INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Hematologic Toxicity: Advise patients to return for regular blood counts and to report any symptoms associated with hematologic toxicity (such as weakness, fatigue, pallor, shortness of breath, easy bruising, petechiae, purpura, fever) to their physician see Warnings and Precautions (5.1), Adverse Reactions (6.1) ]. Infection: Advise patients of the signs or symptoms of infection (e.g., fever) and report to the physician immediately if any occur see Warnings and Precautions (5.3), Adverse Reactions (6.1) ]. Hepatic and Renal Toxicity: Advise patients to avoid medications including over the counter and herbal medications, which may be hepatotoxic or nephrotoxic, during the days of clofarabine injection administration. Also, advise patients of the possibility of developing liver function abnormalities and to immediately report signs or symptoms of jaundice. Advise patients of the signs or symptoms of renal failure/ acute renal failure see Warnings and Precautions (5.7, 5.8) ]. Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome: Advise patients of the signs or symptoms of SIRS, such as fever, tachycardia, tachypnea, dyspnea and symptoms suggestive of hypotension see Warnings and Precautions (5.5), Adverse Reactions (6.1) ]. Pregnancy and Breastfeeding: Advise male and female patients with reproductive potential to use effective contraceptive measures to prevent pregnancy see Warnings and Precautions (5.11), Use in Specific Populations (8.1) ]. Advise female patients to avoid breastfeeding during clofarabine injection treatment see Use in Specific Populations (8.3) ]. Gastrointestinal Disorders: Advise patients that they may experience nausea, vomiting, and/or diarrhea with clofarabine injection. If these symptoms are significant, they should seek medical attention see Warnings and Precautions (5.9) ]. Rash: Advise patients that they may experience skin rash with clofarabine injection. If this symptom issignificant, they should seek medical attention.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the label:Myelosuppression see Warnings and Precautions (5.1) Hemorrhage see Warnings and Precautions (5.2) Serious Infections see Warnings and Precautions (5.3) Hyperuricemia (Tumor Lysis) see Warnings and Precautions (5.4) Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome see Warnings and Precautions (5.5) Venous Occlusive Disease of the Liver see Warnings and Precautions (5.6) Hepatotoxicity see Warnings and Precautions (5.7) Renal Toxicity see Warnings and Precautions (5.8) Enterocolitis see Warnings and Precautions (5.9) Skin Reactions see Warnings and Precautions (5.10) . Myelosuppression see Warnings and Precautions (5.1) . Hemorrhage see Warnings and Precautions (5.2) . Serious Infections see Warnings and Precautions (5.3) . Hyperuricemia (Tumor Lysis) see Warnings and Precautions (5.4) . Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome see Warnings and Precautions (5.5) . Venous Occlusive Disease of the Liver see Warnings and Precautions (5.6) . Hepatotoxicity see Warnings and Precautions (5.7) . Renal Toxicity see Warnings and Precautions (5.8) . Enterocolitis see Warnings and Precautions (5.9) . Skin Reactions see Warnings and Precautions (5.10) . 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. 6) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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/m 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 lists adverse reactions by System Organ Class, including severe or life-threatening (NCI CTC Grade or Grade 4), reported in >=5% of the 115 patients in the 52 mg/m 2/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)Worst NCI Common Terminology Criteria Grade Patients with more than one preferred term within 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. ALL/AML (N=115)345System Organ Class Preferred Term N%N%N%N%Blood and Lymphatic System DisordersFebrile neutropenia6355595133..Neutropenia11103387..Cardiac DisordersPericardial effusion98..11..Tachycardia403565....Gastrointestinal DisordersAbdominal pain403587....Abdominal pain upper9811....Diarrhea64561412....Gingival or mouth bleeding20178711..Nausea8473161411..Oral mucosal petechiae6544....Proctalgia9822....Stomatitis8711....Vomiting90789811..General Disorders and Administration Site ConditionsAsthenia12101111..Chills393433....Fatigue39343322..Irritability111011....Mucosal inflammation181622....Edema141222....Pain17157611..Pyrexia45391614....Hepatobiliary DisorderJaundice9822....Infections and InfestationsBacteremia109109....Candidiasis8711....Catheter related infection14121311....Cellulitis9876....Clostridium colitis8765....Herpes simplex111065....Herpes zoster8765....Oral candidiasis131122....Pneumonia1110651111Sepsis, including septic shock1917654498Staphylococcal bacteremia765411..Staphylococcal sepsis655411..Upper respiratory tract infection6511....Metabolism and Nutrition DisordersAnorexia34306587..Musculoskeletal and Connective Tissue DisordersArthralgia10933....Back pain121033....Bone pain111033....Myalgia1614......Pain in extremity343065....Neoplasms Benign, Malignant and Unspecified (incl. cysts and polyps)Tumor lysis syndrome7676....Nervous System DisordersHeadache494365....Lethargy121011....Somnolence111011....Psychiatric DisordersAgitation6511....Anxiety242122....Renal and Urinary DisordersHematuria151322....Respiratory, Thoracic and Mediastinal DisordersDyspnea15136522..Epistaxis31271513....Pleural effusion14124422..Respiratory distress1210544411Tachypnea1094411..Skin and Subcutaneous Tissue DisordersErythema1311......Palmar-plantar erythrodysesthesia syndrome181687....Petechiae302676....Pruritus494311....Rash443887....Rash pruritic98......Vascular DisordersFlushing2219......Hypertension151365....Hypotension3329131198... 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 lists the incidence of treatment-emergent laboratory abnormalities after clofarabine injection administration at 52 mg/m among pediatric patients with ALL and AML (N=115). Table 2: Incidence of Treatment-Emergent Laboratory Abnormalities after clofarabine injection AdministrationParameterAny GradeGrade or higherAnemia (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%. 6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of clofarabine injection. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 fatalitiesMetabolism and nutrition disorders: hyponatremiaSkin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) (including fatal cases).. 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Clofarabine is sequentially metabolized intracellularly to the 5-monophosphate metabolite by deoxycytidine kinase and mono- and di-phospho-kinases to the active 5-triphosphate metabolite. Clofarabine has affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. Clofarabine inhibits DNA synthesis by decreasing cellular deoxynucleotide triphosphate pools through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through incorporation into the DNA chain by competitive inhibition of DNA polymerases. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome 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 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 dose, similar concentrations were obtained over 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 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 InteractionsIn 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 substrate of human transporters OAT1, OAT3, and OCT1. 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 toxicity should be monitored when administered with other hOAT1, hOAT3, hOCT1 and hOCT2 substrates or inhibitors.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Seventy-eight (78) pediatric patients with ALL were exposed to Clofarabine. Seventy (70) of the patients received the recommended pediatric dose of clofarabine 52 mg/m daily for days as an intravenous (IV) infusion. Dose Escalation Study in Pediatric Patients with Hematologic MalignanciesThe safety and efficacy of clofarabine injection were evaluated in pediatric patients with refractory or relapsed hematologic malignancies in an open-label, dose-escalation, noncomparative study. The starting dose of clofarabine injection was 11.25 mg/m 2/day IV infusion daily 5 and escalated to 70 mg/m 2/day IV infusion daily 5. This dosing schedule was repeated every to weeks depending on toxicity and response. Nine of 17 ALL patients were treated with clofarabine injection 52 mg/m daily for days. In the 17 ALL patients there were complete remissions (12%) and partial remissions (12%) at varying doses. Dose-limiting toxicities (DLTs) in this study were reversible hyperbilirubinemia and elevated transaminase levels and skin rash, experienced at 70 mg/m 2. As result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m 2/day for days. Single-Arm Study in Pediatric ALLClofarabine injection was evaluated in an open-label, single-arm study of 61 pediatric patients with relapsed/refractory ALL. Patients received dose of 52 mg/m over hours for consecutive days repeated every to 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 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 study endpoint. Response rates for these studies were determined by an unblinded Independent Response Review Panel (IRRP).Table 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 (41%), (44%) or or more (15%) cycles. The median number of cycles was (range 1-12). The median time between cycles was 28 days with range of 12 to 55 days.Table 3: Results in Single-Arm Pediatric ALLN=61CR Complete responseCRp Complete response without platelet recovery 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) Does not include patients who were transplanted (duration of response, including response after transplant, in these patients was 28.6 to 107.7 weeks). 10.7 (4.3 to 58.6)Six (9.8%) patients achieved PR; the clinical relevance of PR in this setting is unknown.Of 35 patients who were refractory to their immediately preceding induction regimen, (17%) achieved CR or CRp. Of 18 patients who had at least prior hematopoietic stem cell transplant (HSCT), (28%) achieved CR or CRp.Among the 12 patients who achieved at least CRp, patients achieved the best response after cycle of clofarabine, patients required courses and patient achieved CR after cycles of therapy.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over hours daily for consecutive days of 28-day cycle. Repeat cycles every 2-6 weeks. 2.1) Provide supportive care, such as intravenous infusion fluids, antihyperuricemic treatment, and alkalinization of urine throughout the days of clofarabine injection administration to reduce the risk of tumor lysis and other adverse events. 2.1) Discontinue clofarabine injection if hypotension develops during the days of administration. 2.1) Reduce the dose in patients with renal impairment. 2.1) Use dose modification for toxicity. 2.3) Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over hours daily for consecutive days of 28-day cycle. Repeat cycles every 2-6 weeks. 2.1) Provide supportive care, such as intravenous infusion fluids, antihyperuricemic treatment, and alkalinization of urine throughout the days of clofarabine injection administration to reduce the risk of tumor lysis and other adverse events. 2.1) Discontinue clofarabine injection if hypotension develops during the days of administration. 2.1) Reduce the dose in patients with renal impairment. 2.1) Use dose modification for toxicity. 2.3) 2.1 Recommended Dosage. Administer the recommended pediatric dose of 52 mg/m as an intravenous infusion over hours daily for consecutive days. Treatment cycles are repeated following recovery or return to baseline organ function, approximately every to weeks. The dosage is based on the patients body surface area (BSA), calculated using 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 days of Clofarabine injection administration to reduce the effects of tumor lysis and other adverse events.Discontinue Clofarabine injection if hypotension develops during the days of administration.Monitor renal and hepatic function during the 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 dosage recommendation in patients with CrCL less than 30 mL/min see Use in Specific Populations (8.7) ]. Treatment cycles are repeated following recovery or return to baseline organ function, approximately every to weeks. The dosage is based on the patients body surface area (BSA), calculated using 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 days of Clofarabine injection administration to reduce the effects of tumor lysis and other adverse events.. Discontinue Clofarabine injection if hypotension develops during the days of administration.. Monitor renal and hepatic function during the 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 dosage recommendation in patients with CrCL less than 30 mL/min see Use in Specific Populations (8.7) ]. 2.2Supportive 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 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.. 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 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.. 2.3Dose 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 patients ANC is >=0.75 10 9/L. If patient experiences Grade 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 patient develops clinically significant infection, until the infection is controlled, then restart at the full dose.Withhold clofarabine injection for Grade 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 25% dose reduction when resolution or return to baseline.Discontinue clofarabine injection administration for Grade non-infectious non-hematologic toxicity.Discontinue clofarabine injection administration if patient shows early signs or symptoms of SIRS or capillary leak (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures.Discontinue clofarabine injection administration if Grade or higher increases in creatinine or bilirubin are noted. Re-institute clofarabine injection with 25% dose reduction, when the patient is stable and organ function has returned to baseline. If hyperuricemia is anticipated (tumor lysis), initiate measures to control uric acid. Hematologic Toxicity Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patients ANC is >=0.75 10 9/L. If patient experiences Grade neutropenia (ANC <0.5 10 9/L) lasting >=4 weeks, reduce dose by 25% for the next cycle. Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patients ANC is >=0.75 10 9/L. If patient experiences Grade 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 patient develops clinically significant infection, until the infection is controlled, then restart at the full dose.Withhold clofarabine injection for Grade 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 25% dose reduction when resolution or return to baseline.Discontinue clofarabine injection administration for Grade non-infectious non-hematologic toxicity.Discontinue clofarabine injection administration if patient shows early signs or symptoms of SIRS or capillary leak (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures.Discontinue clofarabine injection administration if Grade or higher increases in creatinine or bilirubin are noted. Re-institute clofarabine injection with 25% dose reduction, when the patient is stable and organ function has returned to baseline. If hyperuricemia is anticipated (tumor lysis), initiate measures to control uric acid. Withhold clofarabine injection if patient develops clinically significant infection, until the infection is controlled, then restart at the full dose.. Withhold clofarabine injection for Grade 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 25% dose reduction when resolution or return to baseline.. Discontinue clofarabine injection administration for Grade non-infectious non-hematologic toxicity.. Discontinue clofarabine injection administration if patient shows early signs or symptoms of SIRS or capillary leak (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures.. Discontinue clofarabine injection administration if Grade or higher increases in creatinine or bilirubin are noted. Re-institute clofarabine injection with 25% dose reduction, when the patient is stable and organ function has returned to baseline. If hyperuricemia is anticipated (tumor lysis), initiate measures to control uric acid. 2.4Reconstitution/Preparation. Clofarabine injection should be filtered through 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 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 (15-30C).. 2.5Incompatibilities. Do not administer any other medications through the same intravenous line.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The population pharmacokinetics of clofarabine injection were studied in 40 pediatric patients aged 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 dose, similar concentrations were obtained over 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 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 InteractionsIn 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 substrate of human transporters OAT1, OAT3, and OCT1. 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 toxicity should be monitored when administered with other hOAT1, hOAT3, hOCT1 and hOCT2 substrates or inhibitors.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage. Administer the recommended pediatric dose of 52 mg/m as an intravenous infusion over hours daily for consecutive days. Treatment cycles are repeated following recovery or return to baseline organ function, approximately every to weeks. The dosage is based on the patients body surface area (BSA), calculated using 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 days of Clofarabine injection administration to reduce the effects of tumor lysis and other adverse events.Discontinue Clofarabine injection if hypotension develops during the days of administration.Monitor renal and hepatic function during the 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 dosage recommendation in patients with CrCL less than 30 mL/min see Use in Specific Populations (8.7) ]. Treatment cycles are repeated following recovery or return to baseline organ function, approximately every to weeks. The dosage is based on the patients body surface area (BSA), calculated using 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 days of Clofarabine injection administration to reduce the effects of tumor lysis and other adverse events.. Discontinue Clofarabine injection if hypotension develops during the days of administration.. Monitor renal and hepatic function during the 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 dosage recommendation in patients with CrCL less than 30 mL/min see Use in Specific Populations (8.7) ].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Embryo-fetal Toxicity: fetal harm can occur when administered to pregnant woman. Women should be advised to avoid becoming pregnant when receiving clofarabine injection. 5.11, 8.1) Embryo-fetal Toxicity: fetal harm can occur when administered to pregnant woman. Women should be advised to avoid becoming pregnant when receiving clofarabine injection. 5.11, 8.1) 8.1 Pregnancy. Pregnancy Category DClofarabine injection may cause fetal harm when administered to pregnant woman.Clofarabine was teratogenic in rats and rabbits. Developmental toxicity (reduced fetal body weight and increased post-implantation loss) and increased incidences of malformations and variations (gross external, soft tissue, skeletal and retarded ossification) were observed in rats receiving 54 mg/m 2/day (approximately equivalent to the recommended clinical dose on mg/m basis), and in rabbits receiving 12 mg/m 2/day (approximately 23% of the recommended clinical dose on mg/m basis). There are no adequate and well-controlled studies in pregnant women using clofarabine. If this drug is used during pregnancy, or 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 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.. 8.6Adults 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 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 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).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Myelosuppression: May be severe and prolonged. Monitor complete blood counts and platelet counts during clofarabine injection 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 result of bone marrow suppression. Monitor for signs and symptoms of infection; discontinue clofarabine injection 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 injection immediately if suspected. 5.5) Venous Occlusive Disease of the Liver: Monitor for and discontinue clofarabine injection if suspected. 5.6) Hepatotoxicity: Severe and fatal hepatotoxicity. Monitor liver function, for signs and symptoms of hepatitis and hepatic failure. Discontinue clofarabine injection immediately for Grade 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) Myelosuppression: May be severe and prolonged. Monitor complete blood counts and platelet counts during clofarabine injection 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 result of bone marrow suppression. Monitor for signs and symptoms of infection; discontinue clofarabine injection 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 injection immediately if suspected. 5.5) Venous Occlusive Disease of the Liver: Monitor for and discontinue clofarabine injection if suspected. 5.6) Hepatotoxicity: Severe and fatal hepatotoxicity. Monitor liver function, for signs and symptoms of hepatitis and hepatic failure. Discontinue clofarabine injection immediately for Grade 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) 5.1Myelosuppression. 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 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) ]. 5.2Hemorrhage 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) ]. 5.3Infections. 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. 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. 5.4Hyperuricemia (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 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/m hydrocortisone on Days 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 25% dose reduction. 5.6 Venous Occlusive Disease of the Liver. Patients who have previously received 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 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 or less within 15 days. Grade or elevated bilirubin occurred in 13% of patients, with events reported as Grade hyperbilirubinemia (2%), one of which resulted in treatment discontinuation and one patient had multi-organ failure and died. Eight patients (7%) had Grade or 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 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 or elevated creatinine occurred in 8% of patients and acute renal failure was reported as Grade in three patients (3%) and Grade 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) ]. 5.11Embryo-fetal Toxicity. Clofarabine injection can cause fetal harm when administered to 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) ].