Celebrex

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.

Some studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increase the risk of GI side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.

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 Patients on lithium treatment should be closely monitored when CELEBREX is introduced or withdrawn.

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.)

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

There is an increased risk of bleeding, via inhibition of platelet function, where antiplatelet agents are combined with NSAIDs. 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 (see Warnings and Precautions, Hematologic, Antiplatelet Effects).

No interaction data is available for the co-administration of celecoxib and digoxin. However an increase in serum digoxin level has been noted with some NSAIDS.

The use of CELEBREX in addition to any other NSAID, including over-the-counter ones (such as ASA and ibuprofen) for analgesic and/or anti-inflammatory effects is not recommended because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions.

The exception is the use of low dose ASA for cardiovascular protection, when another NSAID is being used for its analgesic/anti-inflammatory effect, keeping in mind that combination NSAID therapy is associated with additive adverse reactions.

Some NSAIDs (e.g. ibuprofen) may interfere with the antiplatelet effects of low dose ASA, possibly by competing with ASA for access to the active site of cyclooxygenase-1.

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%.

When CELEBREX capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in C_max and AUC, which is thought to be due to the low solubility of the drug in aqueous media.

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. Furthermore, patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Consider starting treatment at half the lowest recommended dose.

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.

Interactions with laboratory tests have not been established.

Although this interaction has not been studied with celecoxib, co-administration of cyclosporin or tacrolimus and any NSAID may increase the nephrotoxic effect of cyclosporin or tacrolimus due to the NSAID's effect on renal prostaglandins. Renal function should be monitored when celecoxib and either of these drugs is used in combination.

The interaction of CELEBREX with herbal medications or supplements has not been studied.

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, gold compounds, indapamide, insulin, nephrotoxic agents, non-steroidal anti-inflammatory agents, oral contraceptives, potassium supplements, probenecid, valproic acid, zidovudine.

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 Action and Clinical 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.

Clinical studies, as well as post marketing observations, have shown that NSAIDs can reduce the effects of diuretics. 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.

NSAIDs may diminish the antihypertensive effects of Angiotensin Converting Enzyme (ACE) inhibitors. This interaction should be given consideration. Combinations of ACE inhibitors, angiotensin-II antagonists, or diuretics with NSAIDs might have an increased risk for acute renal failure and hyperkalemia. Blood pressure and renal function (including electrolytes) should be monitored more closely in this situation, as occasionally there can be a substantial increase in blood pressure

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).

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.

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

No dosage adjustment is necessary for patients with creatinine clearance >30 mL/min (see Action and Clinical Pharmacology, Pharmacokinetics, Special Populations and Conditions). CELEBREX is contraindicated in patients with severe renal impairment (estimated creatinine clearance <30 mL/min) (see Contraindications).

Patients who are known, or suspected to be CYP2C9 poor metabolizers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution. The maximum recommended dose in CYP2C9 poor metabolizers is 100 mg daily. (see Warnings and Precautions, Special Populations).

Patients who miss one or more doses of CELEBREX (celecoxib) should not increase the dose of CELEBREX to compensate for the missed dose or doses, but should continue therapy as soon as possible, then take the next dose at the scheduled time.

CELEBREX can be taken with or without food.

CELEBREX capsule should be introduced at the lowest dose in patients with mild hepatic impairment (Child-Pugh 5-6). The daily recommended dose of CELEBREX capsules in patients with moderate hepatic impairment (Child-Pugh 7-9) should be reduced by 50% and should be given at the lowest dose of 100 mg once daily (see Action and Clinical Pharmacology, Pharmacokinetics, Special Populations and Conditions). CELEBREX is contraindicated in patients with severe hepatic impairment (Child-Pugh >9) (see Contraindications).

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.

Use of CELEBREX should be limited to the lowest effective dose for the shortest possible duration of treatment (see Contraindications and Warnings and Precautions).

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.

In the elderly, frail and debilitated, the dosage should be reduced to the lowest level providing control of symptoms, and adjusted when necessary (see Warnings and Precautions, Special Populations, Geriatrics (>65 years of age)).

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.

conjunctivitis.

acute renal failure.

prostatic disorder.

Two studies involving patients with sporadic adenomatous polyps were conducted with celecoxib: the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Colorectal Sporadic Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint of cardiovascular death, myocardial infarction, or stroke (adjudicated) 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, as shown in Table 3.

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

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

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

taste perversion.

bronchospasm.

aggravated epilepsy, aseptic meningitis, ageusia, anosmia.

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

ecchymosis, epistaxis, thrombocythemia.

A total of 896 patients were treated with CELEBREX in placebo- and active-controlled ankylosing spondylitis studies for a maximum duration of 12 weeks. CELEBREX was also studied in one long-term open label extension study up to 2 years in 215 patients with ankylosing spondylitis. The average daily dose was 200 mg. The types of adverse events reported in the ankylosing spondylitis studies were generally similar to those reported in the arthritis studies. The percentage of patients with hypertension (6.1%) and serious GI adverse events (3.7%) in the 2­year, open­label extension study, were greater than those reported in the 12­week studies, respectively of 0.7% and 0.0 %. The most common Gastro-Intestinal disorders reported in the 2-year extension study compared to those reported in the 12­week studies include Diarrhea (15.0% vs. 4.5%), Abdominal Pain upper (13.6 % vs. 3.8%), Dyspepsia (9.8% vs. 3.7%), Nausea (5.6% vs. 2.8%) and Abdominal Pain (5.6% vs. 1.5%). The percentage of patients with cardio-vascular events (1.4%) in the 2-year open-label extension study was similar to that observed in the CLASS trials.

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

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

hypoglycemia.

myositis.

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

sepsis, sudden death.

vasculitis, cerebral hemorrhage.

anemia.

deafness, ear abnormality, earache, tinnitus.

palpitation, tachycardia.

pancytopenia, agranulocytosis, aplastic anemia, leukopenia.

gastrointestinal hemorrhage, acute pancreatitis.

confusion, hallucinations.

Indications and dosages of the PreSAP and APC trials are not approved in Canada. Exposure to CELEBREX in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years; Among adverse reactions that occurred in higher percentages of patients than in the arthritis pre- marketing trials (treatment durations up to 12 weeks; (see Adverse Reactions, Clinical Trial Adverse Drug Reactions—New Drug Submission (NDS) Arthritis Trials), hypertension was reported at an incidence of 12.5 % in the celecoxib group (400-800 mg daily dose) compared to 9.8% in the placebo group.

menstrual disorder.

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

Additional reports of serious adverse events temporally associated with CELEBREX during worldwide post-marketing experience are included below. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or clearly establish a causal relationship to CELEBREX exposure.

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.

congestive heart failure, heart failure, myocardial infarction.

decreased hearing.

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.

acute renal failure, interstitial nephritis, hyponatremia.

Serious bleeding (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).

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

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

liver failure (with fatal outcome), fulminant hepatitis (with fatal outcome), liver necrosis, hepatitis, jaundice.

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

ataxia.

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

cholelithiasis, hepatitis, jaundice, liver failure.

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 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.

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

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

serious allergic reactions, anaphylactic shock.

thrombocytopenia.

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

Safety and Efficacy have not been established in the paediatric population (see Contraindications).

Evidence from clinical studies and postmarket experience suggests that use in geriatric population is associated with differences in safety (see Warnings and Precautions, Special Populations, Geriatrics (>65 years of age)).

Each white to off-white hard gelatin capsule, with gold ink band on body marked in white with “200” and with gold ink band on cap marked in white with “7767”, contains: celecoxib 200 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate; shell: edible ink (ferric oxide [E172]), gelatin and titanium dioxide (E171). Bottles of 100 and 500.

Each white to off white hard gelatin capsule, with blue ink band on body marked in white with “100” and with blue ink band on cap marked in white with “7767”, contains: celecoxib 100 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate; shell: edible ink (indigotine [E132]), gelatin and titanium dioxide (E171). Bottles of 100 and 500.

Renal function (serum creatinine and serum urea etc.) should be monitored in high-risk populations, such as the elderly, patients with advanced renal disease, patients with cardiovascular disease and diabetes mellitus, as well as in the setting of concomitant use of diuretics and ACE inhibitors (see Contraindications). If abnormal renal tests persist or worsen, CELEBREX should be discontinued.

Patients on long-term treatment with NSAIDs, including CELEBREX, should have their electrolytes such as serum potassium checked regularly if they exhibit any signs or symptoms of renal disease.

See Contraindications, Coronary Artery Bypass Graft Surgery.

Patients who are known, or suspected to be CYP2C9 poor metabolizers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution. The maximum recommended dose in CYP2C9 poor metabolizers is 100 mg daily. (See Drug Interactions.)

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 Drug Interactions, Drug-Drug Interactions, Glucocorticoids).

ASA-induced asthma is an uncommon but very important indication of ASA and NSAID sensitivity. It occurs more frequently in patients with asthma who have nasal polyps.

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

Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of bleeding. Concurrent therapy of CELEBREX with warfarin requires close monitoring of the international normalized ratio (INR).

Even with therapeutic INR monitoring, increased bleeding may occur.

CELEBREX is contraindicated for use during the third trimester of pregnancy because of risk of premature closure of the ductus arteriosus and the potential to prolong parturition.

Caution should be exercised in prescribing CELEBREX during the first and second trimesters of pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or the embryo-fetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy.

In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-fetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

As with other NSAIDs, borderline elevations of one or more liver enzyme tests (AST, ALT, alkaline phosphatase) may occur in up to 15% of patients. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continuing therapy.

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 evaluated for evidence of the development of a more severe hepatic reaction while on therapy with CELEBREX. Severe hepatic reactions, including liver necrosis and hepatic failure (with fatal outcome or requiring liver transplant), fulminant hepatitis (with fatal outcome), and jaundice have been reported with CELEBREX.

Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop (e.g. jaundice), or if systemic manifestations occur (e.g., eosinophilia, associated with rash, etc.), CELEBREX should be discontinued (see Contraindications).

If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.

Patients older than 65 years (referred to in this document as older or elderly) and frail or debilitated patients are more susceptible to a variety of adverse reactions from NSAIDs. The incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal GI events are in this population. Older patients are also at risk of lower esophageal injury including ulceration and bleeding. For such patients, consideration should be given a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision.

CELEBREX has been studied in elderly patients. Of the total number of patients who received CELEBREX in clinical trials, more than 3300 patients (25 %) were 65-74 years of age, while approximately 1300 additional patients (10 %) were 75 years and over (see Adverse Reactions). 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 (see Warnings and Precautions, Gastrointestinal (GI) and Adverse Reactions, Adverse Drug Reaction Overview).

Some NSAIDs are associated with 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 a NSAID. Should urinary symptoms occur, in the absence of alternate explanation, treatment with CELEBREX should be stopped to ascertain if symptoms disappear. This should be done before urological investigations or treatments are carried out.

(See Contraindications.)

Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus, hearing loss, insomnia or depression with the use of NSAIDs, such as CELEBREX. If patients experience such adverse reaction(s), they should exercise caution in carrying out activities that require alertness.

Frail or debilitated patients may tolerate side effects less well and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse event, the lowest effective dose should be used for the shortest possible duration. As with other NSAIDs, caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic or cardiac function. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

CELEBREX is not recommended for use with other NSAIDs , with the exception of low-dose ASA for cardiovascular prophylaxis, because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions (see Drug Interactions, Drug-Drug Interactions, Acetylsalicylic Acid (ASA) or Other NSAIDs).

Serious GI toxicity (sometimes fatal), such as peptic/duodenal ulceration, inflammation, perforation, obstruction and gastrointestinal bleeding, can occur at any time, with or without warning symptoms, in patients treated with NSAIDs, such as 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 CELEBREX, even in the absence of previous GI tract symptoms. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered (see Warnings and Precautions, Special Populations, Geriatrics (>65 years of age)).

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. Most 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 to 6 months, and in about 2% to 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 has its risks.

Caution should be taken if prescribing CELEBREX to patients with a prior history of peptic/duodenal ulcer disease and/or gastrointestinal bleeding as these individuals have a greater than 10-fold higher risk for developing a GI bleed when taking NSAID than patients with neither of these risk factors. Other risk factors for GI ulceration and bleeding include the following: H. pylori infection, increased age, prolonged use of NSAID therapy, excess alcohol intake, smoking, poor general health status or concomitant therapy with any of the following:

• Anticoagulants (e.g. warfarin)

  
  

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

  
  

• Oral corticosteroids (e.g. prednisone)

  
  

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

  
  

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 (celecoxib) exhibited a low incidence of gastroduodenal ulceration and serious clinically significant GI events within clinical trials (see Adverse Reactions, Clinical Trial Adverse Drug Reactions—New Drug Submission (NDS) Arthritis Trials). In a prospective long-term outcome study (CLASS), there were no significant differences in the incidence of complicated ulcers between patients who received a higher-than-therapeutic dose of CELEBREX (400 mg BID) for OA and RA, in the presence of concomitant ASA (N=882 patients), compared to ibuprofen 800 mg TID and diclofenac 75 mg BID. The incidence of complicated and symptomatic ulcers was lower for CELEBREX than for Ibuprofen in patients not taking ASA. In active-controlled studies, the endoscopic gastroduodenal ulceration rate observed with all doses of CELEBREX was less than what was seen with the NSAID comparator and, in placebo-controlled studies, was similar to that seen with placebo.

(See Contraindications.)

The use of CELEBREX, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. Therefore, in women who have difficulties conceiving, or who are undergoing investigation of infertility, withdrawal of CELEBREX should be considered.

Use of NSAIDs, such as CELEBREX, can promote sodium retention in a dose-dependent manner, which can lead to fluid retention and edema, and consequences of increased blood pressure and exacerbation of congestive heart failure. Thus, caution should be exercised in prescribing CELEBREX in patients with a history of congestive heart failure, compromised cardiac function, hypertension, increased age or other conditions predisposing to fluid retention (see Warnings and Precautions, Cardiovascular).

Use of NSAIDs, such as CELEBREX, can increase the risk of hyperkalemia, especially in patients with diabetes mellitus, renal failure, increased age, or those receiving concomitant therapy with adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, cyclosporin, or some diuretics.

Electrolytes should be monitored periodically (see Contraindications).

Fluid retention has been observed in 2.1% of patients taking CELEBREX in clinical trials (see Adverse Reactions, Clinical Trial Adverse Drug Reactions—New Drug Submission (NDS) Arthritis Trials). In a prospective long-term outcome study (CLASS), hypertension was observed in 2.0%, 3,1% and 2.0% of patients receiving 400 mg BID CELEBREX (N=3987), 800 mg TID ibuprofen (N=1985) and 75 mg BID diclofenac (N=1996), respectively. The corresponding rates for edema were: 3.7%, 5.2% and 3.5%, respectively (see Adverse Reactions, Clinical Trial Adverse Drug Reactions—New Drug Submission (NDS) Arthritis Trials).

CELEBREX should not be given to patients with the complete or partial syndrome of ASA-intolerance (rhinosinusitis, urticaria/angioedema, nasal polyps, asthma) in whom asthma, anaphylaxis, urticaria/angioedema, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse reaction (see Contraindications).

Patients sensitive to one NSAID may be sensitive to any of the other NSAID as well.

CELEBREX in common with other NSAIDs, may mask signs and symptoms of an underlying infectious disease.

See Warnings and Precautions, Neurologic.

As with NSAIDs in general, anaphylactoid reactions have occured in patients without known prior exposure to CELEBREX. In post-marketing experience, very rare cases of anaphylactic/anaphylactoid reactions and angioedema have been reported in patients receiving CELEBREX. CELEBREX should not be given to patients with the ASA-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 NSAIDs (see Contraindications).

Patients on long-term treatment with NSAIDs, including CELEBREX, should have their hemoglobin, hematocrit, and blood cell count checked if they exhibit any signs or symptoms of anemia or blood loss.

Concurrent therapy of CELEBREX with warfarin requires close monitoring of the international normalized ratio (INR).

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).

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

Anemia is sometimes seen in patients receiving NSAIDs, including CELEBREX. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including CELEBREX, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.

In controlled clinical trials the incidence of anemia was 0.6% with CELEBREX and 0.4% with placebo. 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, Drug-Drug Interactions and Adverse Reactions, Post-Market Adverse Drug Reactions).

See Warnings and Precautions, Skin.

See Warnings and Precautions, Infection, Aseptic Meningitis.

Rarely, 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.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike acetylsalicylic acid (ASA), their effect on platelet function is quantitatively less, or of shorter duration, and is reversible. CELEBREX does not appear to inhibit platelet aggregation at indicated dosages.

CELEBREX and other NSAIDs have no proven efficacy as antiplatelet agents and should not be used as a substitute for Acetylsalicylic Acid (ASA) or other antiplatelet agents for prophylaxis of cardiovascular thromboembolic diseases. Antiplatelet therapies (e.g. ASA) should not be discontinued. There is some evidence that use of NSAIDs with ASA can markedly attenuate the cardioprotective effects of ASA (see Drug Interactions, Drug-Drug Interactions, Acetylsalicylic Acid (ASA) or Other NSAIDs).

Concomitant administration of CELEBREX with low dose ASA increases the risk of GI ulceration and associated complications.

In rare cases, serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and erythema multiforme have been associated with the use of some NSAIDs. Because the rate of these reactions is low, they have usually been noted during post-marketing surveillance in patients taking other medications also associated with the potential development of these serious skin reactions. Thus, causality is not clear. These reactions are potentially life threatening but may be reversible if the causative agent is discontinued and appropriate treatment instituted. Patients should be advised that if they experience a skin rash they should discontinue their NSAID and contact their physician for assessment and advice, including which additional therapies to discontinue.

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 (see Adverse Reactions, Post-Market Adverse Drug Reactions). 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.

(See Contraindications.)

Patient with symptoms and/or signs of liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with CELEBREX. If abnormal liver tests persist or worsen, CELEBREX should be discontinued.

(Hypertension): Blood pressure should be monitored regularly during therapy with CELEBREX.

A pharmacokinetic study in subjects with mild (Child-Pugh 5-6) and moderate (Child-Pugh 7-9) hepatic impairment has shown that steady-state celecoxib AUC is increased about 40% and 180%, respectively, above that seen in healthy control subjects. Therefore, CELEBREX capsules should be introduced at a reduced dose in patients with moderate hepatic impairment. Patients with severe hepatic impairment have not been studied. The use of CELEBREX in patients with severe hepatic impairment is not recommended (see Contraindications).

At steady state, elderly subjects (over 65 years old) had a 40% higher C_max and a 50% higher AUC compared to the young subjects. In elderly females, celecoxib C_max and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Dose adjustment in the elderly is not generally necessary. However, for elderly patients of less than 50 kg in body weight, initiate therapy at the lowest recommended dose, and as with all other NSAIDs, exercise caution in the use of higher doses.

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.

The pharmacokinetics of celecoxib have been evaluated in approximately 1500 individuals. In addition to healthy, young and elderly volunteers (male and female), pharmacokinetic measurements have been done in patients and also in special populations including individuals with hepatic or renal impairment.

CELEBREX (celecoxib) is a non-steroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and anti-pyretic activities in animals. The mechanism of action of CELEBREX is believed to be related to inhibition of cyclooxygenase-2 (COX-2). COX-2 is expressed at high levels in inflamed tissues where it is induced by mediators of inflammation. COX-2 also plays physiological roles in a limited number of tissues, including those of the female reproductive tract, the kidney and possibly the vascular endothelium. COX-2 has the same catalytic activity as COX-1. COX-1 is expressed constitutively in most tissues including the gastrointestinal tract, kidney, lungs, brain, and platelets. The prostaglandins produced by COX-1 play key roles in the maintenance of physiological functions such as platelet aggregation and are among the factors that maintain the GI mucosal barrier. At therapeutic concentrations (see Dosage and Administration) celecoxib inhibits COX-2 and does not inhibit COX-1.

Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in black patients compared to Caucasians. The cause and clinical significance of this finding is unknown.

When CELEBREX (celecoxib) capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. 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 capsules can be administered without regard to the timing of meals.

Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabelled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t_½) determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 mL/min.

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 (see Contraindications).

Summary of Single Dose (200 mg) Disposition Kinetics of Celecoxib in Healthy Subjects^a

Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors. Cytochrome P450 2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*3 polymorphism. Patients who are known or suspected to be P450 2C9 poor metabolizers based on a previous history should be administered celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. The maximum recommended dose in CYP2C9 poor metabolizers is 100 mg daily. (See Warnings and Precautions, Special Populations, CYP2C9 Poor Metabolizers and Drug Interactions.)

In a pharmacokinetic study of celecoxib 200 mg administered once daily in healthy volunteers, genotyped as either CYP2C9*1/*1, CYP2C9*1/*3, or CYP2C9*3/*3, the median C_max and AUC_0-24 of celecoxib on Day 7 were approximately 4-fold and 7-fold, respectively, in subjects genotyped as CYP2C9*3/*3 compared to other genotypes. In three separate single dose studies, involving a total of 5 subjects genotyped as CYP2C9*3/*3, single-dose AUC_0-24 increased by approximately 3-fold compared to normal metabolizers. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3-1.0% among different ethnic groups.