CELECOXIB- celecoxib_capsule

Celecoxib has analgesic, anti-inflammatory, and antipyretic properties. in vivo Platelets Fluid Retention 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 Subjects under fasting conditions (n=36, 19 to 52 yrs. ) Mean (%CV) PK Parameter Values C max T max Effective t 1/2 V ss CL/F, L/hr 705 (38) 2. 2 (31) 429 (34) 27. 7 (28) Food Effects max Coadministration of celecoxib capsules with an aluminum- and magnesium-containing antacids resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in C max 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 C max max 1/2 see Dosage and Administration (2) Distribution In vitro 1 ss Elimination Metabolism Excretion 1/2 Specific Populations Geriatric max max see Use in Specific Populations (8. 5) Pediatric Twice-daily administration of 50 mg capsules to JRA patients weighing >=12 kg 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. 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 In vitro studies In vivo studies have shown the following: Aspirin see Drug Interactions (7). Lithium see Drug Interactions (7) Fluconazole see Drug Interactions (7) Other Drugs see Drug Interactions (7) in vivo 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 *1/*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 is indicated Celecoxib is a nonsteroidal anti-inflammatory drug indicated for: Osteoarthritis (OA) ( 1. 1 Rheumatoid Arthritis (RA) ( 1. 2 Juvenile Rheumatoid Arthritis (JRA) in patients 2 years and older ( 1. 3 Ankylosing Spondylitis (AS) ( 1. 4 Acute Pain (AP) ( 1. 5 Primary Dysmenorrhea (PD) ( 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 ( 2. 1 OA: 200 mg once daily or 100 mg twice daily ( 2. 1 RA: 100 mg to 200 mg twice daily ( 2. 2 JRA: 50 mg twice daily in patients 10 kg to 25 kg. 100 mg twice daily in patients more than 25 kg ( 2. 3 AS: 200 mg once daily single dose or 100 mg twice daily. If no effect is observed after 6 weeks, a trial of 400 mg (single or divided doses) may be of benefit ( 2. 4 AP and PD: 400 mg initially, followed by 200 mg dose if needed on first day. On subsequent days, 200 mg twice daily as needed ( 2. 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 and other treatment options before deciding to use celecoxib. 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 > < 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 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: Cardiovascular Thrombotic Events [ see Warnings and Precautions (5. 1) GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions (5. 2) Hepatotoxicity [ see Warnings and Precautions (5. 3) Hypertension [ see Warnings and Precautions (5. 4) Heart Failure and Edema [ see Warnings and Precautions (5. 5) Renal Toxicity and Hyperkalemia [ see Warnings and Precautions (5. 6) Anaphylactic Reactions [ see Warnings and Precautions (5. 7) Serious Skin Reactions [ see Warnings and Precautions (5. 9) Hematologic Toxicity [ 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 ScieGen Pharmaceuticals, Inc. , at 855-724-3436 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. Pre-marketing Controlled Arthritis Trials Table 1: Adverse Events Occurring in >=2% of Celecoxib Capsules Patients from Pre-marketing Controlled Arthritis Trials Celecoxib Capsules Placebo NAP DCF IBU N=4,146 N=1,864 N=1,366 N=387 N=345 Gastrointestinal Abdominal Pain 4. 0% Diarrhea 5. 8% Dyspepsia 8. 8% Flatulence 2. 5% Nausea 3. 7% Body as a whole Back Pain 2. 9% Peripheral Edema 2. 5% Injury-Accidental 2. 2% Central, Peripheral Nervous system Dizziness 2. 3% Headache 15. 4% Psychiatric Insomnia 2. 4% Respiratory Pharyngitis 2. 6% Rhinitis 2. 6% Sinusitis 5. 8% Upper Respiratory Infection 8. 9% Skin Rash 2. 2% Celecoxib capsules 100 mg to 200 mg twice daily or 200 mg once daily; 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 : Juvenile Rheumatoid Arthritis Study 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 Celecoxib Celecoxib Naproxen System Organ Class 3 mg/kg 6 mg/kg 7. 5 mg/kg Preferred Term N=77 N=82 N=83 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 Diarrhea NOS 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 Adverse reactions from long-term, placebo-controlled polyp prevention studies see Clinical Studies (14. 7) Adverse events from celecoxib pre-marketing controlled arthritis trials Celecoxib Capsules (400 mg to 800 mg daily) Placebo N = 2,285 N=1,303 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. 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:.

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 History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 In the setting of CABG surgery ( 4.

Infertility 8. 3 Risk Summary Use of NSAIDs, including celecoxib, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of celecoxib use between about 20 and 30 weeks of gestation and avoid celecoxib use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations Data Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including celecoxib, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryo-fetal deaths and an increase in diaphragmatic hernias were observed in rats administered celecoxib daily during the period of organogenesis at oral doses approximately 6 times the maximum recommended human dose (MRHD) of 200 mg twice daily. In addition, structural abnormalities (e. , septal defects, ribs fused, sternebrae fused and sternebrae misshapen) were observed in rabbits given daily oral doses of celecoxib during the period of organogenesis at approximately 2 times the MRHD (see Data The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the general U. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including celecoxib, can cause premature closure of the fetal ductus arteriosus ( see Data Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If celecoxib treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue celecoxib and follow up according to clinical practice ( see Data Labor or Delivery There are no studies on the effects of celecoxib during labor or delivery. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data The available data do not establish the presence or absence of developmental toxicity related to the use of celecoxib. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data 0-24 0-24 0-24 0-24 Risk Summary Infertility 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. 5) and Clinical Studies (14. 3) see Dosage and Administration (2. 4), Warnings and Precautions (5. 15) Adverse Reactions (6. 1), Animal Toxicology (13. 2) , Clinical Studies (14. 3) 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 in patients with severe hepatic impairment is not recommended [ see Dosage and Administration (2. 7) Clinical Pharmacology (12. 3) Celecoxib is not recommended in patients with severe renal insufficiency [ see Warnings and Precautions (5. 6) and 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 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. 7) and Clinical Pharmacology (12.

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 with anticoagulants (e. , warfarin), antiplatelet drugs (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) In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 mg to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 mg to 325 mg). Intervention: Concomitant use of celecoxib 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 and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib 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 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 and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of celecoxib 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). Celecoxib has no effect on methotrexate pharmacokinetics. Intervention: During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of celecoxib 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. 2) Intervention: The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of celecoxib 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 and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 mL/min to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e. , diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e. , meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. CYP2C9 Inhibitors or inducers Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration 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 with CYP2C9 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 with CYP2D6 substrates. 3 Corticosteroids Clinical Impact: Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding. Intervention: Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [ see Warnings and Precautions (5. 2) Drugs that Interfere with Hemostasis (e. , warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]) 7 Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers 7 ACE Inhibitors and ARBs 7 Diuretics 7 Digoxin 7.

OVERDOSAGE
Symptoms following acute NSAID overdosages 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 occurred, but were rare [ see Warnings and precautions (5.2 5.4 5.6)
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 has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. Celecoxib capsules 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 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. Although celecoxib capsules 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 mg to 200 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 has 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 was 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 mm 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) Design The PRECISION trial was a double-blind randomized controlled trial of cardiovascular safety in OA and RA patients with or at high risk for cardiovascular disease comparing celecoxib with naproxen and ibuprofen. Patients were randomized to a starting dose of 100 mg twice daily of celecoxib, 600 mg three times daily of ibuprofen, or 375 mg twice daily of naproxen, with the option of escalating the dose as needed for pain management. Based on labeled doses, OA patients randomized to celecoxib could not dose escalate. The primary endpoint, the Antiplatelet Trialists’ Collaboration (APTC) composite, was an independently adjudicated composite of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, and non-fatal stroke with 80% power to evaluate non-inferiority. All patients were prescribed open-label esomeprazole (20 mg to 40 mg) for gastroprotection. Treatment randomization was stratified by baseline low-dose aspirin use. Additionally, there was a 4-month substudy assessing the effects of the three drugs on blood pressure as measured by ambulatory monitoring. Results Among subjects with OA, only 0. 2% (17/7259) escalated celecoxib to the 200 mg twice daily dose, whereas 54. 7% (3946/7208) escalated ibuprofen to 800 mg three times daily, and 54. 8% (3937/7178) escalated naproxen to the 500 mg twice daily dose. Among subjects with RA, 55. 7% (453/813) escalated celecoxib to the 200 mg twice daily dose, 56. 5% (470/832) escalated ibuprofen to 800 mg three times daily, and 54. 6% (432/791) escalated naproxen to the 500 mg twice daily dose; however, the RA population accounted for only 10% of the trial population. Because relatively few celecoxib patients overall (5. 8% [470/8072]) dose-escalated to 200 mg twice daily, the results of the PRECISION trial are not suitable for determining the relative CV safety of celecoxib at 200 mg twice daily compared to ibuprofen and naproxen at the doses taken. Primary Endpoint The trial had two prespecified analysis populations: Intent-to-treat population (ITT): Comprised of all randomized subjects followed for a maximum of 30 months Modified Intent-to-treat population (mITT): Comprised of all randomized subjects who received at least one dose of study medication and had at least one post-baseline visit followed until the earlier of treatment discontinuation plus 30 days, or 43 months Celecoxib, at the 100 mg twice daily dose, as compared with either naproxen or ibuprofen at the doses taken, met all four prespecified non-inferiority criteria (p<0. 001 for non-inferiority in both comparisons) for the APTC endpoint, a composite of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, and non-fatal stroke [ see Table 5 The primary analysis results for ITT and mITT are described in Table 5. Primary Analysis of the Adjudicated APTC Composite Endpoint Intent-To-Treat Analysis (ITT, through month 30) Celecoxib Ibuprofen Naproxen N 8,072 8,040 7,969 Subjects with Events 188 (2. 5%) Pairwise Comparison Celecoxib vs. Naproxen Celecoxib vs. Ibuprofen Ibuprofen vs. Naproxen HR (95% CI) 0. 31) Modified Intent-To-Treat Analysis (mITT, on treatment plus 30 days, through month 43) Celecoxib Ibuprofen Naproxen N 8,030 7,990 7,933 Subjects with Events 134 (1. 8%) Pairwise Comparison Celecoxib vs. 40) Table 6. Summary of the Adjudicated APTC Components 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 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%) 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 In the PRECISION-ABPM substudy, among the total of 444 analyzable patients at Month 4, celecoxib dosed at 100 mg twice daily decreased mean 24-hour systolic blood pressure (SBP) by 0. 3 mmHg, whereas ibuprofen and naproxen at the doses taken increased mean 24-hour SBP by 3. 6 mmHg, respectively. These changes resulted in a statistically significant and clinically meaningful difference of 3. 9 mmHg (p=0. 0009) between celecoxib and ibuprofen and a non-statistically significant difference of 1. 119) mmHg between celecoxib and naproxen. 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 capsules: 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. 5) with celecoxib 400 mg twice daily and 2. 8 (95% CI 1. 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. 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 capsules 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 capsules (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=3,105). 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 capsules 400 mg twice daily are described in Table 7. Table 7 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. Table7: Complicated and Symptomatic Ulcer Rates in Patients Taking Celecoxib Capsules 400 mg Twice Daily (Kaplan-Meier Rates at 9 months [%]) Based on Risk Factors All Patients Celecoxib Capsules alone (n=3,105) 0. 78 Celecoxib Capsules with ASA (n=882) 2. 19 Patients <65 Years Celecoxib Capsules alone (n=2,025) 0. 47 Celecoxib Capsules with ASA (n=403) 1. 26 Patients >=65 Years Celecoxib Capsules alone (n=1,080) 1. 40 Celecoxib Capsules 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) 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. 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. 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. In the CLASS study, the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on celecoxib capsules 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4. 7%, respectively. The rates of hypertension from the CLASS trial in the celecoxib, ibuprofen and diclofenac-treated patients were 2. 5%, respectively. 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. 2) Clinical Studies (14. 7) 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 capsules 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. 7) The incidence of endoscopic ulcers was studied in two 12-week, placebo-controlled studies in 2,157 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 capsules (50 mg to 400 mg twice daily). The incidence for naproxen 500 mg twice daily was 16. 6% in the two studies, for placebo was 2. 3%, and for all doses of celecoxib the incidence ranged between 2. There have been no large, clinical outcome studies to compare clinically relevant GI outcomes with celecoxib capsules 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.

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