CELECOXIB- celecoxib_capsule

Celecoxib has analgesic, anti-inflammatory, and antipyretic properties. in vitro in vivo Platelets Celecoxib exhibits dose-proportional increase in exposure after oral administration up to 200 mg twice daily and less than proportional increase at higher doses. It has extensive distribution and high protein binding. It is primarily metabolized by CYP2C9 with a half-life of approximately 11 hours. Absorption max max [see Food Effects] Table 4 Summary of Single Dose (200 mg) Disposition Kinetics of Celecoxib in Healthy Subjects 1 Mean (% CV) PK Parameter Values Cmax,ng/mL Tmax,hr Effectivet 1/2 Vss/F,L CL/F,L/hr 705(38) 2. 2(31) 429(34) 27. 7(28) 1 Food Effects max max max 1/2 see Dosage and Administration (2) Distribution 1 ss Elimination Metabolism Excretion 1/2 Specific Populations Geriatric max max see Use in Specific Populations (8. 5) Pediatric see Dosage and Administration (2. 4) Race Hepatic Impairment see Dosage and Administration (2. 7) Use in Specific Populations (8. 6) Renal Impairment see Warnings and Precautions (5. 6) Drug Interaction Studies Aspirin see Drug Interactions (7) Lithium see Drug Interactions (7) Fluconazole seeb Drug Interactions (7) Other Drugs see Drug Interactions (7) 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. 0% in various ethnic groups. [ see Dosage and Administration (2.

Celecoxib capsule are indicated Celecoxib capsules are nonsteroidal anti-inflammatory drug indicated for: 1. 6 For the management of the signs and symptoms of OA [ see Clinical Studies (14. 1) For the management of the signs and symptoms of RA [ see Clinical Studies (14. 2) For the management of the signs and symptoms of JRA in patients 2 years and older [ see Clinical Studies (14. 3) For the management of the signs and symptoms of AS [ see Clinical Studies (14. 4) For the management of acute pain in adults [ see Clinical Studies (14. 5) For the management of primary dysmenorrhea [ see Clinical Studies (14.

Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. 5 Hepatic Impairment: Reduce daily dose by 50% in patients with moderate hepatic impairment (Child-Pugh Class B). 3 Poor Metabolizers of CYP2C9 Substrates: Consider a dose reduction by 50% (or alternative management for JRA) in patients who are known or suspected to be CYP2C9 poor metabolizers. 3 Carefully consider the potential benefits and risks of celecoxib capsules and other treatment options before deciding to use celecoxib capsules. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5) For OA, the dosage is 200 mg per day administered as a single dose or as 100 mg twice daily. For RA, the dosage is 100 mg to 200 mg twice daily. For JRA, the dosage 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 AS, the dosage 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. For management of Acute Pain and Treatment of Primary Dysmenorrhea, the dosage 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. Hepatic Impairment see Warnings and Precautions (5. 3), Use in Specific Populations (8. 6) Clinical Pharmacology (12. 3) Poor Metabolizers of CYP2C9 Substrates In adult 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), initiate treatment with half of the lowest recommended dose. see Use in Specific populations (8. 8) Clinical Pharmacology (12.

The following adverse reactions are discussed in greater detail in other sections of the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 12) Most common adverse reactions in arthritis trials (>2% and >placebo) are: abdominal pain, diarrhea, dyspepsia, flatulence, peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, rash ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Nivagen Pharmaceuticals, Inc. at 1-877-977-0687 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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. Of the celecoxib capsules-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 capsules 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 capsules 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. Pre-marketing Controlled Arthritis Trials Table 1: Adverse Events Occurring in >=2% of Celecoxib Capsules Patients from Pre-marketing Controlled Arthritis Trials CBX Placebo NAP DCF IBU Gastrointestinal Body as a whole Central, Peripheral Nervous system Psychiatric Respiratory Skin CBX = Celecoxib capsules 100 mg to 200 mg twice daily or 200 mg once daily; NAP = Naproxen 500 mg twice daily; In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7. 1% for patients receiving celecoxib capsules 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. 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. 9% of patients treated with Celecoxib capsules (100 mg to 200 mg twice daily or 200 mg once daily): Gastrointestinal: Cardiovascular: General: Central, peripheral, Nervous system: Hearing and vestibular: Heart rate and rhythm: Liver and biliary: Metabolic and nutritional: Musculoskeletal: Platelets (bleeding or clotting): Psychiatric: Hemic: Respiratory: Skin and appendages: Application site disorders: Urinary: The following serious adverse events (causality not evaluated) occurred in <0. 1% of patients Cardiovascular: Gastrointestinal: General: Liver and biliary: Hemic and lymphatic: Nervous: see Drug Interactions (7) Renal: The Celecoxib Long-Term Arthritis Safety Study [ see Clinical Studies ( 14. 7 Hematological Events: see Clinical Pharmacology ( 12. 2 Withdrawals/Serious Adverse Events: 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 Celecoxib Celecoxib Naproxen Any Event 64 70 72 Eye Disorders 5 5 5 Gastrointestinal 26 24 36 Abdominal pain NOS 4 7 7 Abdominal pain upper 8 6 10 Vomiting NOS 3 6 11 DiarrheaNOS 5 4 8 Nausea 7 4 11 General 13 11 18 Pyrexia 8 9 11 Infections 25 20 27 Nasopharyngitis 5 6 5 Injury and Poisoning 4 6 5 Investigations* 3 11 7 Musculoskeletal 8 10 17 Arthralgia 3 7 4 Nervous System 17 11 21 Headache NOS 13 10 16 Dizziness (excl vertigo) 1 1 7 Respiratory 8 15 15 Cough 7 7 8 Skin & Subcutaneous 10 7 18 * 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 Other Pre-Approval Studies Adverse Events from Ankylosing Spondylitis Studies: Adverse Events from Analgesia and Dysmenorrhea Studies: The APC and PreSAP Trials see clinical Studies (14. 7) see Adverse events pre-marketing controlled arthritis trials Celecoxib (400 to 800 mg daily) N = 2285 Placebo Diarrhea 10. 0% Gastroesophageal reflux disease 4. 1% Nausea 6. 3% Vomiting 3. 1% Dyspnea 2. 6% Hypertension 12. 8% Nephrolithiasis 2. 8% The following additional adverse reactions occurred in >=0. 1% and <1% of patients taking celecoxib capsules, 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: Eye disorders: Ear and labyrinth: Cardiac disorders: Vascular disorders: Reproductive system and breast disorders: Investigations: Injury, poisoning and procedural complications The following adverse reactions have been identified during post approval use of celecoxib capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure Cardiovascular: General: Liver and biliary: Hemic and lymphatic: Metabolic: Nervous: Renal: Skin and Appendages:.

Celecoxib capsules are contraindicated in the following patients: Known hypersensitivity (e. , anaphylactic reactions and serious skin reactions) to celecoxib, any components of the drug product [see Warnings and Precautions (5. 9 History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs, have been reported in such patients [see Warnings and Precautions (5. 8 In the setting of CABG surgery [see Warnings and Precautions (5. 1) In patients who have demonstrated allergic-type reactions to sulfonamides [see Warnings and Precautions (5. 7) Known hypersensitivity to celecoxib, or any components of the drug product or sulfonamides ( 4 4 4.

Infertility 8. 3 Risk Summary Clinical Considerations, Data Premature Closure of Fetal Ductus Arteriosus Oligohydramnios/Neonatal Renal Impairment see Data Clinical Considerations Fetal/Neonatal Adverse Reactions see Data see Data Labor or Delivery Human Data Animal data 0-24 0-24 0-24 0-24 Risk Summary Infertility Females Celecoxib capsules are 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 capsules 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 non­selective NSAIDs [ see Boxed Warning, Warnings and Precautions(5. 5) 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). When NSAIDs including celecoxib are used in patients with systemic onset JRA, monitor patients for signs and symptoms of abnormal clotting or bleeding, 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. 4) Warnings and Precautions (5. 15) Adverse Reactions (6. 1) 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) Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions (5. 14) see Warnings and Precautions (5. 6) 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. 7) Clinical Pharmacology (12. 3) Celecoxib capsules is not recommended in patients with severe renal insufficiency [ see Warnings and Precautions (5. 6) Clinical Pharmacology (12. 3) In patients who are known or suspected to be poor CYP2C9 metabolizers (i. , CYP2C9*3/*3), based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) administer celecoxib capsules starting with half the lowest recommended dose. Alternative management should be considered in JRA patients identified to be CYP2C9 poor metabolizers. [ see Dosage and Administration (2.

See Table 3 for clinically significant drug interactions with celecoxib. Table 3: Clinically Significant Drug Interactions with Celecoxib Drugs That Interfere with Hemostasis Clinical Impact: Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e. , warfarin), antiplatelet agents (e. , aspirin), (SSRIs), and (SNRIs) for signs of bleeding [ see Warnings and Precautions (5. 12) Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5. 2) Intervention: Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5. 12) ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e. , furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5. 6) Digoxin Clinical Impact: The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. Intervention: During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e. , neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of celecoxib capsule and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of Celecoxib with other NSAIDs or salicylates (e. , diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5. Intervention: The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. CYP2C9 Inhibitors or inducers Clinical Impact: 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 (e. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e. rifampin) may lead to compromised efficacy of celecoxib. Intervention: Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered withCYP2C9 inhibitors or inducers. [ see Clinical Pharmacology (12. 3) CYP2D6 substrates Clinical Impact: In vitro in vivo Intervention: Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered withCYP2D6 substrates. 3) Corticosteroids Clinical Impact: Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. Intervention: Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5. 2) Drugs that Interfere with Hemostasis (e. warfarin, aspirin, selective serotonin reuptake inhibitor [SSRIs] / serotonin norepinephrine reuptake inhibitors [SNRIs]): Angiotensin converting enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta- Blockers ACE Inhibitors and ARBs Diuretics Digoxin.

OVERDOSAGE
Symptoms following acute NSAID over dosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occured, but were rare [ see Warnings and Precautions (5.2 5.4 5.6) Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
NONCLINICAL TOXICOLOGY
Carcinogenesis 0-24 0-24 Mutagenesis in vivo Impairment of Fertility 0-24 0-24 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.
CLINICAL STUDIES
Celecoxib capsules have demonstrated significant reduction in joint pain compared to placebo. Celecoxib capsules were 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 capsules 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 capsules 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 capsules 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. Celecoxib capsules have demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. Celecoxib capsules were 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 capsules 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 capsules 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. 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 twice daily, celecoxib 6 mg/kg twice daily, and naproxen 7. 5 mg/kg twice daily treatment groups, respectively. The efficacy and safety of celecoxib capsules for JRA have not been studied beyond six months. The long-term cardiovascular toxicity in children exposed to celecoxib capsules have not been evaluated and it is unknown if the long-term risk may be similar to that seen in adults exposed to celecoxib capsules or other COX-2 selective and non-selective NSAIDs [ (see Boxed Warning, Warnings and Precautions (5. 15) Celecoxib capsules were evaluated in AS patients in two placebo- and active-controlled clinical trials of 6 and 12 weeks duration. Celecoxib capsules 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 capsules doses in a comparison of mean change from baseline, but there was a greater percentage of patients who responded to celecoxib capsules 400 mg, 53%, than to celecoxib capsules 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. In acute analgesic models of post-oral surgery pain, post-orthopedic surgical pain, and primary dysmenorrhea, celecoxib capsules relieved pain that was rated by patients as moderate to severe. Single doses [ see Dosage and Administration (2. 6) Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION; NCT00346216) Design Results Primary Endpoint see Table 5 Table 5. Primary Analysis of the Adjudicated APTC Composite Endpoint Intent-To-Treat Analysis (ITT, through month 30) Ce lecoxib Ibuprofen Na proxen N 8,072 8,040 7,969 Subjects with Events 188 (2. 5%) Pairwise Comparison Ce lecoxib vs. Naproxen Ce lecoxib vs. Ibuprofen Ibuprofen vs. Naproxen HR (95% CI) 0. 31) Modified Intent-To-Treat Analysis (mITT, on treatment plus 30 days, through month 43) Ce lecoxib Ibuprofen Na proxen N 8,030 7,990 7,933 Subjects with Events 134 (1. 8%) Pairwise Comparison Ce lecoxib vs. 40) Table 6. Summary of the Adjudicated APTC Components* Intent-To-Treat Analysis (ITT, through month 30) Celecoxib Ibuprofen Naproxen N 8,072 8,040 7,969 CV Death 68 (0. 1%) Non-fatal MI 76 (0. 8%) Non-fatal Stroke 51 (0. 7%) Modified Intent-To-Treat Analysis (mITT, on treatment plus 30 days, through month 43) N 8,030 7,990 7,933 CV Death 35 (0. 6%) Non-Fatal MI 58 (0. 7%) Non-Fatal Stroke 43 (0. 6%) *A patient may have experienced more than one component; therefore, the sum of the components is larger than the number of patients who experienced the composite outcome In the ITT analysis population through 30 months, all-cause mortality was 1. 6% in the celecoxib group, 1. 8% in the ibuprofen group, and 2. 0% in the naproxen group. Ambulatory Blood Pressure Monitoring (ABPM) Substudy Adenomatous Polyp Prevention Studies see Warnings and Precautions (5. 4) Table 7: 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 capsules alone or celecoxib capsules 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. 2) Adverse Reactions (6. 1) see Warnings and Precautions (5. 2) Clinical Studies (14. 7) see Clinical Studies (14.

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