3) For the relief of signs and symptoms of ankylosing spondylitis.

4) For the management of acute pain in adults.

5) For the treatment of primary dysmenorrhea.

6) To reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis (FAP), as an adjunct to usual care (e.g., endoscopic surveillance, surgery).

CONTRAINDICATIONS:

CELECOXIB is contraindicated in patients with known hypersensitivity to CELECOXIB. CELECOXIB should not be given to patients who have demonstrated allergic-type reactions to sulfonamides. CELECOXIB should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. CELECOXIB is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.

CLINICAL PHARMACOLOGY:

Mechanism of Action: The mechanism of action of CELECOXIB is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, CELECOXIB does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme.

Fluid Retention

Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone.

Pharmacokinetics:

Absorption

Peak plasma levels of CELECOXIB occur approximately 3 hrs after an oral dose. Under fasting conditions, both peak plasma levels (cmax) and area under the curve (AUC) are roughly dose proportional up to 200 mg BID. Absolute bioavailability studies have not been conducted. With multiple dosing, steady state conditions are reached on or before Day 5.

Food Effects

When 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%. Coadministration of CELECOXIB with an aluminum- and magnesium-containing antacid resulted in a reduction in plasma CELECOXIB concentrations with a decrease of 37% in cmax and 10% in AUC.

Distribution

CELECOXIB is highly protein bound (~97%) within the clinical dose range. Metabolism

CELECOXIB metabolism is primarily mediated via cytochrome P450 2C9. Excretion

CELECOXIB is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine.

Special Populations

Geriatric: At steady state, elderly subjects (over 65 years old) had a 40% higher cmax and a 50% higher AUC compared to the young subjects.

Hepatic Insufficiency: The daily recommended dose of CELECOXIB capsules should be reduced by approximately 50% in patients with moderate (Child-Pugh Class B) hepatic impairment.

Renal Insufficiency: Similar to other NSAIDs, CELECOXIB is not recommended in patients with severe renal insufficiency.

Drug Interactions

General: Significant interactions may occur when CELECOXIB is administered together with drugs that inhibit P450 2C9.

Clinical studies with CELECOXIB have identified potentially significant interactions with fluconazole and lithium. Experience with nonsteroidal anti-inflammatory drugs (NSAIDs) suggests the potential for interactions with furosemide and ACE inhibitors. The effects of CELECOXIB on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, methotrexate, phenytoin, and tolbutamide have been studied in vivo and clinically important interactions have not been found.

CLINICAL STUDIES

Osteoarthritis (OA): CELECOXIB has demonstrated significant reduction in joint pain compared to placebo. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100 mg BID or 200 mg QD.

Rheumatoid Arthritis (RA): CELECOXIB has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. Although CELECOXIB 100 mg BID and 200 mg BID provided similar overall effectiveness, some patients derived additional benefit from the 200 mg BID dose.

Analgesia, including primary dysmenorrhea: In acute analgesic models of post-oral surgery pain, post-orthopedic surgical pain, and primary dysmenorrhea, CELECOXIB relieved pain that was rated by patients as moderate to severe.

Ankylosing Spondylitis (AS): CELECOXIB was evaluated in AS patients in two placebo- and active-controlled clinical trials of 6 and 12 weeks duration. CELECOXIB at doses of 100 mg BID, 200 mg QD and 400 mg QD was shown to be statistically superior to placebo in these studies.

Familial Adenomatous Polyposis (FAP): CELECOXIB was evaluated to reduce the number of adenomatous colorectal polyps.

Endoscopic Studies

The correlation between findings of short-term endoscopic studies with CELECOXIB and the relative incidence of clinically significant serious upper GI events with long-term use has not been established.

WARNINGS:

Cardiovascular Risk

CELECOXIB may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with duration of use.

CELECOXIB is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal Risk

NSAIDs, including CELECOXIB, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.

Hypertension

As with all NSAIDS, CELECOXIB can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs, including CELECOXIB.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Advanced Renal Disease

Therefore, treatment with CELECOXIB is not recommended in these patients with advanced renal disease.

Anaphylactoid Reactions

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

Skin Reactions

CELECOXIB is a sulfonamide and can cause serious skin adverse events such as exfoliative dermatitis, Stevens Johnson syndrome (SJS), and toxic epidermal necrolysis (TENS), which can be fatal.

Pregnancy

In late pregnancy CELECOXIB should be avoided because it may cause premature closure of the ductus arteriosus.

Familial Adenomatous Polyposis (FAP):

Treatment with CELECOXIB in FAP has not been shown to reduce the risk of gastrointestinal cancer or the need for prophylactic colectomy or other FAP-related surgeries.

PRECAUTIONS:

Hepatic Effects: Borderline elevations of one or more liver associated enzymes may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST (approximately 3 or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), CELECOXIB should be discontinued.

Hematological Effects: Anemia is sometimes seen in patients receiving CELECOXIB.

Preexisting Asthma: Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, CELECOXIB should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Laboratory Tests: Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have a CBC and a chemistry profile checked periodically. If abnormal liver tests or renal tests persist or worsen, CELECOXIB should be discontinued.

Pregnancy: Pregnancy Category C.

Nursing mothers: Limited data from one subject indicate that CELECOXIB is also excreted in human milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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

Geriatric Use

As with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients.

Drug Interactions:

General: CELECOXIB metabolism is predominantly mediated via cytochrome P450 2C9 in the liver. Co-administration of CELECOXIB with drugs that are known to inhibit 2C9 should be done with caution. There is a potential for an in vivo drug interaction with drugs that are metabolized by P450 2D6.

ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors.

Aspirin: CELECOXIB can be used with low-dose aspirin. However, concomitant administration of aspirin with CELECOXIB increases the rate of GI ulceration or other complications. Because of its lack of platelet effects, CELECOXIB is not a substitute for aspirin for cardiovascular prophylaxis.

Fluconazole: Concomitant administration of fluconazole at 200 mg QD resulted in a two-fold increase in CELECOXIB plasma concentration.

Furosemide: Clinical studies, as well as post marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients.

Lithium: Patients on lithium treatment should be closely monitored when CELECOXIB is introduced or withdrawn.

Warfarin: Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing CELECOXIB therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding .

SIDE EFFECTS:

Adverse events from CELECOXIB premarketing controlled arthritis trials: Table 3 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.

Table 3
Adverse Events Occurring in >2% of CELEB REX Patients From CELECOXIB Premarketing Controlled Arthritis Trials

OVERDOSAGE:

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.

DOSAGE AND ADMINISTRATION:

For osteoarthritis and rheumatoid arthritis, the lowest dose of CELECOXIB should be sought for each patient. These doses can be given without regard to timing of meals.

Osteoarthritis: For relief of the signs and symptoms of osteoarthritis the recommended oral dose is 200 mg per day administered as a single dose or as 100 mg twice per day.

Rheumatoid arthritis: For relief of the signs and symptoms of rheumatoid arthritis the recommended oral dose is 100 to 200 mg twice per day.

Ankylosing Spondylitis (AS): For the management of the signs and symptoms of AS, the recommended dose of CELECOXIB is 200 mg daily single (once per day) or divided (twice per day) doses. If no effect is observed after 6 weeks, a trial of 400 mg daily may be worthwhile. If no effect is observed after 6 weeks on 400 mg daily, a response is not likely and consideration should be given to alternate treatment options.

Management of Acute Pain and Treatment of Primary Dysmenorrhea: The recommended dose of CELECOXIB is 400 mg initially, followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily as needed.

Familial adenomatous polyposis (FAP): Usual medical care for FAP patients should be continued while on CELECOXIB. To reduce the number of adenomatous colorectal polyps in patients with FAP, the recommended oral dose is 400 mg twice per day to be taken with food.

Special Populations

Hepatic insufficiency: The daily recommended dose of CELECOXIB capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by approximately 50%. The use of CELECOXIB in patients with severe hepatic impairment is not recommended.

How Supplied: Pack of 100 capsuless in 10 blisters.

stotage: Store at 25°C (77°F); excursions permitted to 15-30°C.

Reference: PDR 2000, page 2334

                  USPDI for Professional Health Care, 2004, Page 746

                  Martindale 2005, Page 25