inue clofarabine injection 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 injection. (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) 5.1 myelosuppression clofarabine injection 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 injection treatment and appears to be dose-dependent. monitor complete blood counts [see dosage and administration (2.3)]. 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 injection 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 injection treatment, including fungal, viral and bacterial infections. monitor patients for signs and symptoms of infection, discontinue clofarabine injection, and treat promptly. 5.4 hyperuricemia (tumor lysis) administration of clofarabine injection 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 injection 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 multi-organ failure. close monitoring for this syndrome and early intervention may reduce the risk. immediately discontinue clofarabine injection and provide appropriate supportive measures. the use of prophylactic steroids (e.g., 100 mg/m2 hydrocortisone on days 1 through 3) may be of benefit in preventing signs or symptoms of sirs or capillary leak. consider use of diuretics and/or albumin. after the patient is stabilized and organ function has returned to baseline, re-treatment with clofarabine injection 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/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). 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 mono-therapy studies were considered related to study drug. monitor for and discontinue clofarabine injection if vod is suspected. 5.7 hepatotoxicity severe and fatal hepatotoxicity, including hepatitis and hepatic failure, has occurred with the use of clofarabine injection [see adverse reactions (6.2)]. in clinical studies, grade 3-4 liver enzyme elevations were observed in pediatric patients during treatment with clofarabine injection 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 injection 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 multi-organ 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 multi-organ failure. monitor hepatic function and for signs and symptoms of hepatitis and hepatic failure. discontinue clofarabine injection immediately for grade 3 or greater liver enzyme and/or bilirubin elevations [see adverse reactions (6.1)]. 5.8 renal toxicity clofarabine injection may cause acute renal failure. in clofarabine injection 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 injection. hematuria occurred in 13% of clofarabine injection treated patients overall. monitor patients for renal toxicity and interrupt or discontinue clofarabine injection as necessary [see adverse reactions (6.1)]. 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 [see adverse reactions (6.2)]. 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 clofarabine injection can cause fetal harm when administered to a pregnant woman. intravenous doses of clofarabine in rats and rabbits administered during organogenesis caused an increase in resorptions, malformations, and variations [see use in specific populations (8.1)].

sing the actual height and weight before the start of each cycle. to prevent drug incompatibilities, no other medications should be administered through the same intravenous line. provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the 5 days of clofarabine injection administration to reduce the effects of tumor lysis and other adverse events. discontinue clofarabine injection if hypotension develops during the 5 days of administration. monitor renal and hepatic function during the 5 days of clofarabine injection administration [see warnings and precautions (5.7, 5.8)]. monitor patients taking medications known to affect blood pressure. monitor cardiac function during administration of clofarabine injection. reduce the dose by 50% in patients with creatinine clearance (crcl) between 30 and 60 ml/min. there is insufficient information to make a dosage recommendation in patients with crcl less than 30 ml/min [see use in specific populations (8.7)]. 2.2 supportive medications and medications to avoid consider prophylactic anti-emetic medications as clofarabine injection is moderately emetogenic. consider the use of prophylactic steroids to mitigate systemic inflammatory response syndrome (sirs) or capillary leak syndrome (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema). minimize exposure to drugs with known renal toxicity during the 5 days of clofarabine injection administration since the risk of renal toxicity may be increased. consider avoiding concomitant use of medications known to induce hepatic toxicity. 2.3 dose modifications and reinitiation of therapy hematologic toxicity administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patient’s anc is ≥0.75 × 10 9 /l. if a patient experiences a grade 4 neutropenia (anc <0.5 × 10 9 /l) lasting ≥4 weeks, reduce dose by 25% for the next cycle. non-hematologic toxicity withhold clofarabine injection if a patient develops a clinically significant infection, until the infection is controlled, then restart at the full dose. withhold clofarabine injection for a grade 3 non-infectious non-hematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting controlled by antiemetic therapy). re-institute clofarabine injection administration at a 25% dose reduction when resolution or return to baseline. 2.4 reconstitution/preparation clofarabine injection should be filtered through a sterile 0.2 micron syringe filter and then diluted with 5% dextrose injection, usp, or 0.9% sodium chloride injection, usp, prior to intravenous (iv) infusion to a final concentration between 0.15 mg/ml and 0.4 mg/ml. use within 24 hours of preparation. store diluted clofarabine injection at room temperature (15-30 º c). 2.5 incompatibility do not administer any other medications through the same intravenous line.

chiae. (6) to report suspected adverse reactions, contact fosun pharma usa inc. at 1-866-611-3762 or fda at 1-800-fda-1088 or www.fda.gov/medwatch. 6.1 clinical trials experience because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. the data described below reflect exposure to clofarabine injection in 115 pediatric patients with relapsed or refractory acute lymphoblastic leukemia (all) (70 patients) or acute myelogenous leukemia (aml) (45 patients). in total, 115 pediatric patients treated in clinical trials received the recommended dose of clofarabine injection 52 mg/m2 daily × 5. the median number of cycles was 2. the median cumulative amount of clofarabine injection received by pediatric patients during all cycles was 540 mg. most common adverse reactions (≥25%): vomiting, nausea, diarrhea, febrile neutropenia, pruritus, headache, bacteremia, pyrexia, rash, tachycardia, abdominal pain, chills, fatigue, anorexia, pain in extremity, hypotension, epistaxis, and petechiae. table 1 lists adverse reactions by system organ class, including severe or life-threatening (nci ctc grade 3 or grade 4), reported in ≥5% of the 115 patients in the 52 mg/m2/day dose group (pooled analysis of pediatric patients with all and aml). more detailed information and follow-up of certain events is given below. table 1: most commonly reported (≥5% overall) adverse reactions by system organ class (n=115 pooled analysis) system organ class¹ preferred term¹ all/am (n=115) worst nci common terminology criteria grade¹ 3 4 5 n % n % n % n % blood and lymphatic system disorders febrile neutropenia 63 55 59 51 3 3 neutropenia 11 10 3 3 8 7 . . cardiac disorders pericardial effusion 9 8 . . 1 1 . . tachycardia 40 35 6 5 . . . . gastrointestinal disorders abdominal pain 40 35 8 7 . . . . abdominal pain upper 9 8 1 1 . . . . diarrhea 64 56 14 12 . . . . gingival or mouth bleeding 20 17 8 7 1 1 . . nausea 84 73 16 14 1 1 . . oral mucosal petechiae 6 5 4 4 . . . . proctalgia 9 8 2 2 . . . . stomatitis 8 7 1 1 . . . . vomiting 90 78 9 8 1 1 . . general disorders and administration site conditions asthenia 12 10 1 1 1 1 . . chills 39 34 3 3 . . . . fatigue 39 34 3 3 2 2 . . irritability 11 10 1 1 . . . . mucosal inflammation 18 16 2 2 . . . . edema 14 12 2 2 . . . . pain 17 15 7 6 1 1 . . pyrexia 45 39 16 14 . . . . hepatobiliary disorder jaundice 9 8 2 2 . . . . infections and infestations bacteremia 10 9 10 9 . . . . candidiasis 8 7 1 1 . . . . catheter related infection 14 12 13 11 . . . . cellulitis 9 8 7 6 . . . . clostridium colitis 8 7 6 5 . . . . herpes simplex 11 10 6 5 . . . . herpes zoster 8 7 6 5 . . . . oral candidiasis 13 11 2 2 . . . . pneumonia 11 10 6 5 1 1 1 1 ¹ patients with more than one preferred term within a soc are counted only once in the soc totals. patients with more than one occurrence of the same preferred term are counted only once within that term and at the highest severity grade. table 1: most commonly reported (≥5% overall) adverse reactions by system organ class (n=115 pooled analysis) (continued) system organ class¹ preferred term¹ all/aml (n=115) worst nci common terminology criteria grade¹ 3 4 5 n % n % n % n % infections and infestations (continued) sepsis, including septic shock 19 17 6 5 4 4 9 8 staphylococcal bacteremia 7 6 5 4 1 1 . . staphylococcal sepsis 6 5 5 4 1 1 . . upper respiratory tract infection 6 5 1 1 . . . . metabolism and nutrition disorders anorexia 34 30 6 5 8 7 . . musculoskeletal and connective tissue disorders arthralgia 10 9 3 3 . . . . back pain 12 10 3 3 . . . . bone pain 11 10 3 3 . . . . myalgia 16 14 . . . . . . pain in extremity 34 30 6 5 . . . . neoplasms benign, malignant and unspecified (incl. cysts and polyps) tumor lysis syndrome 7 6 7 6 . . . . nervous system disorders headache 49 43 6 5 . . . . lethargy 12 10 1 1 . . . . somnolence 11 10 1 1 . . . . psychiatric disorders agitation 6 5 1 1 . . . . anxiety 24 21 2 2 . . . . renal and urinary disorders hematuria 15 13 2 2 . . . . respiratory, thoracic and mediastinal disorders dyspnea 15 13 6 5 2 2 . . epistaxis 31 27 15 13 . . . . pleural effusion 14 12 4 4 2 2 . . respiratory distress 12 10 5 4 4 4 1 1 tachypnea 10 9 4 4 1 1 . . skin and subcutaneous tissue disorders erythema 13 11 . . . . . . palmar-plantar erythrodysesthesia syndrome 18 16 8 7 . . . . petechiae 30 26 7 6 . . . . pruritus 49 43 1 1 . . . . rash 44 38 8 7 . . . . rash pruritic 9 8 . . . . . . vascular disorders flushing 22 19 . . . . . . hypertension 15 13 6 5 . . . . hypotension 33 29 13 11 9 8 . . ¹ patients with more than one preferred term within a soc are counted only once in the soc totals. patients with more than one occurrence of the same preferred term are counted only once within that term and at the highest severity grade. the following less common adverse reactions have been reported in 1-4% of the 115 pediatric patients with all or aml: gastrointestinal disorders: cecitis, pancreatitis hepatobiliary disorders: hyperbilirubinemia immune system disorders: hypersensitivity infections and infestations: bacterial infection, enterococcal bacteremia, escherichia bacteremia, escherichia sepsis, fungal infection, fungal sepsis, gastroenteritis adenovirus, infection, influenza, parainfluenza virus infection, pneumonia fungal, pneumonia primary atypical, respiratory syncytial virus infection, sinusitis, staphylococcal infection investigations: blood creatinine increased psychiatric disorders: mental status change respiratory, thoracic and mediastinal disorder: pulmonary edema table 2 lists the incidence of treatment-emergent laboratory abnormalities after clofarabine injection administration at 52 mg/m2 among pediatric patients with all and aml (n=115). table 2: incidence of treatment-emergent laboratory abnormalities after clofarabine injection administration parameter any grade grade 3 or higher anemia (n=114) 83% 75% leukopenia (n=114) 88% 88% lymphopenia (n=113) 82% 82% neutropenia (n=113) 64% 64% thrombocytopenia (n=114) 81% 80% elevated creatinine (n=115) 50% 8% elevated sgot (n=100) 74% 36% elevated sgpt (n=113) 81% 43% elevated total bilirubin (n=114) 45% 13% 6.2 postmarketing experience the following adverse reactions have been identified during post-approval use of clofarabine injection. 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. decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal connection to clofarabine injection. gastrointestinal disorders: gastrointestinal hemorrhage including fatalities. metabolism and nutrition disorders: hyponatremia. skin and subcutaneous tissue disorders: stevens-johnson syndrome (sjs), toxic epidermal necrolysis (ten) (including fatal cases).

if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with clofarabine. all patients should be advised to use effective contraceptive measures to prevent pregnancy. 8.3 nursing mothers it is not known whether clofarabine or its metabolites are excreted in human milk. because of the potential for tumorigenicity shown for clofarabine in animal studies and the potential for serious adverse reactions, women treated with clofarabine should not nurse. female patients should be advised to avoid breastfeeding during treatment with clofarabine injection. 8.4 pediatric use safety and effectiveness have been established in pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia. 8.5 geriatric use safety and effectiveness of clofarabine injection has not been established in geriatric patients aged 65 and older. 8.6 adults with hematologic malignancies safety and effectiveness have not been established in adults. 8.7 renal impairment reduce the clofarabine injection starting dose by 50% in patients with crcl of 30 to 60 ml/min. there is insufficient information to make a dosage recommendation in patients with crcl less than 30 ml/min or in patients on dialysis. the pharmacokinetics of clofarabine in patients with renal impairment and normal renal function were obtained from a population pharmacokinetic analysis of three pediatric and two adult studies. in patients with crcl 60 to less than 90 ml/min (n=47) and crcl 30 to less than 60 ml/min (n=30), the average auc of clofarabine increased by 60% and 140%, respectively, compared to patients with normal (n=66) renal function (crcl greater than 90 ml/min).

ts should be advised to use effective contraceptive measures to prevent pregnancy.

�€™- triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome c and apoptosis-inducing factor, leading to programmed cell death. clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro. 12.3 pharmacokinetics the population pharmacokinetics of clofarabine injection were studied in 40 pediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or refractory acute lymphoblastic leukemia (all) or acute myelogenous leukemia (aml). at the given 52 mg/m 2 dose, similar concentrations were obtained over a wide range of body surface areas (bsas). clofarabine was 47% bound to plasma proteins, predominantly to albumin. based on non-compartmental analysis, systemic clearance and volume of distribution at steady-state were 28.8 l/h/m 2 and 172 l/m 2 , respectively. the terminal half-life was 5.2 hours. no apparent difference in pharmacokinetics was observed between patients with all and aml or between males and females. no relationship between clofarabine or clofarabine triphosphate exposure and toxicity or response was found in this population. based on 24-hour urine collections in the pediatric studies, 49-60% of the dose is excreted in the urine unchanged. in vitro studies using isolated human hepatocytes indicate very limited metabolism (0.2%). the pathways of non-hepatic elimination remain unknown. clofarabine has not been studied in patients with hepatic impairment. drug-drug interactions in vitro studies suggested that clofarabine undergoes limited metabolism and does not inhibit or induce major cyp enzymes. cyp inhibitors and inducers are unlikely to affect the metabolism of clofarabine. clofarabine is unlikely to affect the metabolism of cyp substrates. however, no in vivo drug interaction studies have been conducted. an in vitro transporter study suggested that clofarabine is a substrate of human transporters oat1, oat3, and oct1. a preclinical study using perfused rat kidney demonstrated that the renal excretion of clofarabine was decreased by cimetidine, an inhibitor of the hoct2. although the clinical implications of this finding have not been determined, signs of clofarabine injection toxicity should be monitored when administered with other hoat1, hoat3, hoct1 and hoct2 substrates or inhibitors.

o studies using isolated human hepatocytes indicate very limited metabolism (0.2%). the pathways of non-hepatic elimination remain unknown. clofarabine has not been studied in patients with hepatic impairment. drug-drug interactions in vitro studies suggested that clofarabine undergoes limited metabolism and does not inhibit or induce major cyp enzymes. cyp inhibitors and inducers are unlikely to affect the metabolism of clofarabine. clofarabine is unlikely to affect the metabolism of cyp substrates. however, no in vivo drug interaction studies have been conducted. an in vitro transporter study suggested that clofarabine is a substrate of human transporters oat1, oat3, and oct1. a preclinical study using perfused rat kidney demonstrated that the renal excretion of clofarabine was decreased by cimetidine, an inhibitor of the hoct2. although the clinical implications of this finding have not been determined, signs of clofarabine injection toxicity should be monitored when administered with other hoat1, hoat3, hoct1 and hoct2 substrates or inhibitors.

nth iv dog study, cell degeneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed in dogs receiving 0.375 mg/kg/day (7.5 mg/m 2 /day, approximately 14% of the clinical recommended dose on a mg/m 2 basis). ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (225 mg/m 2 /day, approximately 4-fold of recommended human dose on a mg/m 2 basis), the only dose administered to female mice. the effect on human fertility is unknown.

eneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed in dogs receiving 0.375 mg/kg/day (7.5 mg/m 2 /day, approximately 14% of the clinical recommended dose on a mg/m 2 basis). ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (225 mg/m 2 /day, approximately 4-fold of recommended human dose on a mg/m 2 basis), the only dose administered to female mice. the effect on human fertility is unknown.

) in this study were reversible hyperbilirubinemia and elevated transaminase levels and skin rash, experienced at 70 mg/m 2 . as a result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m 2 /day for 5 days. single-arm study in pediatric all clofarabine injection was evaluated in an open-label, single-arm study of 61 pediatric patients with relapsed/refractory all. patients received a dose of 52 mg/m 2 over 2 hours for 5 consecutive days repeated every 2 to 6 weeks for up to 12 cycles. there was no dose escalation in this study. all patients had disease that had relapsed after and/or was refractory to two or more prior therapies. most patients, 38/61 (62%), had received >2 prior regimens and 18/61 (30%) of the patients had undergone at least 1 prior transplant. the median age of the treated patients was 12 years, 61% were male, 39% were female, 44% were caucasian, 38% were hispanic, 12% were african-american, 2% were asian and 5% were other race. the overall remission (or) rate (complete remission [cr] + cr in the absence of total platelet recovery [crp]) was evaluated. cr was defined as no evidence of circulating blasts or extramedullary disease, an m1 bone marrow (≤5% blasts), and recovery of peripheral counts [platelets ≥100 × 10 9 /l and absolute neutrophil count (anc) ≥1.0 × 10 9 /l]. crp was defined as meeting all criteria for cr except for recovery of platelet counts to ≥100 × 10 9 /l. partial response (pr) was also determined, defined as complete disappearance of circulating blasts, an m2 bone marrow (≥5% and ≤25% blasts), and appearance of normal progenitor cells or an m1 marrow that did not qualify for cr or crp. duration of remission was also evaluated. transplantation rate was not a study endpoint. response rates for these studies were determined by an unblinded independent response review panel (irrp). table 3 summarizes results for the pediatric all study. responses were seen in both pre-b and t-cell immunophenotypes of all. the median cumulative dose was 530 mg (range 29-2815 mg) in 1 (41%), 2 (44%) or 3 or more (15%) cycles. the median number of cycles was 2 (range 1-12). the median time between cycles was 28 days with a range of 12 to 55 days. table 3: results in single-arm pediatric all n=61 cr % [95% ci] 11.5 (4.7, 22.2) crp % [95% ci] 8.2 (2.7, 18.1) median duration of cr plus crp (range in weeks)1 10.7 (4.3 to 58.6) cr = complete response crp = complete response without platelet recovery 1 does not include 4 patients who were transplanted (duration of response, including response after transplant, in these 4 patients was 28.6 to 107.7 weeks). six (9.8%) patients achieved a pr; the clinical relevance of a pr in this setting is unknown. of 35 patients who were refractory to their immediately preceding induction regimen, 6 (17%) achieved a cr or crp. of 18 patients who had at least 1 prior hematopoietic stem cell transplant (hsct), 5 (28%) achieved a cr or crp. among the 12 patients who achieved at least a crp, 6 patients achieved the best response after 1 cycle of clofarabine, 5 patients required 2 courses and 1 patient achieved a cr after 3 cycles of therapy.