Drug interactions between Bextra and clofarabine

valdecoxib ↔ clofarabine

Applies to:Bextra (valdecoxib) and clofarabine

GENERALLY AVOID: Coadministration with drugs that are nephrotoxic may reduce the clearance of clofarabine, which is primarily eliminated by renal excretion, and potentiate the risk of renal toxicity associated with clofarabine use. In clinical trials for clofarabine, grade 3 or 4 elevations in creatinine occurred in 8% of patients, and acute renal failure was reported in 3% at grade 3 and 2% at grade 4. Nonsteroidal anti-inflammatory drugs (NSAIDs) can also adversely affect the kidney, particularly when given at high dosages or for prolonged periods. Elevations in serum creatinine and BUN, tubular necrosis, glomerulitis, renal papillary necrosis, acute interstitial nephritis, nephrotic syndrome, and renal failure have been reported during chronic use. In patients with prerenal conditions whose renal perfusion may be dependent on the function of prostaglandins, NSAIDs may precipitate overt renal decompensation via a dose-related inhibition of prostaglandin synthesis. Patients at greatest risk include patients with impaired renal function, heart failure, liver dysfunction, or substantial sodium and/or volume depletion (e.g., due to diuretics).

GENERALLY AVOID: The liver is a known target organ for clofarabine toxicity, and concomitant use of agents known to induce hepatotoxicity may potentiate the risk of liver injury. In clinical trials for clofarabine, grade 3 or 4 elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) occurred in 36% and 44% of patients, respectively, while grade 3 or 4 elevations in bilirubin occurred in 13%. The majority of hepatobiliary enzyme elevations occurred within 10 days of clofarabine administration and returned to <=grade 2 within 15 days. However, some patients discontinued treatment due to hepatobiliary enzyme elevations. Rarely, veno-occlusive disease (in patients who have previously received a hematopoietic stem cell transplant and concomitantly treated with other chemotherapeutic agents) and other severe hepatotoxic events have been observed. Nonsteroidal anti-inflammatory drugs (NSAIDs) can also adversely affect the liver. Borderline elevations of serum transaminases, LDH, and alkaline phosphatase have been reported in up to 15% of patients treated with NSAIDs. These abnormalities may progress, remain unchanged, or regress with continuing therapy. Notable liver enzyme elevations exceeding 3 times the upper limit of normal have occurred in approximately 1% of patients in clinical trials. In addition, rare cases of severe hepatotoxicity, including liver necrosis, hepatic failure, jaundice and fatal fulminant hepatitis, have been reported. Some NSAIDs such as bromfenac, nimesulide, and lumiracoxib have been withdrawn from the market, or have never been marketed, due to severe hepatotoxicity.

MANAGEMENT: If possible, drugs that are potentially nephrotoxic including NSAIDs should be avoided during the 5 days of clofarabine administration. Because NSAIDs are also potentially hepatotoxic, it may be appropriate to avoid them altogether in some patients during clofarabine therapy. If an NSAID is required, ibuprofen appears to have the highest liver safety profile among NSAIDs, while diclofenac and sulindac have been linked to a higher frequency of liver damage. Patients treated with clofarabine should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, light-colored stools, and jaundice. Renal and hepatic function should be monitored prior to and daily during the 5 days of clofarabine administration. If substantial (e.g., grade 3 or higher) increases in creatinine or bilirubin are noted, discontinue clofarabine administration until the patient is stable and organ function has returned to baseline, at which time clofarabine may be reinstituted (generally with a 25% dose reduction).