warnings and cautions
5 WARNINGS AND PRECAUTIONS Myelosuppression: May be severe and prolonged. Monitor complete blood counts and platelet counts during clofarabine therapy. ( 5.1 ) Hemorrhage: Serious and fatal cerebral, gastrointestinal and pulmonary hemorrhage. Monitor platelets and coagulation parameters and treat accordingly. ( 5.2 ) Infections: Severe and fatal sepsis as a result of bone marrow suppression. Monitor for signs and symptoms of infection; discontinue clofarabine and treat promptly. ( 5.3 ) Tumor Lysis syndrome: Anticipate, monitor for signs and symptoms and treat promptly. ( 5.4 ) Systemic Inflammatory Response Syndrome (SIRS) or Capillary Leak Syndrome: Monitor for and discontinue clofarabine immediately if suspected. ( 5.5 ) Venous Occlusive Disease of the Liver: Monitor for and discontinue clofarabine if suspected. ( 5.6 ) Hepatotoxicity: Severe and fatal hepatotoxicity. Monitor liver function, for signs and symptoms of hepatitis and hepatic failure. Discontinue clofarabine immediately for Grade 3 or greater liver enzyme and/or bilirubin elevations. ( 5.7 ) Renal Toxicity: Increased creatinine and acute renal failure; monitor renal function and interrupt or discontinue clofarabine. ( 5.8 ) Enterocolitis: Serious and fatal enterocolitis, occurring more frequently within 30 days of treatment and with combination chemotherapy. Monitor patients for signs and symptoms of enterocolitis and treat promptly. ( 5.9 ) Skin Reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases. Discontinue for exfoliative or bullous rash, or if SJS or TEN is suspected. ( 5.10 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.11 ) 5.1 Myelosuppression Clofarabine causes myelosuppression which may be severe and prolonged. Febrile neutropenia occurred in 55% and non-febrile neutropenia in an additional 10% of pediatric patients in clinical trials. At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia. Myelosuppression is usually reversible with interruption of clofarabine treatment and appears to be dose-dependent. Monitor complete blood counts [see Dosage and Administration ( 2.4 )] . 5.2 Hemorrhage Serious and fatal hemorrhage, including cerebral, gastrointestinal and pulmonary hemorrhage, has occurred. The majority of the cases were associated with thrombocytopenia. Monitor platelets and coagulation parameters and treat accordingly [see Adverse Reactions ( 6.2 )] . 5.3 Infections Clofarabine increases the risk of infection, including severe and fatal sepsis, and opportunistic infections. At baseline, 48% of the pediatric patients had one or more concurrent infections. A total of 83% of patients experienced at least one infection after clofarabine treatment, including fungal, viral and bacterial infections. Monitor patients for signs and symptoms of infection, discontinue clofarabine, and treat promptly. 5.4 Tumor Lysis Syndrome Administration of clofarabine may result in tumor lysis syndrome associated with the break-down metabolic products from peripheral leukemia cell death. Monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome and initiate preventive measures including adequate intravenous fluids and measures to control uric acid. 5.5 Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome Clofarabine may cause a cytokine release syndrome (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that may progress to the systemic inflammatory response syndrome (SIRS) with capillary leak syndrome and organ impairment which may be fatal. Monitor patients frequently for these conditions. In clinical trials, SIRS was reported in two patients (2%); capillary leak syndrome was reported in four patients (4%). Symptoms included rapid onset of respiratory distress, hypotension, pleural and pericardial effusion, and multiorgan failure. Close monitoring for this syndrome and early intervention may reduce the risk. Immediately discontinue clofarabine and provide appropriate supportive measures. The use of prophylactic steroids (e.g., 100 mg/m 2 hydrocortisone on Days 1 through 3) may be of benefit in preventing signs or symptoms of SIRS or capillary leak syndrome. Consider use of diuretics and/or albumin. After the patient is stabilized and organ function has returned to baseline, retreatment with clofarabine can be considered with a 25% dose reduction. 5.6 Venous Occlusive Disease of the Liver Patients who have previously received a hematopoietic stem cell transplant (HSCT) are at higher risk for veno-occlusive disease (VOD) of the liver following treatment with clofarabine (40 mg/m 2 ) when used in combination with etoposide (100 mg/m 2 ) and cyclophosphamide (440 mg/m 2 ). Severe hepatotoxic events have been reported in a combination study of clofarabine in pediatric patients with relapsed or refractory acute leukemia. Two cases (2%) of VOD in the monotherapy studies were considered related to study drug. Monitor for and discontinue clofarabine if VOD is suspected. 5.7 Hepatotoxicity Severe and fatal hepatotoxicity, including hepatitis and hepatic failure, has occurred with the use of clofarabine . In clinical studies, Grade 3-4 liver enzyme elevations were observed in pediatric patients during treatment with clofarabine at the following rates: elevated aspartate aminotransferase (AST) occurred in 36% of patients; elevated alanine aminotransferase (ALT) occurred in 44% of patients. AST and ALT elevations typically occurred within 10 days of clofarabine administration and returned to Grade 2 or less within 15 days. Grade 3 or 4 elevated bilirubin occurred in 13% of patients, with 2 events reported as Grade 4 hyperbilirubinemia (2%), one of which resulted in treatment discontinuation and one patient had multiorgan failure and died. Eight patients (7%) had Grade 3 or 4 elevations in serum bilirubin at the last time point measured; these patients died due to sepsis and/or multiorgan failure. Monitor hepatic function, and for signs and symptoms of hepatitis and hepatic failure. Discontinue clofarabine immediately for Grade 3 or greater liver enzyme and/or bilirubin elevations [see Dosage and Administration ( 2.4 )] . 5.8 Renal Toxicity Clofarabine may cause acute renal failure. In clofarabine treated patients in clinical studies, Grade 3 or 4 elevated creatinine occurred in 8% of patients and acute renal failure was reported as Grade 3 in three patients (3%) and Grade 4 in two patients (2%). Patients with infection, sepsis, or tumor lysis syndrome may be at increased risk of renal toxicity when treated with clofarabine. Hematuria occurred in 13% of clofarabine treated patients overall. Monitor patients for renal toxicity and interrupt or discontinue clofarabine as necessary [see Dosage and Administration ( 2.4 )] . 5.9 Enterocolitis Fatal and serious cases of enterocolitis, including neutropenic colitis, cecitis, and C. difficile colitis, have occurred during treatment with clofarabine. This has occurred more frequently within 30 days of treatment, and in the setting of combination chemotherapy. Enterocolitis may lead to necrosis, perforation, hemorrhage or sepsis complications. Monitor patients for signs and symptoms of enterocolitis and treat promptly. 5.10 Skin Reactions Serious and fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Discontinue clofarabine for exfoliative or bullous rash, or if SJS or TEN is suspected [see Adverse Reactions ( 6.2 )] . 5.11 Embryo-Fetal Toxicity Based on findings from animal reproductive studies and the drug's mechanism of action, clofarabine can cause fetal harm when administered to a pregnant woman. Intravenous doses of clofarabine in rats and rabbits administered during organogenesis at doses that were below the maximum recommended human dose of 52 mg/m 2 based on body surface area (mg/m 2 ) caused an increase in resorptions, malformations, and variations. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment with clofarabine and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with clofarabine and for 3 months after the last dose [see Use in Specific Populations ( 8.1 )] .