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 Clolar administration to reduce the risk of tumor lysis and other adverse reactions. (2.1)Discontinue Clolar if hypotension develops during the days of administration. (2.1)Reduce the dose in patients with renal impairment. (2.2)Use dose modification for toxicity. (2.4). 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 Clolar administration to reduce the risk of tumor lysis and other adverse reactions. (2.1). Discontinue Clolar if hypotension develops during the days of administration. (2.1). Reduce the dose in patients with renal impairment. (2.2). Use dose modification for toxicity. (2.4). 2.1 Recommended Dosage. Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over hours daily for consecutive days.Repeat treatment cycles following recovery or return to baseline organ function, approximately every to weeks. Base dosage on the patients body surface area (BSA), calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, do not administer other medications through the same intravenous line. Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patients ANC is >=0.75 109/L.Provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the days of Clolar administration to reduce the effects of tumor lysis and other adverse reactions.Discontinue Clolar if hypotension develops during the days of administration.Monitor renal and hepatic function during the days of Clolar administration [see Warnings and Precautions (5.7, 5.8)].Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Clolar.. Repeat treatment cycles following recovery or return to baseline organ function, approximately every to weeks. Base dosage on the patients body surface area (BSA), calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, do not administer other medications through the same intravenous line. Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patients ANC is >=0.75 109/L.. Provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the days of Clolar administration to reduce the effects of tumor lysis and other adverse reactions.. Discontinue Clolar if hypotension develops during the days of administration.. Monitor renal and hepatic function during the days of Clolar administration [see Warnings and Precautions (5.7, 5.8)].. Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Clolar.. 2.2 Recommended Dosage Reduction for Renal Impairment 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)].. 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)].. 2.3 Potential Concomitant Medications and Medications to Avoid. Consider prophylactic antiemetic medications as Clolar 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 Clolar administration since the risk of renal toxicity may be increased.Avoid concomitant use of medications known to induce hepatic toxicity.. Consider prophylactic antiemetic medications as Clolar 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 Clolar administration since the risk of renal toxicity may be increased.. Avoid concomitant use of medications known to induce hepatic toxicity.. 2.4 Dose Modifications and Reinitiation of Therapy after Adverse Reactions. Hematologic ToxicityIf patient experiences Grade neutropenia (ANC <0.5 109/L) lasting >=4 weeks, reduce dose by 25% for the next cycle.. If patient experiences Grade neutropenia (ANC <0.5 109/L) lasting >=4 weeks, reduce dose by 25% for the next cycle.. Non-hematologic ToxicityWithhold Clolar if patient develops clinically significant infection, until the infection is controlled, then restart at the full dose.Withhold Clolar 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 Clolar administration at 25% dose reduction when resolution or return to baseline.Discontinue Clolar administration for Grade non-infectious non-hematologic toxicity.Discontinue Clolar administration if patient shows early signs or symptoms of SIRS or capillary leak syndrome (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures.Discontinue Clolar administration if Grade or higher increases in creatinine or bilirubin are noted. Re-institute Clolar 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 Clolar if patient develops clinically significant infection, until the infection is controlled, then restart at the full dose.. Withhold Clolar 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 Clolar administration at 25% dose reduction when resolution or return to baseline.. Discontinue Clolar administration for Grade non-infectious non-hematologic toxicity.. Discontinue Clolar administration if patient shows early signs or symptoms of SIRS or capillary leak syndrome (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures.. Discontinue Clolar administration if Grade or higher increases in creatinine or bilirubin are noted. Re-institute Clolar 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.. 2.5 Reconstitution/Preparation Filter Clolar through sterile 0.2 micron syringe filter and then dilute with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion to final concentration between 0.15 mg/mL and 0.4 mg/mL. Use within 24 hours of preparation. Store diluted Clolar at room temperature (15C to 30C).Discard unused portion in vial.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant 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 syndrome) [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 syndrome) [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 Genzyme Corporation at 1-800-RX-CLOLAR 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 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 Clolar 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 Clolar 52 mg/m2 daily 5. The median number of cycles was 2. The median cumulative amount of Clolar 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 CTCAE Grade 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 ClassPatients with more than one adverse reaction (MedDRA preferred term) within SOC are counted only once in the SOC totals. Patients with more than one occurrence of the same adverse reaction (MedDRA preferred term) are counted only once within that reaction and at the highest severity grade. Adverse Reaction (MedDRA Preferred Term) ALL/AML (All Grades, N=115)Worst Grade (NCI Common Terminology Criteria) 345N%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 adverse reactions were reported in <5% of the 115 pediatric patients with ALL or AML:Gastrointestinal Disorders: cecitis, pancreatitisHepatobiliary Disorders: hyperbilirubinemiaImmune System Disorders: hypersensitivityInfections 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 infectionInvestigations: blood creatinine increasedPsychiatric Disorders: mental status changeRespiratory, Thoracic and Mediastinal Disorder: pulmonary edemaTable lists the incidence of treatment-emergent laboratory abnormalities after Clolar administration at 52 mg/m2 among pediatric patients with ALL and AML (N=115).Table 2: Incidence of Treatment-Emergent Laboratory Abnormalities after Clolar 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%. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of Clolar. 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.Gastrointestinal disorders: gastrointestinal hemorrhage including fatalities.Metabolism 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. 12.1Mechanism 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 Clolar 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/m2 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/m2 and 172 L/m2, 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% to 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 Clolar 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 Clolar. Seventy (70) of the patients received the recommended pediatric dose of Clolar 52 mg/m2 daily for days as an intravenous infusion.. Dose Escalation Study in Pediatric Patients with Hematologic MalignanciesThe safety and efficacy of Clolar were evaluated in pediatric patients with refractory or relapsed hematologic malignancies in an open-label, dose-escalation, noncomparative study (NCT00042341, Phase II, Open Label Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Lymphoblastic Leukemia). The starting dose of Clolar was 11.25 mg/m2/day intravenous infusion daily 5 and escalated to 70 mg/m2/day intravenous infusion daily 5. This dosing schedule was repeated every to weeks depending on toxicity and response. Nine of 17 ALL patients were treated with Clolar 52 mg/m2 daily for days. In the 17 ALL patients there were complete remissions (12%) and partial remissions (12%) at varying doses. Dose-limiting toxicities in this study were reversible hyperbilirubinemia and elevated transaminase levels and skin rash, experienced at 70 mg/m2. As result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m2/day for days.. Single-Arm Study in Pediatric ALLClolar was evaluated in an open-label, single-arm study of 61 pediatric patients with relapsed/refractory ALL. Patients received dose of 52 mg/m2 intravenous infusion 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 >=100 109/L and absolute neutrophil count (ANC) >=1x 109/L]. CRp was defined as meeting all criteria for CR except for recovery of platelet counts to >=100 109/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.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical 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 Clolar 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 Clolar 52 mg/m2 daily 5. The median number of cycles was 2. The median cumulative amount of Clolar 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 CTCAE Grade 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 ClassPatients with more than one adverse reaction (MedDRA preferred term) within SOC are counted only once in the SOC totals. Patients with more than one occurrence of the same adverse reaction (MedDRA preferred term) are counted only once within that reaction and at the highest severity grade. Adverse Reaction (MedDRA Preferred Term) ALL/AML (All Grades, N=115)Worst Grade (NCI Common Terminology Criteria) 345N%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 adverse reactions were reported in <5% of the 115 pediatric patients with ALL or AML:Gastrointestinal Disorders: cecitis, pancreatitisHepatobiliary Disorders: hyperbilirubinemiaImmune System Disorders: hypersensitivityInfections 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 infectionInvestigations: blood creatinine increasedPsychiatric Disorders: mental status changeRespiratory, Thoracic and Mediastinal Disorder: pulmonary edemaTable lists the incidence of treatment-emergent laboratory abnormalities after Clolar administration at 52 mg/m2 among pediatric patients with ALL and AML (N=115).Table 2: Incidence of Treatment-Emergent Laboratory Abnormalities after Clolar 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%.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Hematologic ToxicityAdvise 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)].. InfectionAdvise 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)].. Hepatic and Renal ToxicityAdvise patients to avoid medications including over the counter and herbal medications, which may be hepatotoxic or nephrotoxic, during the days of Clolar 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 SyndromeAdvise 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)].. PregnancyAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.3)]. Advise female patients of reproductive potential to use effective contraception during treatment with Clolar and for at least months after the last dose [see Use in Specific Populations (8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with Clolar and for at least months after the last dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].. LactationAdvise females not to breastfeed during treatment with Clolar and for weeks after the last dose [see Use in Specific Populations (8.2)].. Gastrointestinal DisordersAdvise patients that they may experience nausea, vomiting, and/or diarrhea with Clolar. If these symptoms are significant, they should seek medical attention [see Warnings and Precautions (5.9)].. RashAdvise patients that they may experience skin rash with Clolar. If this symptom is significant, they should seek medical attention.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The population pharmacokinetics of Clolar 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/m2 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/m2 and 172 L/m2, 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% to 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 Clolar toxicity should be monitored when administered with other hOAT1, hOAT3, hOCT1 and hOCT2 substrates or inhibitors.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryIn animal reproduction studies, intravenous administration of clofarabine to pregnant rats and rabbits during organogenesis at doses approximately 0.2 to 1-times the maximum recommended human dose of 52 mg/m2 based on body surface area (BSA) resulted in embryo-fetal mortality, alterations to growth, and structural abnormalities (see Data). Advise pregnant women of the potential risk to fetus. There are no available data on Clolar use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Clofarabine should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal dataIntravenous administration of clofarabine to pregnant rats during organogenesis (gestation days [GD] 7-17) at doses of 1, or mg/kg/day (equivalent to 6, 18, 54 mg/m2/day) resulted in maternal toxicities at the mg/kg dose, as indicated by reduced body weights and food consumption. Developmental toxicity (i.e., reduced fetal body weights and increased postimplantation loss) and increased incidences of external, soft tissue, and skeletal malformations and variations (including retarded ossification) were observed at mg/kg/day (54 mg/m2; approximately equivalent to the recommended human dose based on BSA). Altered ossification patterns (extra metacarpal or metatarsal ossification) were observed in single fetuses at lower doses of clofarabine (1 and mg/kg/day; 0.1- and 0.3-times the recommended human dose based on BSA).When clofarabine was administered intravenously to pregnant rabbits during organogenesis (GD 6-18) at doses of 0.1, 0.3, or mg/kg/day (equivalent to 1.2, 3.6, 12 mg/m2/day), developmental toxicity (i.e., reduced fetal body weights and increased postimplantation loss) and increased incidences of external, soft tissue, and skeletal malformations and variations (including retarded ossification) were observed at the mg/kg/day dose (12 mg/m2; 0.2-times the recommended human dose based on BSA). Alterations in ossification patterns (increase in the average numbers of ossified thoracic vertebrae and rib pairs, and reduction in the average number of forepaw metacarpals) and abdominal wall defect were observed at 0.3 mg/kg/day (3.6 mg/m2; 0.1-times the recommended human dose based on BSA).

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage. Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over hours daily for consecutive days.Repeat treatment cycles following recovery or return to baseline organ function, approximately every to weeks. Base dosage on the patients body surface area (BSA), calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, do not administer other medications through the same intravenous line. Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patients ANC is >=0.75 109/L.Provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the days of Clolar administration to reduce the effects of tumor lysis and other adverse reactions.Discontinue Clolar if hypotension develops during the days of administration.Monitor renal and hepatic function during the days of Clolar administration [see Warnings and Precautions (5.7, 5.8)].Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Clolar.. Repeat treatment cycles following recovery or return to baseline organ function, approximately every to weeks. Base dosage on the patients body surface area (BSA), calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, do not administer other medications through the same intravenous line. Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patients ANC is >=0.75 109/L.. Provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the days of Clolar administration to reduce the effects of tumor lysis and other adverse reactions.. Discontinue Clolar if hypotension develops during the days of administration.. Monitor renal and hepatic function during the days of Clolar administration [see Warnings and Precautions (5.7, 5.8)].. Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Clolar.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryIn animal reproduction studies, intravenous administration of clofarabine to pregnant rats and rabbits during organogenesis at doses approximately 0.2 to 1-times the maximum recommended human dose of 52 mg/m2 based on body surface area (BSA) resulted in embryo-fetal mortality, alterations to growth, and structural abnormalities (see Data). Advise pregnant women of the potential risk to fetus. There are no available data on Clolar use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Clofarabine should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal dataIntravenous administration of clofarabine to pregnant rats during organogenesis (gestation days [GD] 7-17) at doses of 1, or mg/kg/day (equivalent to 6, 18, 54 mg/m2/day) resulted in maternal toxicities at the mg/kg dose, as indicated by reduced body weights and food consumption. Developmental toxicity (i.e., reduced fetal body weights and increased postimplantation loss) and increased incidences of external, soft tissue, and skeletal malformations and variations (including retarded ossification) were observed at mg/kg/day (54 mg/m2; approximately equivalent to the recommended human dose based on BSA). Altered ossification patterns (extra metacarpal or metatarsal ossification) were observed in single fetuses at lower doses of clofarabine (1 and mg/kg/day; 0.1- and 0.3-times the recommended human dose based on BSA).When clofarabine was administered intravenously to pregnant rabbits during organogenesis (GD 6-18) at doses of 0.1, 0.3, or mg/kg/day (equivalent to 1.2, 3.6, 12 mg/m2/day), developmental toxicity (i.e., reduced fetal body weights and increased postimplantation loss) and increased incidences of external, soft tissue, and skeletal malformations and variations (including retarded ossification) were observed at the mg/kg/day dose (12 mg/m2; 0.2-times the recommended human dose based on BSA). Alterations in ossification patterns (increase in the average numbers of ossified thoracic vertebrae and rib pairs, and reduction in the average number of forepaw metacarpals) and abdominal wall defect were observed at 0.3 mg/kg/day (3.6 mg/m2; 0.1-times the recommended human dose based on BSA).. 8.2 Lactation. Risk SummaryThere are no data on the presence of clofarabine in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child including genotoxicity, advise patients not to breastfeed during treatment with Clolar, and for at least weeks after the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating Clolar.. Contraception. FemalesClolar can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients to use effective contraception during treatment with Clolar and for months after the last dose. MalesBased on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Clolar and for at least months after the last dose [see Nonclinical Toxicology (13.1)].. Infertility. FemalesBased on findings from animal studies, Clolar may impair female fertility [see Nonclinical Toxicology (13.1)]. The reversibility of the effect on fertility is unknown.. MalesBased on findings from animal studies, Clolar may impair male fertility [see Nonclinical Toxicology (13.1)]. The reversibility of the effect on fertility is unknown.. 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 Clolar 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 Clolar 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 Clolar 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 Clolar 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 Clolar immediately if suspected. (5.5) Venous Occlusive Disease of the Liver: Monitor for and discontinue Clolar if suspected. (5.6)Hepatotoxicity: Severe and fatal hepatotoxicity. Monitor liver function, for signs and symptoms of hepatitis and hepatic failure. Discontinue Clolar 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 Clolar. (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. (5.11). Myelosuppression: May be severe and prolonged. Monitor complete blood counts and platelet counts during Clolar 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 Clolar 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 Clolar immediately if suspected. (5.5) Venous Occlusive Disease of the Liver: Monitor for and discontinue Clolar if suspected. (5.6). Hepatotoxicity: Severe and fatal hepatotoxicity. Monitor liver function, for signs and symptoms of hepatitis and hepatic failure. Discontinue Clolar 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 Clolar. (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. (5.11). 5.1 Myelosuppression. Clolar 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 Clolar 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. Clolar 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 Clolar treatment, including fungal, viral and bacterial infections. Monitor patients for signs and symptoms of infection, discontinue Clolar, and treat promptly.. 5.4 Tumor Lysis Syndrome Administration of Clolar 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. Clolar 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 multiorgan failure. Close monitoring for this syndrome and early intervention may reduce the risk. Immediately discontinue Clolar and provide appropriate supportive measures. The use of prophylactic steroids (e.g., 100 mg/m2 hydrocortisone on Days 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 Clolar 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/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). 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 monotherapy studies were considered related to study drug. Monitor for and discontinue Clolar if VOD is suspected.. 5.7 Hepatotoxicity. Severe and fatal hepatotoxicity, including hepatitis and hepatic failure, has occurred with the use of Clolar. In clinical studies, Grade 3-4 liver enzyme elevations were observed in pediatric patients during treatment with Clolar 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 Clolar 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 multiorgan 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 multiorgan failure. Monitor hepatic function, and for signs and symptoms of hepatitis and hepatic failure. Discontinue Clolar immediately for Grade or greater liver enzyme and/or bilirubin elevations [see Dosage and Administration (2.4)].. 5.8 Renal Toxicity. Clolar may cause acute renal failure. In Clolar 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 Clolar. Hematuria occurred in 13% of Clolar treated patients overall. Monitor patients for renal toxicity and interrupt or discontinue Clolar as necessary [see Dosage and Administration (2.4)].. 5.9 Enterocolitis. Fatal and serious cases of enterocolitis, including neutropenic colitis, cecitis, and 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)].. 5.11Embryo-Fetal Toxicity. Based on findings from animal reproductive studies and the drugs mechanism of action, Clolar can cause fetal harm when administered to 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/m2 based on body surface area (mg/m2) caused an increase in resorptions, malformations, and variations. Advise females of reproductive potential of the potential risk to fetus and to use an effective method of contraception during treatment with Clolar and for at least months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Clolar and for at least months after the last dose [see Use in Specific Populations (8.1)].