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

Post-Myocardial Infarction Patients: Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-myocardial infarction 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-myocardial infarction 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-myocardial infarction, 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 myocardial infarction unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If celecoxib is used in patients with a recent myocardial infarction, monitor patients for signs of cardiac ischemia.

Risk Factors for GI Bleeding, Ulceration, and Perforation: Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants; or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. 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 aspirin (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 (14.3)].

Strategies to Minimize the GI Risks in NSAID-Treated Patients:

• Use the lowest effective dosage for the shortest possible duration.
• Avoid administration of more than one NSAID at a time.
• Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
• If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue CONSENSI until a serious GI adverse event is ruled out.
• In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)].

Renal Toxicity

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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors or the ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of celecoxib in patients with advanced renal disease. The renal effects of celecoxib may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating celecoxib. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of celecoxib [see Drug Interactions (7)]. Avoid the use of celecoxib in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If celecoxib is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Pre-Marketing Controlled Arthritis Trials

The table below lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving celecoxib from 12 controlled studies conducted in patients with osteoarthritis or rheumatoid arthritis 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.

Adverse Events Occurring in ≥ 2% of Celecoxib Patients from Pre-Marketing Controlled Arthritis Trials

	CBX N=4146	Placebo N=1864	NAP N=1366	DCF N=387	IBU N=345
CBX = Celecoxib 100 – 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 Pain	4.1%	2.8%	7.7%	9.0%	9.0%
Diarrhea	5.6%	3.8%	5.3%	9.3%	5.8%
Dyspepsia	8.8%	6.2%	12.2%	10.9%	12.8%
Flatulence	2.2%	1.0%	3.6%	4.1%	3.5%
Nausea	3.5%	4.2%	6.0%	3.4%	6.7%
Body as a whole
Back Pain	2.8%	3.6%	2.2%	2.6%	0.9%
Peripheral Edema	2.1%	1.1%	2.1%	1.0%	3.5%
Injury-Accidental	2.9%	2.3%	3.0%	2.6%	3.2%
Central, Peripheral Nervous System
Dizziness	2.0%	1.7%	2.6%	1.3%	2.3%
Headache	15.8%	20.2%	14.5%	15.5%	15.4%
Psychiatric
Insomnia	2.3%	2.3%	2.9%	1.3%	1.4%
Respiratory
Pharyngitis	2.3%	1.1%	1.7%	1.6%	2.6%
Rhinitis	2.0%	1.3%	2.4%	2.3%	0.6%
Sinusitis	5.0%	4.3%	4.0%	5.4%	5.8%
Upper Respiratory Infection	8.1%	6.7%	9.9%	9.8%	9.9%
Skin
Rash	2.2%	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 - 1.9% of patients treated with celecoxib (100 - 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: Hypersensitivity, allergic reaction, chest pain, cyst not otherwise specified (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 enzyme increased [including serum glutamic oxaloacetic transaminase (SGOT) increased, serum glutamic pyruvic transaminase (SGPT) increased]

Metabolic and nutritional: BUN increased, creatine phosphokinase (CPK) increased, hypercholesterolemia, hyperglycemia, hypokalemia, non-protein nitrogen (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:

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

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

General: Sepsis, sudden death

Liver and biliary: Cholelithiasis

Hemic and lymphatic: Thrombocytopenia

Nervous: Ataxia, suicide [see Drug Interactions (7)]

Renal: Acute renal failure

The Celecoxib Long-Term Arthritis Safety Study [see Clinical Studies (14.3)]

Juvenile Rheumatoid Arthritis Study

In a 12-week, double-blind, active-controlled study, 242 juvenile rheumatoid arthritis patients 2 years to 17 years of age were treated with celecoxib or naproxen; 77 juvenile rheumatoid arthritis patients were treated with celecoxib 3 mg/kg twice daily, 82 patients were treated with celecoxib 6 mg/kg twice daily, and 83 patients were treated with naproxen 7.5 mg/kg twice daily. 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. Compared with naproxen, celecoxib at doses of 3 and 6 mg/kg twice daily 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 juvenile rheumatoid arthritis among treatment groups.

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

Adverse Events Occurring in ≥5% of Juvenile Rheumatoid Arthritis 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
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
Infection	25	20	27
Nasopharyngitis	5	6	5
Injury and Poisoning	4	6	5
InvestigationsAbnormal 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	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

Other Pre-Approval Studies

The APC and PreSAP Trials

CYP3A Inhibitors: Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology (12.3)].

CYP3A Inducers: No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.

Simvastatin: Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12.3)].

Immunosuppressants: Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3)].

Celecoxib

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 of 200 mg twice daily. In addition, structural abnormalities (e.g., 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 maximum recommended human dose (MRHD). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as celecoxib, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Amlodipine

The available data from post-marketing reports and a small study with Norvasc use in pregnant women with mild to moderate chronic hypertension did not identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy (see Clinical Considerations, Data). In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately 10 and 20-times the MRHD, respectively. However, in rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5 fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose (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 U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Disease-Associated Maternal and/or Embryo/Fetal Risk
Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

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 CONSENSI, can cause premature closure of the fetal ductus arteriosus (see Data) .

Labor or Delivery

There are no studies on the effects of CONSENSI during labor or delivery. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth (see Data).

Human Data

Animal Data

Celecoxib

A clinical lactation study in six volunteers administered a single oral dose of 200 mg celecoxib [median maternal celecoxib dose of 3.3 mg/kg (range of 2.3-3.7)] at 6.5 to 15 months postpartum (mean 11 months) and in the final stage of weaning. showed that the median total amount of celecoxib present in milk was 0.011 mg (range 0.004-0.042) or 0.04% (range 0.01-0.15) of the maternal single dose (weight adjusted). The estimated daily infant dose was 0.013 mg/kg/day (range 0.011-0.021), which is 0.13 to 0.33% of the clinically used celecoxib dose for pediatric patients.

A clinical lactation study in three breastfeeding mothers who had been taking 200 mg celecoxib orally once daily for many weeks and who were at steady state (group 1) and two breastfeeding mothers administered a single 200-mg oral dose of celecoxib (group 2) averaging 12 months post-partum (range 3-22 months). The mean average concentration of celecoxib in milk during the 8-hour interval following administration of celecoxib for all five mothers was 66 µg/L (95% CI: 41 89). The estimated mean absolute infant dose was 9.8 µg/kg/day (95% CI: 6.2-13.4), which is 0.1 to 0.25% of the dose clinically used for pediatric patients. Comparison of this to the weight-normalized maternal dose yields an estimated mean relative infant dose of 0.30% (95% CI: 0.19-0.39)

Amlodipine

An observational clinical lactation study of 31 lactating women who were receiving amlodipine within 3 weeks after delivery for pregnancy-induced hypertension showed a median concentration of amlodipine in milk 24 hours after a mean maternal oral dose of approximately 6 mg/day for 7 to 9 days of 11.5 ng/mL (interquartile range of 9.84-18.0 ng/mL). The mean maternal body weight-adjusted dose was 0.0987 ± 0.0366 mg/kg. The median plasma concentration of amlodipine was 15.5 (interquartile range of 12.0-22.8 ng/mL). The median amlodipine concentration ratio of milk to plasma was 0.85 (interquartile range of 0.743-1.08). The median estimated infant daily dose was 4.17 µg/kg/day (interquartile range of 3.05 to 6.32 µg/kg/day), approximately 1.7 to 3.3% of the recommended dose for an average 6-year old (20 kg). The median relative infant daily dose was 4.18% (interquartile range of 3.12%-7.25%).

Infertility

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 (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 prostaglandin E2 (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.

Hemodynamics: Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105–114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90–104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in GFR and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Electrophysiologic Effects: Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Absorption

Peak plasma levels of celecoxib occur approximately 3 hours after an oral dose. Under fasting conditions, both peak plasma levels (C _max) and AUC are roughly dose-proportional up to 200 mg twice daily; at higher doses, there are less than proportional increases in C _max and AUC presumably due to the low solubility of the drug in aqueous media. 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 the table below.

Summary of Single Dose (200 mg) Disposition Kinetics of Celecoxib in Healthy Subjects Subjects under fasting conditions (n=36, 19-52 yrs.)

Mean (%CV) Pharmacokinetic Parameter Values
C max, ng/mL	T max, hr	Effective t½, hr	Vss/F, L	CL/F, L/hr
705 (38)	2.8 (37)	11.2 (31)	429 (34)	27.7 (28)

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 C _max, T _max, or t½ after administration of capsule contents on applesauce.

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, α₁-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.

Elimination

Specific Populations

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 Impairment

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 should be reduced by approximately 50% in patients with moderate (Child-Pugh Class B) hepatic impairment. Because CONSENSI is not available in lower strengths of celecoxib, CONSENSI is not recommended in patients with moderate hepatic impairment. Patients with severe hepatic impairment (Child- Pugh Class C) have not been studied. The use of CONSENSI in patients with severe hepatic impairment is not recommended [see Use in Specific Populations (8.6)].

Renal Impairment

In a cross-study comparison, celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 35-60 mL/min) than that seen in subjects with normal renal function. No significant relationship was found between GFR and celecoxib clearance. Patients with severe renal insufficiency have not been studied. Similar to other NSAIDs, CONSENSI is not recommended in patients with severe renal insufficiency [see Warnings and Precautions (5.8)].

Drug Interaction Studies

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

In vivo studies have shown the following:

Drug Interactions

In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Carcinogenesis

Celecoxib was not carcinogenic in Sprague-Dawley rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females (approximately 2-to 4-times 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.

Mutagenesis

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.

Impairment of Fertility

Celecoxib had no effect on male or female fertility or male reproductive function in rats at oral doses up to 600 mg/kg/day (approximately 11-times human exposure at 200 mg twice daily based on the AUC_0-24). At ≥50 mg/kg/day (approximately 6-times human exposure based on the AUC_0-24 at 200 mg twice daily) there was increased preimplantation loss.

Adult Patients: The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose-related within the recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black patients and in white patients.

Cardiovascular Outcomes Trial: Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen(PRECISION; NCT00346216)

Adenomatous Polyp Prevention Studies (NCT00005094 and NCT00141193)

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 CV 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 CV 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 CV 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 osteoarthritis patients and 2,200 rheumatoid arthritis patients. Patients received celecoxib 400 mg twice daily (4-fold and 2-fold the recommended osteoarthritis and rheumatoid arthritis 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 (GI bleeding, perforation or obstruction). Patients were allowed to take concomitant low-dose (≤ 325 mg/day) ASA for CV 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 the table below. The table 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.

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 CV thromboembolic adverse events (including myocardial infarction, 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. In the CLASS study, the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on celecoxib 400 mg twice daily (4-fold and 2-fold the recommended osteoarthritis and rheumatoid arthritis doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively. 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.

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 (14.3)].

A randomized, double-blind study in 430 rheumatoid arthritis 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 (14.3)].

The incidence of endoscopic ulcers was studied in two 12-week, placebo-controlled studies in 2157 osteoarthritis and rheumatoid arthritis 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%-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.