CELECOXIB: Package Insert and Label Information (Page 2 of 6)
5.6 Renal Toxicity and Hyperkalemia
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.
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoadosteronism state.
5.7 Anaphylactic Reactions
Celecoxib has been associated with anaphylactic reactions in patients with and without known hypersensitivity to celecoxib and in patients with aspirin sensitive asthma. Celecoxib is a sulfonamide and both NSAIDs and sulfonamides may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people [see Contraindications (4) and Warnings and Precautions (5.8)].
Seek emergency help if any anaphylactic reaction occurs.
5.8 Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, celecoxib is contraindicated in patients with this form of aspirin sensitivity [ see Contraindications (4) ]. When celecoxib is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
5.9 Serious Skin Reactions
Serious skin reactions have occurred following treatment with celecoxib, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). These serious events may occur without warning and can be fatal.
Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of celecoxib at the first appearance of skin rash or any other sign of hypersensitivity. Celecoxib is contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications (4) ].
5.10 Premature Closure of Fetal Ductus Arteriosus
Celecoxib may cause premature closure of the ductus arteriosus. Avoid use of NSAIDs, including celecoxib, in pregnant women starting at 30 weeks of gestation (third trimester) [ see Use in Specific Populations (8.1) ].
5.11 Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with celecoxib has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
In controlled clinical trials the incidence of anemia was 0.6% with celecoxib and 0.4% with placebo. Patients on long-term treatment with celecoxib should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.
NSAIDs, including celecoxib, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [ see Drug Interactions (7) ].
5.12 Masking of Inflammation and Fever
The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
5.13 Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [ see Warnings and Precautions (5.2, 5.3, 5.6)].
In controlled clinical trials, elevated BUN occurred more frequently in patients receiving celecoxib compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established.
5.14 Disseminated Intravascular Coagulation (DIC)
Because of the risk of disseminated intravascular coagulation with use of celecoxib in pediatric patients with systemic onset JRA, monitor patients for signs and symptoms of abnormal clotting or bleeding, and inform patients and their caregivers to report symptoms as soon as possible.
6. ADVERSE REACTIONS
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 (5.11) ]
6.1 Clinical Trials Experience
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-treated patients in the pre-marketing controlled clinical trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients received a total daily dose of celecoxib of 200 mg (100 mg twice daily or 200 mg once daily) or more, including more than 400 treated at 800 mg (400 mg twice daily). Approximately 3,900 patients received celecoxib at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more.
Pre-marketing Controlled Arthritis Trials
Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving celecoxib from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence.
|CBX N=4146||Placebo N=1864||NAP N=1366||DCF N=387||IBU N=345|
|CBX = Celecoxib 100 mg to 200 mg twice daily or 200 mg once daily;|
|NAP = Naproxen 500 mg twice daily;|
|DCF = Diclofenac 75 mg twice daily;|
|IBU = Ibuprofen 800 mg three times daily.|
|Body as a whole|
|Central, Peripheral Nervous system|
|Upper Respiratory Infection||8.1%||6.7%||9.9%||9.8%||9.9%|
In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving celecoxib and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the celecoxib treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of celecoxib patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain.
The following adverse reactions occurred in 0.1% to 1.9% of patients treated with celecoxib (100 mg to 200 mg twice daily or 200 mg once daily):
Gastrointestinal : Constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, vomiting
Cardiovascular: Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction
General : Hypersensitivity, allergic reaction, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain
Central, peripheral nervous system: Leg cramps, hypertonia, hypoesthesia, migraine, paresthesia, vertigo
Hearing and vestibular : Deafness, tinnitus
Heart rate and rhythm : Palpitation, tachycardia
Liver and biliary : Hepatic enzyme increased (including SGOT increased, SGPT increased)
Metabolic and nutritional : blood urea nitrogen (BUN) increased, creatine phosphokinase (CPK) increased, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increased, creatinine increased, alkaline phosphatase increased, weight increased
Musculoskeletal : Arthralgia, arthrosis, myalgia, synovitis, tendinitis
Platelets (bleeding or clotting) : Ecchymosis, epistaxis, thrombocythemia,
Psychiatric : Anorexia, anxiety, appetite increased, depression, nervousness, somnolence
Respiratory : Bronchitis, bronchospasm, bronchospasm aggravated, cough, 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 per foration, gastrointestinal 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 (7.1)]
Renal : Acute renal failure
The Celecoxib Long-Term Arthritis Safety Study [see Special Studies(14.7) ]
Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on celecoxib 400 mg twice daily (0.5%) compared to patients on either diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower incidence of events with celecoxib was maintained with or without aspirin use [ see Clinical Pharmacology (12.2) ].
Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for celecoxib, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., causing hospitalization or felt to be life-threatening or otherwise medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and 8%, respectively).
Juvenile Rheumatoid Arthritis Study
In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were treated with Celecoxib or naproxen; 77 JRA patients were treated with celecoxib 3 mg/kg 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 (Table 2). 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 JRA among treatment groups.
In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were treated with celecoxib 6 mg/kg 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.
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
N = 77
|Celecoxib 6 mg/kg N = 82||Naproxen 7.5 mg/kg N = 83|
|Abdominal pain NOS||4||7||7|
|Abdominal pain upper||8||6||10|
|Injury and Poisoning||4||6||5|
|Dizziness (excl vertigo)||1||1||7|
|Skin & Subcutaneous||10||7||18|
Other Pre-Approval Studies
Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with celecoxib in placebo- and active-controlled AS studies. Doses up to 400 mg once daily were studied. The types of adverse events reported in the AS studies were similar to those reported in the OA/RA studies.
Adverse Events from Analgesia and Dysmenorrhea Studies: Approximately 1,700 patients were treated with celecoxib in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose of study medication. Doses up to 600 mg/day of celecoxib were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only additional adverse event reported was post-dental extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies.
The APC and PreSAP Trials
Adverse reactions from long-term, placebo-controlled polyp prevention studies: Exposure to celecoxib in the APC and PreSAP trials was 400 mg to 800 mg daily for up to 3 years [ see Special Studies Adenomatous Polyp Prevention Studies (14.7) ].
Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing trials (treatment durations up to 12 weeks; see Adverse events from celecoxib pre-marketing controlled arthritis trials, above). The adverse reactions for which these differences in patients treated with celecoxib were greater as compared to the arthritis pre-marketing trials were as follows:
(400 to 800 mg daily) N = 2285
|Gastroesophageal reflux disease||4.7%||3.1%|
The following additional adverse reactions occurred in ≥ 0.1% and < 1% of patients taking celecoxib, at an incidence greater than placebo in the long-term polyp prevention studies, and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in the long-term, placebo-controlled polyp prevention studies:
Nervous system disorders: Cerebral infarction
Eye disorders : Vitreous floaters, conjunctival hemorrhage
Ear and labyrinth : Labyrinthitis
Cardiac disorders : Angina unstable, aortic valve incompetence, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy
Vascular disorders : Deep vein thrombosis
Reproductive system and breast disorders : Ovarian cyst
Investigations : Blood potassium increased, blood sodium increased, blood testosterone decreased
Injury, poisoning and procedural complications: Epicondylitis, tendon rupture
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