Celecoxib - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity.

Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop • Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs.

Monitor blood pressure ( 5.4 , 7 ) • Heart Failure and Edema : Avoid use of celecoxib capsules in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure • Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.

Avoid use of celecoxib capsules in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function • Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs • Exacerbation of Asthma Related to Aspirin Sensitivity : Celecoxib capsules are contraindicated in patients with aspirin-sensitive asthma.

Monitor patients with preexisting asthma (without aspirin sensitivity) • Serious Skin Reactions : Discontinue celecoxib capsules at first appearance of skin rash or other signs of hypersensitivity • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically. • Fetal Toxicity : Limit use of NSAIDs, including celecoxib capsules, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction.

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. ( 5.11 , 8.1 ) • Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.12 , 7 ) 5.1 Cardiovascular Thrombotic Events Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal.

Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs.

The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease.

However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate.

Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment.

The increase in CV thrombotic risk has been observed most consistently at higher doses.

In the APC (Adenoma Prevention with Celecoxib) trial, there was about a threefold increased risk of the composite endpoint of cardiovascular death, MI, or stroke for the celecoxib capsules 400 mg twice daily and celecoxib capsules 200 mg twice daily treatment arms compared to placebo.

The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction [see Clinical Studies ].

A randomized controlled trial entitled the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs.

Ibuprofen Or Naproxen (PRECISION) was conducted to assess the relative cardiovascular thrombotic risk of a COX-2 inhibitor, celecoxib, compared to the non-selective NSAIDs naproxen and ibuprofen.

Celecoxib 100 mg twice daily was non-inferior to naproxen 375 to 500 mg twice daily and ibuprofen 600 to 800 mg three times daily for the composite endpoint of the Antiplatelet Trialists' Collaboration (APTC), which consists of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, and nonfatal stroke [see Clinical Studies ].

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible.

Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms.

Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

The concurrent use of aspirin and an NSAID, such as celecoxib, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions ].

Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.

NSAIDs are contraindicated in the setting of CABG [see Contraindications ].

Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment.

In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients.