CELECOXIB: Package Insert and Label Information (Page 3 of 6)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of celecoxib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure

Cardiovascular : Vasculitis, deep venous thrombosis

General: Anaphylactoid reaction, angioedema

Liver and biliary : Liver necrosis, hepatitis, jaundice, hepatic failure

Hemic and lymphatic : Agranulocytosis, aplastic anemia, pancytopenia, leucopenia

Metabolic: Hypoglycemia, hyponatremia

Nervous : Aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage

Renal : Interstitial nephritis

7. DRUG INTERACTIONS

See Table 3 for clinically significant drug interactions with Celecoxib.

Table 3: Clinically Significant Drug Interactions with Celecoxib

Drugs That Interfere with Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding [ see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, Celecoxib (200 mg to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 mg to 325 mg).
Intervention:	Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11) ]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ] . When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance . The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2) ] .
Intervention:	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	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 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient’s medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	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 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient’s medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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

Risk Summary

Use of NSAIDs, including celecoxib, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including celecoxib, in pregnant women starting at 30 weeks of gestation.

There are no adequate and well-controlled studies of celecoxib in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryo-fetal deaths and an increase in diaphragmatic hernias were observed in rats administered celecoxib daily during the period of organogenesis at oral doses approximately 6 times the maximum recommended human dose (MRHD) of 200 mg twice daily. In addition, structural abnormalities (e.g., septal defects, ribs fused, sternebrae fused and sternebrae misshapen) were observed in rabbits given daily oral doses of celecoxib during the period of organogenesis at approximately 2 times the MRHD [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as celecoxib, resulted in increased pre- and post-implantation loss.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss.

Clinical Considerations

Labor or Delivery

There are no studies on the effects of celecoxib during labor or delivery. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data

Human Data

The available data do not establish the presence or absence of developmental toxicity related to the use of celecoxib.

Animal data

Celecoxib at oral doses ≥150 mg/kg/day (approximately 2 times the human exposure at 200 mg twice daily as measured by AUC _0-24 ), 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 times human exposure based on the AUC _0-24 at 200 mg twice daily for RA) throughout organogenesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses at oral doses ≥50 mg/kg/day (approximately 6 times human exposure based on the AUC _0-24 at 200 mg twice daily for RA).

Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 7-fold human exposure as measured by the AUC _0-24 at 200 mg twice daily). The effects of celecoxib on labor and delivery in pregnant women are unknown.