As a group, selective COX-2 inhibitors, including CELEBREX, are associated with an increased risk of adverse cardiovascular events, a risk that is similar to those associated with most NSAIDs. As for all NSAIDs, CELEBREX should be prescribed at the lowest effective dose and for the shortest possible duration.

Some patients with pre-existing hypertension may develop worsening of blood pressure control when placed on an NSAID and regular monitoring of blood pressure should be performed under such circumstances. NSAIDs may exacerbate congestive heart failure.

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.

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.

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.

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).

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

(See Contraindications).

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, 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.

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.

CELEBREX may mask the usual signs of infection.

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.

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.

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).

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.

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.

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.

• 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.

  
  

(See Contraindications and Warnings and Precautions).

(See Contraindications).

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

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.

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.

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.

Table 1: CELEBREX

Adverse Events Occurring in ≥2% of CELEBREX Patients from Original NDS Arthritis Trials

In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving CELEBREX and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the CELEBREX treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of CELEBREX patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain.

The adverse event profile from the long-term outcomes trial (at 4- and 2-fold the recommended doses for OA and RA respectively) is similar to those reported in the arthritis-controlled trials. In the arthritis-controlled trials, the CELEBREX endoscopic gastroduodenal ulceration rate was consistently less than what was seen with the NSAID comparators. In the long-term outcome study however, there was no statistically significant difference for the incidence of complicated ulcers (perforation, obstruction, or bleeding) among the CELEBREX 400 mg BID and NSAID comparators. The major differences in study design and patient populations preclude direct comparison between the GI endpoint results in the arthritis controlled and the long-term outcome trials.

The incidences of withdrawals due to adverse events and the incidences of selected serious adverse events (i.e., those causing hospitalization or felt to be life-threatening or otherwise medically significant) observed in this trial are shown in Table 2. No significant differences were seen across treatment groups in the incidences of serious adverse events (see Table 2).

Table 2: CELEBREX

Summary of Withdrawal and Serious Cardiovascular Adverse Event Data from the CLASS Trial. Incidence Rates (%) in all OA and RA Patients and in Patients without ASA

	Celecoxib 400 mg BID	Diclofenac 75 mg BID	Ibuprofen 800 mg TID
All Patients	(n=3987)	(n=1996)	(n=1985)
All Withdrawals	22.4	26.5a	23.0
Withdrawals for GI symptoms	12.2	16.6a	13.4
Serious Adverse Events	6.8	5.6	6.0
Myocardial Infarction (fatal and nonfatal)	0.5	0.2	0.5
Deep Vein Thrombosis	0.2	0.3	0.0
Cardiac Failure	0.2	0.1	0.5
Unstable Angina	0.2	0.2	0.0
Cerebrovascular Disorder	0.1	0.3	0.3
Patients Without ASA	(n=3105)	(n=1551)	(n=1573)
All Withdrawals	21.2	25.4a	22.5
Withdrawals for GI symptoms	11.5	15.4a	13.2
Serious Adverse Events	5.0	4.2	4.3
Myocardial Infarction (fatal and nonfatal)	0.2	0.1	0.1
Deep Vein Thrombosis	0.2	0.2	0.0
Cardiac Failure	0.1	<0.1	0.3
Unstable Angina	<0.1	0.0	0.0
Cerebrovascular Disorder	<0.1	0.3	0.1

^a. p<0.05 vs celecoxib.

The following adverse events occurred in 0.1-1.9% of patients regardless of causality: CELEBREX (100-200 mg BID or 200 mg QD).

constipation, diverticulitis, dry mouth, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, stomatitis, tenesmus, tooth disorder, vomiting.

aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction.

allergy aggravated, allergic reaction, asthenia, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain.

herpes simplex, herpes zoster, infection bacterial, infection fungal, infection soft tissue, infection viral, moniliasis, moniliasis genital, otitis media.

leg cramps, hypertonia, hypoesthesia, migraine, neuralgia, neuropathy, paresthesia, vertigo.

breast fibroadenosis, breast neoplasm, breast pain, dysmenorrhea, menstrual disorder, vaginal hemorrhage, vaginitis.

prostatic disorder.

deafness, ear abnormality, earache, tinnitus.

palpitation, tachycardia.

ALT increased, AST increased, hepatic function abnormal.

urea increased, CPK increased, diabetes mellitus, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increase, creatinine increased, alkaline phosphatase increased, weight increase.

arthralgia, arthrosis, bone disorder, fracture accidental, myalgia, neck stiffness, synovitis, tendinitis.

ecchymosis, epistaxis, thrombocythemia.

anorexia, anxiety, appetite increased, depression, nervousness, somnolence.

anemia.

bronchitis, bronchospasm, bronchospasm aggravated, coughing, dyspnea, laryngitis, pneumonia.

alopecia, dermatitis, nail disorder, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria.

cellulitis, dermatitis contact, injection site reaction, skin nodule.

taste perversion.

albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus, urinary incontinence, urinary tract infection.

blurred vision, cataract, conjunctivitis, eye pain, glaucoma.

Approximately 1700 patients were treated with CELEBREX in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose (up to 400 mg) of study medication. Doses up to 600 mg/day of CELEBREX were studied in primary dysmenorrhea and post-orthopaedic surgery pain studies. The types of adverse experiences in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only new adverse event reported was alveolar osteitis (dry socket) in the post-oral surgery pain studies.

In approximately 700 patients treated with CELEBREX in the post-general and orthopaedic surgery pain studies, the most commonly reported adverse experiences were nausea, vomiting, headache, dizziness and fever.

Other serious adverse reactions which occur rarely (estimated <0.1%) regardless of causality: the following adverse events have occurred rarely in patients taking CELEBREX.

syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis.

intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, cholelithiasis, ileus.

thrombocytopenia.

cholelithiasis, hepatitis, jaundice, liver failure.

hypoglycemia.

ataxia.

acute renal failure.

sepsis, sudden death.

Reports from postmarketing experience include headache, nausea and arthralgia, also the following very rare (<1/10 000, including isolated cases). Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

pancytopenia, agranulocytosis, aplastic anemia, leukopenia.

serious allergic reactions, anaphylactic shock.

confusion, hallucinations.

aggravated epilepsy, aseptic meningitis, ageusia, anosmia.

decreased hearing.

congestive heart failure, heart failure, myocardial infarction.

vasculitis.

bronchospasm.

gastrointestinal hemorrhage, acute pancreatitis.

hepatitis, jaundice.

angioedema, isolated reports of skin exfoliation including: Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme.

menstrual disorder.

myositis.

acute renal failure, interstitial nephritis.

Serious bleeding events (some of them fatal) have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving CELEBREX concurrently with warfarin or similar agents (see Drug Interactions).

Celecoxib metabolism is predominantly mediated via cytochrome P450 2C9 in the liver (commonly used drugs which are also substrates and/or inhibitors for cytochrome P450 2C9 include warfarin, fluoxetine, fluconazole, phenytoin, and tolbutemide). Co-administration of celecoxib with drugs that are known to inhibit 2C9 should be done with caution.

In vitro studies indicate that celecoxib, although not a substrate, is a relatively weak inhibitor of cytochrome P450 2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by P450 2D6.

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

Because of its lack of platelet effects, CELEBREX is not a substitute for ASA for cardiovascular prophylaxis. Therefore, in CELEBREX patients with an indication for cardiovascular prophylaxis, anti-platelet therapies should be used as medically indicated.

ASA is a known risk factor for GI ulceration. As with all other NSAIDs the concomitant administration of ASA with CELEBREX results in an increased rate of GI ulceration or other complications, compared to use of CELEBREX alone. In the long-term outcomes study (at 4- and 2-fold the recommended doses for OA and RA respectively), there was no statistically significant difference for the incidence of complicated ulcers between CELEBREX and comparator groups in patients taking ASA. Concomitant low dose ASA use increased the rate of complicated ulcers to four times that of patients not taking ASA. Resulting incidence rate for complicated ulcers in patients taking CELEBREX and ASA was 1.02%.

Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing CELEBREX therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. The effect of celecoxib on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of 2-5 mg of warfarin (dose sufficient to prolong prothrombin times to 1.2 to 1.7 times their baseline values). In these subjects, celecoxib did not alter the anticoagulant effect of warfarin as determined by prothrombin time. However, in post-marketing experience, serious bleeding events (some of them fatal) have been reported, predominantly in the elderly, in association with increases in prothrombin time, in patients receiving CELEBREX concurrently with warfarin or similar agents. (See Adverse Reactions, Post-market Adverse Drug Reactions.)

The effect of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide and tolbutemide has been studied and clinically important interactions have not been found.

Clinical studies, as well as post marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. Although prospective studies of CELEBREX with diuretics have not been conducted, no adverse reactions indicative of elevations in blood pressure were seen in clinical trials in which arthritis patients were taking CELEBREX concurrently with diuretics (n=485). No adverse reactions indicative of sodium retention or renal impairment were seen in clinical trials in patients taking CELEBREX concurrently with diuretics.

Reports suggest that NSAIDs may diminish the antihypertensive effects of Angiotensin Converting Enzyme (ACE) inhibitors. This interaction should be given consideration. Although prospective studies of CELEBREX with ACE inhibitors have not been conducted, no adverse reactions indicative of elevations in blood pressure were seen in clinical trials in which arthritis patients were taking CELEBREX concurrently with ACE inhibitors (n=305).

Oral glucocorticoids should be used with caution since they increase the risk of GI side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.

Co-administration of CELEBREX with an aluminum- and magnesium-containing antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in C_max and 10% in AUC.

CELEBREX did not have a significant effect on the pharmacokinetics of methotrexate.

In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg BID with CELEBREX 200 mg BID as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when CELEBREX is introduced or withdrawn.

Concomitant administration of fluconazole at 200 mg QD resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole (see Pharmacology, Pharmacokinetics, Metabolism). CELEBREX should be introduced at the lowest recommended dose in patients receiving fluconazole.

CELEBREX did not have a significant effect on the pharmacokinetics of ketoconazole.

CELEBREX did not have a significant effect on the pharmacokinetics of phenytoin.

No drug interaction data are available for CELEBREX and the co-administration of the following products: acetaminophen, alcohol, aminoglycosides, bone marrow depressants, butemide, cholestyramine, colchicine, corticosteroids, cyclosporine, digoxin, gold compounds, indapamide, insulin, nephrotoxic agents, nonsteroidal anti-inflammatory agents, oral contraceptives, potassium supplements, probenecid, valproic acid, zidovudine.

The recommended daily dose of CELEBREX (celecoxib) is 200 mg administered as a single dose or as two divided doses (100 mg twice per day). Maximum dose=200 mg a day.

The recommended starting dose of CELEBREX is 100 mg twice per day, which may be increased to 200 mg twice per day if necessary. Maximum dose=200 mg twice a day.

The recommended dose of CELEBREX is 400 mg as a single dose on the first day followed by 200 mg once daily on subsequent days up to a maximum of 7 days. Patients may be instructed to take an additional dose of 200 mg on any given day, if needed. Maximum dose=400 mg a day for up to 7 days.

CELEBREX can be taken with or without food.

No overdoses of CELEBREX were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious toxicity.

Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. No information is available regarding the removal of celecoxib by hemodialysis, but based on its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.