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CELEBREX INFORMATION

(CELECOXIB)

 

Gastrointestinal System (GI)

CELEBREX (celecoxib) exhibited a low incidence of gastroduodenal ulceration and serious clinically significant GI events within clinical trials. However, serious GI toxicity (sometimes severe or fatal), such as peptic ulceration, perforation and bleeding, can occur at any time, with or without warning symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs), including CELEBREX. Minor upper GI problems, such as dyspepsia, commonly occur at any time. Health care providers should remain alert for ulceration and bleeding in patients treated with NSAIDs, including CELEBREX, even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and instructed to discontinue using CELEBREX and seek emergency medical attention if they experience any such symptoms. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Many patients who develop a serious upper GI adverse event on NSAID therapy have no symptoms. Upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue thus, increasing the likelihood of developing a serious GI event at some time during the course of therapy. Even short term therapy may be associated with risk for serious GI adverse events.

As for all NSAIDs, caution should be taken in prescribing CELEBREX to patients with a prior history of ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated patients. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. (see Contraindications)

Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold higher risk for developing a GI bleed than patients with neither of these risk factors. Other risk factors for GI ulceration and bleeding include the following: H. pylori infection, increasing age, longer duration of NSAID therapy, excess alcohol intake, smoking, poor general health status or concomitant therapy with any of the following:

• Anticoagulant (e.g. warfarin)

  
  

• Antiplatelet agent (e.g. ASA, clopidogrel)

  
  

• Oral corticosteroids (e.g. prednisone)

  
  

• Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. citalopram, paroxetine)

  
  

 

There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of CELEBREX when and if these adverse reactions appear.

Celebrex Genitourinary

Some NSAIDs are known to cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Some cases have become severe on continued treatment. Should urinary symptoms occur, treatment with CELEBREX must be stopped immediately to obtain recovery. This should be done before any urological investigations or treatments are carried out.

Celebrex Hematologic

Anemia is sometimes seen in patients receiving CELEBREX. In controlled clinical trials the incidence of anemia was 0.6% with CELEBREX and 0.4% with placebo. Patients on long-term treatment with CELEBREX should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. Serious potentially fatal bleeding events have been reported, predominantly in the elderly, in patients receiving CELEBREX concurrently with warfarin or similar agents. (See Drug Interactions and Adverse Reactions, Post-market Adverse Drug Reactions.)

CELEBREX does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not appear to inhibit platelet aggregation at indicated dosages.

Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of nonsteroidal anti-inflammatory drugs are rare, but could occur with severe consequences.

Celebrex Hepatic/Biliary/Pancreatic

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs. In controlled clinical trials of CELEBREX, the incidence of borderline elevations of liver tests was 6% for CELEBREX and 5% for placebo, and approximately 0.2% of patients taking CELEBREX and 0.3% of patients taking placebo had notable elevations of ALT and AST.

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

Celebrex Hypersensitivity Reactions

Cross-Sensitivity

Patients sensitive to any one of the nonsteroidal anti-inflammatory drugs may be sensitive to any of the other NSAIDs

Anaphylactoid Reactions

As with NSAIDs in general, anaphylactoid reactions may occur in patients without known prior exposure to CELEBREX. In post-marketing experience, very rare cases of anaphylactic reactions and angioedema have been reported in patients receiving CELEBREX.

Serious Skin Reactions

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of CELEBREX. Patients appear to be at higher risk for these events early in the course of therapy: the onset of the event occurring in the majority of cases within the first month of treatment. CELEBREX should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

ASA-Intolerance

CELEBREX should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking ASA or other nonsteroidal anti-inflammatory drugs (see Contraindications). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Infection

CELEBREX may mask the usual signs of infection.

Neurologic

Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of nonsteroidal anti-inflammatory drugs. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.

Aseptic Meningitis

In occasional cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissues diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the physician must be vigilant to the development of this complication.

Renal

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 a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical trials with CELEBREX have shown renal effects similar to those observed with comparator nonsteroidal anti-inflammatory drugs (see Contraindications).

Caution should be used when initiating treatment with CELEBREX in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with CELEBREX.

No information is available from controlled clinical studies regarding the use of CELEBREX in patients with advanced kidney disease. In post-marketing experience, serious renal failure, including the need for dialysis, and fatalities have been reported in patients with impaired renal function. Therefore, treatment with CELEBREX, as with NSAIDs, is not recommended in these patients with advanced renal disease. Kidney function should be monitored, especially in high-risk populations, such as the elderly, patients with cardiovascular disease and diabetes mellitus, as well as in the setting of concomitant use of diuretics and ACE inhibitors (see Contraindications).

Celebrex Fluid and Electrolyte Balance

Fluid retention and edema have been observed in some patients taking CELEBREX (see Adverse Reactions). In the CLASS study, the rates of hypertension in patients on CELEBREX 400 mg BID (4-fold and 2-fold the recommended doses for OA and RA), and common therapeutic doses of ibuprofen (800 mg TID) and diclofenac (75 mg BID) were 2.0%, 3.1% and 2.0%, respectively. The corresponding rates for edema were: 3.7%, 5.2% and 3.5%, respectively. Therefore, as with other nonsteroidal anti-inflammatory drugs known to inhibit prostaglandin synthesis, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. CELEBREX should be used with caution in patients with heart failure, left ventricular dysfunction, hypertension, edema from any cause or other conditions predisposing to fluid retention.

With nonsteroidal anti-inflammatory treatment there is a potential risk of hyperkalemia, particularly in patients with conditions such as diabetes mellitus or renal failure, elderly patients, or in patients receiving concomitant therapy with β-adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients who are at risk.

Respiratory

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

Special Senses—Ophthalmology

Blurred and/or diminished vision has been reported with the use of nonsteroidal anti-inflammatory drugs. If such symptoms develop, CELEBREX should be discontinued and an ophthalmologic examination performed; ophthalmologic examination should be carried out at periodic intervals in any patient receiving CELEBREX for an extended period of time.

Concomitant Therapies

• ASA (Acetylsalicylic Acid): CELEBREX is not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thromboembolic diseases because of the lack of effect on platelet function. Because celecoxib does not inhibit platelet aggregation, anti-platelet therapies (e.g. acetylsalicylic acid) should not be discontinued. (See Drug Interactions, Drug-Drug Interactions, Acetylsalicylic Acid (ASA) or Other NSAIDs.)

  
  

   

  
  

• Corticosteroids: CELEBREX (celecoxib) is not a substitute for corticosteroids. It does not treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

  
  

Special Populations

Pregnant Women

(See Contraindications and Warnings and Precautions).

Nursing Women

(See Contraindications).

Pediatrics

Safety and effectiveness in paediatric patients below the age of 18 years have not been evaluated.

Monitoring and Laboratory Tests

During the controlled clinical trials, there was an increased incidence of hyperchloremia in patients receiving celecoxib compared with patients on placebo. Other laboratory abnormalities that occurred more frequently in the patients receiving celecoxib included hypophosphatemia, and elevated urea. These laboratory abnormalities were also seen in patients who received comparator NSAIDs in these studies. The clinical significance of these abnormalities has not been established.

Adverse Drug Reaction Overview

Of the CELEBREX (celecoxib) treated patients in controlled trials, approximately 4250 were patients with OA, approximately 2100 were patients with RA, and approximately 1050 were patients with post-surgical pain. More than 8500 patients have received a total daily dose of CELEBREX of 200 mg (100 mg BID or 200 mg QD) or more, including more than 400 treated at 800 mg (400 mg BID). Approximately 3900 patients have received CELEBREX at these doses for 6 months or more; approximately 2300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more.

CELEBREX has been extensively studied in elderly patients. Of the total number of patients who received CELEBREX in clinical trials, more than 3300 patients were 65-74 years of age, while approximately 1300 additional patients were 75 years and over. While the incidence of adverse experiences tended to be higher in elderly patients, no substantial differences in safety and effectiveness were observed between these subjects and younger patients. In GI endoscopy studies involving over 800 elderly patients, the rate of gastroduodenal ulceration was not different in elderly patients compared to the young. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In clinical studies comparing renal function as measured by the GFR, urea and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers.

Adverse Events From Original New Drug Submission (NDS) Arthritis Trials

Table 1 lists all adverse events, regardless of causality, occurring in >2% of patients receiving CELEBREX from 12 controlled studies conducted in patients with osteoarthritis and rheumatoid arthritis that included a placebo and/or a positive control group.