CELEBREX (Page 5 of 9)

6.5 The APC and PreSAP Trials

Adverse reactions from long-term, placebo-controlled polyp prevention studies: Exposure to CELEBREX in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years [see Special Studies Adenomatous Polyp Prevention Studies (14.6) ].

Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing trials (treatment durations up to 12 weeks; see Adverse events from CELEBREX pre-marketing controlled arthritis trials, above). The adverse reactions for which these differences in patients treated with CELEBREX were greater as compared to the arthritis pre-marketing trials were as follows:

CELEBREX(400 to 800 mg daily)N = 2285 PlaceboN=1303
Diarrhea 10.5% 7.0%
Gastroesophageal reflux disease 4.7% 3.1%
Nausea 6.8% 5.3%
Vomiting 3.2% 2.1%
Dyspnea 2.8% 1.6%
Hypertension 12.5% 9.8%

The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking CELEBREX, at an incidence greater than placebo in the long-term polyp prevention studies and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in the long-term, placebo-controlled polyp prevention studies:

Nervous system disorders: Cerebral infarction
Eye disorders : Vitreous floaters, conjunctival hemorrhage
Ear and labyrinth : Labyrinthitis
Cardiac disorders : Angina unstable, aortic valve incompetence, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy
Vascular disorders : Deep vein thrombosis
Reproductive system and breast disorders : Ovarian cyst
Investigations : Blood potassium increased, blood sodium increased, blood testosterone decreased
Injury, poisoning and procedural complications: Epicondylitis, tendon rupture

7. DRUG INTERACTIONS

General: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 should be done with caution. Significant interactions may occur when celecoxib is administered together with drugs that inhibit CYP2C9.

In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6.

7.1 Warfarin

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 2–5 mg doses of warfarin. 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 which were fatal, have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving CELEBREX concurrently with warfarin.

7.2 Lithium

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

7.3 Aspirin

CELEBREX can be used with low-dose aspirin. However, concomitant administration of aspirin with CELEBREX increases the rate of GI ulceration or other complications, compared to use of CELEBREX alone [see Warnings and Precautions (5.1, 5.4) and Clinical Studies (14.6)]. Because of its lack of platelet effects, CELEBREX is not a substitute for aspirin for cardiovascular prophylaxis [see Clinical Pharmacology (12.2) ].

7.4 ACE-inhibitors and Angiotensin II Antagonists

Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors and angiotensin II antagonists. This interaction should be given consideration in patients taking CELEBREX concomitantly with ACE-inhibitors and angiotensin II antagonists [see Clinical Pharmacology (12.2 ].

7.5 Fluconazole

Concomitant administration of fluconazole at 200 mg once daily 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 Clinical Pharmacology (12.3) ]. CELEBREX should be introduced at the lowest recommended dose in patients receiving fluconazole.

7.6 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. This response has been attributed to inhibition of renal prostaglandin synthesis.

7.7 Methotrexate

In an interaction study of rheumatoid arthritis patients taking methotrexate, CELEBREX did not have an effect on the pharmacokinetics of methotrexate [see Clinical Pharmacology (12.3) ].

7.8 Concomitant NSAID Use

The concomitant use of CELEBREX with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Pregnancy category D from 30 weeks of gestation onward.

Teratogenic effects: Celecoxib at oral doses ≥150 mg/kg/day (approximately 2-fold human exposure at 200 mg twice daily as measured by AUC0–24 ), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6-fold human exposure based on the AUC0–24 at 200 mg twice daily) throughout organogenesis. There are no studies in pregnant women. CELEBREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic effects: Celecoxib produced pre-implantation and post-implantation losses and reduced embryo/fetal survival in rats at oral dosages ≥50 mg/kg/day (approximately 6-fold human exposure based on the AUC0–24 at 200 mg twice daily). These changes are expected with inhibition of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function, nor are they expected at clinical exposures. No studies have been conducted to evaluate the effect of celecoxib on the closure of the ductus arteriosus in humans. Therefore, use of CELEBREX during the third trimester of pregnancy should be avoided.

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