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”
    • increasing doses of NSAIDs
    • longer use of NSAIDs
    • smoking
    • drinking alcohol
    • older age
    • poor health
    • advanced liver disease
    • bleeding problems

    NSAIDs should only be used: :

    • exactly as prescribed
    • at the lowest dose possible for your treatment
    • for the shortest time needed

    What are NSAIDs?

    NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.

    Who should not take NSAIDs?

    Do not take NSAIDs:

    • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.
    • right before or after heart bypass surgery.

    Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:

    • have liver or kidney problems
    • have high blood pressure
    • have asthma
    • are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.
    • are breastfeeding or plan to breast feed.

    Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first.

    What are the possible side effects of NSAIDs?

    NSAIDs can cause serious side effects, including:

    See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?

    • new or worse high blood pressure
    • heart failure
    • liver problems including liver failure
    • kidney problems including kidney failure
    • low red blood cells (anemia)
    • life-threatening skin reactions
    • life-threatening allergic reactions

    Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.

    Get emergency help right away if you get any of the following symptoms:

    • shortness of breath or trouble breathing
    • chest pain
    • weakness in one part or side of your body
    • slurred speech
    • swelling of the face or throat

    Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:

    • nausea
    • more tired or weaker than usual
    • diarrhea
    • itching
    • your skin or eyes look yellow
    • indigestion or stomach pain
    • flu-like symptoms
    • vomit blood
    • there is blood in your bowel movement or it is black and sticky like tar
    • unusual weight gain
    • skin rash or blisters with fever
    • swelling of the arms, legs, hands and feet

    If you take too much of your NSAID, call your healthcare provider or get medical help right away.

    These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    Other information about NSAIDs

    • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
    • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

    General information about the safe and effective use of NSAIDs

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them.

    If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    APOTEX INC.
    CELECOXIB CAPSULES
    50 mg, 100 mg and 200 mg

     ­­Manufactured by: Manufactured for:
    Apotex Inc Apotex Corp.
    Toronto, Ontario Weston, Florida
    Canada, M9L 1T9USA 33326 ­­

    ­Revised: July 2015

  • Package Labeling:

    Label1Label2

  • INGREDIENTS AND APPEARANCE
    CELECOXIB 
    celecoxib capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 33358-902
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    CELECOXIB (UNII: JCX84Q7J1L) (CELECOXIB - UNII:JCX84Q7J1L) CELECOXIB200 mg
    Inactive Ingredients
    Ingredient NameStrength
    CROSPOVIDONE (UNII: 68401960MK)  
    GELATIN (UNII: 2G86QN327L)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    POVIDONE (UNII: FZ989GH94E)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    SHELLAC (UNII: 46N107B71O)  
    ALCOHOL (UNII: 3K9958V90M)  
    ISOPROPYL ALCOHOL (UNII: ND2M416302)  
    BUTYL ALCOHOL (UNII: 8PJ61P6TS3)  
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    AMMONIA (UNII: 5138Q19F1X)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    DIMETHICONE (UNII: 92RU3N3Y1O)  
    Product Characteristics
    ColorwhiteScoreno score
    ShapeCAPSULESize18mm
    FlavorImprint Code APO;C200
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 33358-902-1515 in 1 BOTTLE; Type 0: Not a Combination Product
    2NDC: 33358-902-3030 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20419706/03/2015
    Labeler - RxChange Co. (781126805)
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