Clolar

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) ] 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to 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/m 2 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 1 lists adverse reactions by System Organ Class, including severe or life-threatening (NCI CTCAE Grade 3 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) System Organ Class Patients with more than one adverse reaction (MedDRA preferred term ) within a 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) 3 4 5 N % N % N % N % Blood and Lymphatic System Disorders Febrile neutropenia 63 55 59 51 3 3 . . Neutropenia 11 10 3 3 8 7 . . Cardiac Disorders Pericardial effusion 9 8 . . 1 1 . . Tachycardia 40 35 6 5 . . . . Gastrointestinal Disorders Abdominal pain 40 35 8 7 . . . . Abdominal pain upper 9 8 1 1 . . . . Diarrhea 64 56 14 12 . . . . Gingival or mouth bleeding 20 17 8 7 1 1 . . Nausea 84 73 16 14 1 1 . . Oral mucosal petechiae 6 5 4 4 . . . . Proctalgia 9 8 2 2 . . . . Stomatitis 8 7 1 1 . . . . Vomiting 90 78 9 8 1 1 . . General Disorders and Administration Site Conditions Asthenia 12 10 1 1 1 1 . . Chills 39 34 3 3 . . . . Fatigue 39 34 3 3 2 2 . . Irritability 11 10 1 1 . . . . Mucosal inflammation 18 16 2 2 . . . . Edema 14 12 2 2 . . . . Pain 17 15 7 6 1 1 . . Pyrexia 45 39 16 14 . . . . Hepatobiliary Disorder Jaundice 9 8 2 2 . . . . Infections and Infestations Bacteremia 10 9 10 9 . . . . Candidiasis 8 7 1 1 . . . . Catheter related infection 14 12 13 11 . . . . Cellulitis 9 8 7 6 . . . . Clostridium colitis 8 7 6 5 . . . . Herpes simplex 11 10 6 5 . . . . Herpes zoster 8 7 6 5 . . . . Oral candidiasis 13 11 2 2 . . . . Pneumonia 11 10 6 5 1 1 1 1 Sepsis, including septic shock 19 17 6 5 4 4 9 8 Staphylococcal bacteremia 7 6 5 4 1 1 . . Staphylococcal sepsis 6 5 5 4 1 1 . . Upper respiratory tract infection 6 5 1 1 . . . . Metabolism and Nutrition Disorders Anorexia 34 30 6 5 8 7 . . Musculoskeletal and Connective Tissue Disorders Arthralgia 10 9 3 3 . . . . Back pain 12 10 3 3 . . . . Bone pain 11 10 3 3 . . . . Myalgia 16 14 . . . . . . Pain in extremity 34 30 6 5 . . . . Neoplasms Benign, Malignant and Unspecified (incl. cysts and polyps) Tumor lysis syndrome 7 6 7 6 . . . . Nervous System Disorders Headache 49 43 6 5 . . . . Lethargy 12 10 1 1 . . . . Somnolence 11 10 1 1 . . . . Psychiatric Disorders Agitation 6 5 1 1 . . . . Anxiety 24 21 2 2 . . . . Renal and Urinary Disorders Hematuria 15 13 2 2 . . . . Respiratory, Thoracic and Mediastinal Disorders Dyspnea 15 13 6 5 2 2 . . Epistaxis 31 27 15 13 . . . . Pleural effusion 14 12 4 4 2 2 . . Respiratory distress 12 10 5 4 4 4 1 1 Tachypnea 10 9 4 4 1 1 . . Skin and Subcutaneous Tissue Disorders Erythema 13 11 . . . . . . Palmar-plantar erythrodysesthesia syndrome 18 16 8 7 . . . . Petechiae 30 26 7 6 . . . . Pruritus 49 43 1 1 . . . . Rash 44 38 8 7 . . . . Rash pruritic 9 8 . . . . . . Vascular Disorders Flushing 22 19 . . . . . . Hypertension 15 13 6 5 . . . . Hypotension 33 29 13 11 9 8 . . The following adverse reactions were reported in <5% of the 115 pediatric patients with ALL or AML: Gastrointestinal Disorders: cecitis, pancreatitis Hepatobiliary Disorders: hyperbilirubinemia Immune System Disorders: hypersensitivity Infections and Infestations: bacterial infection, Enterococcal bacteremia, Escherichia bacteremia, Escherichia sepsis, fungal infection, fungal sepsis, gastroenteritis adenovirus, infection, influenza, parainfluenza virus infection, pneumonia fungal, pneumonia primary atypical, Respiratory syncytial virus infection, sinusitis, staphylococcal infection Investigations: blood creatinine increased Psychiatric Disorders: mental status change Respiratory, Thoracic and Mediastinal Disorder: pulmonary edema Table 2 lists the incidence of treatment-emergent laboratory abnormalities after Clolar administration at 52 mg/m 2 among pediatric patients with ALL and AML (N=115). Table 2: Incidence of Treatment-Emergent Laboratory Abnormalities after Clolar Administration Parameter Any Grade Grade 3 or higher Anemia (N=114) 83% 75% Leukopenia (N=114) 88% 88% Lymphopenia (N=113) 82% 82% Neutropenia (N=113) 64% 64% Thrombocytopenia (N=114) 81% 80% Elevated Creatinine (N=115) 50% 8% Elevated SGOT (N=100) 74% 36% Elevated SGPT (N=113) 81% 43% Elevated Total Bilirubin (N=114) 45% 13% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Clolar. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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).

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Clolar (clofarabine) injection contains clofarabine, a purine nucleoside metabolic inhibitor. The chemical name of clofarabine is 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine. Its molecular formula is C 10 H 11 ClFN 5 O 3 with a molecular weight of 303.68 Daltons. The molecular structure of clofarabine is: Clolar (1 mg/mL) is supplied in a 20 mL, single-dose vial. The 20 mL vial contains 20 mg clofarabine formulated in 20 mL unbuffered normal saline (comprised of Water for Injection, USP, and Sodium Chloride, USP). The pH range of the solution is 4.5 to 7.5. The solution is sterile, clear and practically colorless, and is preservative-free. Chemical Structure

2 DOSAGE AND ADMINISTRATION Administer the recommended pediatric dose of 52 mg/m 2 as an intravenous infusion over 2 hours daily for 5 consecutive days of a 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 5 days of Clolar administration to reduce the risk of tumor lysis and other adverse reactions. ( 2.1 ) Discontinue Clolar if hypotension develops during the 5 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/m 2 as an intravenous infusion over 2 hours daily for 5 consecutive days. Repeat treatment cycles following recovery or return to baseline organ function, approximately every 2 to 6 weeks. Base dosage on the patient's 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 patient's ANC is ≥0.75 × 10 9 /L. Provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the 5 days of Clolar administration to reduce the effects of tumor lysis and other adverse reactions. Discontinue Clolar if hypotension develops during the 5 days of administration. Monitor renal and hepatic function during the 5 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 a dosage recommendation in patients with CrCL less than 30 mL/min [see Use in Specific Populations (8.6) ] . 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 5 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 Toxicity If a patient experiences a Grade 4 neutropenia (ANC <0.5 × 10 9 /L) lasting ≥4 weeks, reduce dose by 25% for the next cycle. Non-hematologic Toxicity Withhold Clolar if a patient develops a clinically significant infection, until the infection is controlled, then restart at the full dose. Withhold Clolar for a Grade 3 non-infectious non-hematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting controlled by antiemetic therapy). Re-institute Clolar administration at a 25% dose reduction when resolution or return to baseline. Discontinue Clolar administration for a Grade 4 non-infectious non-hematologic toxicity. Discontinue Clolar administration if a 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 3 or higher increases in creatinine or bilirubin are noted. Re-institute Clolar with a 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 a 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 a final concentration between 0.15 mg/mL and 0.4 mg/mL. Use within 24 hours of preparation. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. Store diluted Clolar at room temperature (15°C to 30°C). Discard unused portion in vial.

1 INDICATIONS AND USAGE Clolar ® is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. Clolar is a nucleoside metabolic inhibitor indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. ( 1 )

10 OVERDOSAGE There were no known overdoses of Clolar. The highest daily dose administered to a human to date (on a mg/m 2 basis) has been 70 mg/m 2 /day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included Grade 4 hyperbilirubinemia, Grade 2 and 3 vomiting, and Grade 3 maculopapular rash. In a Phase 1 study of adults with refractory and/or relapsed hematologic malignancies, the recommended pediatric dose of 52 mg/m 2 /day was not tolerated.

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 C and apoptosis-inducing factor, leading to programmed cell death. Clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro . 12.3 Pharmacokinetics The population pharmacokinetics of Clolar were studied in 40 pediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). At the given 52 mg/m 2 dose, similar concentrations were obtained over a wide range of body surface areas (BSAs). Clofarabine was 47% bound to plasma proteins, predominantly to albumin. Based on non-compartmental analysis, systemic clearance and volume of distribution at steady-state were 28.8 L/h/m 2 and 172 L/m 2 , respectively. The terminal half-life was 5.2 hours. No apparent difference in pharmacokinetics was observed between patients with ALL and AML or between males and females. No relationship between clofarabine or clofarabine triphosphate exposure and toxicity or response was found in this population. Based on 24-hour urine collections in the pediatric studies, 49% 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 Interactions In vitro studies suggested that clofarabine undergoes limited metabolism and does not inhibit or induce major CYP enzymes. CYP inhibitors and inducers are unlikely to affect the metabolism of clofarabine. Clofarabine is unlikely to affect the metabolism of CYP substrates. However, no in vivo drug interaction studies have been conducted. An in vitro transporter study suggested that clofarabine is a substrate of human transporters OAT1, OAT3, and OCT1. A preclinical study using perfused rat kidney demonstrated that the renal excretion of clofarabine was decreased by cimetidine, an inhibitor of the hOCT2. Although the clinical implications of this finding have not been determined, signs of Clolar toxicity should be monitored when administered with other hOAT1, hOAT3, hOCT1 and hOCT2 substrates or inhibitors.

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 C and apoptosis-inducing factor, leading to programmed cell death. Clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro .

12.3 Pharmacokinetics The population pharmacokinetics of Clolar were studied in 40 pediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). At the given 52 mg/m 2 dose, similar concentrations were obtained over a wide range of body surface areas (BSAs). Clofarabine was 47% bound to plasma proteins, predominantly to albumin. Based on non-compartmental analysis, systemic clearance and volume of distribution at steady-state were 28.8 L/h/m 2 and 172 L/m 2 , respectively. The terminal half-life was 5.2 hours. No apparent difference in pharmacokinetics was observed between patients with ALL and AML or between males and females. No relationship between clofarabine or clofarabine triphosphate exposure and toxicity or response was found in this population. Based on 24-hour urine collections in the pediatric studies, 49% 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 Interactions In vitro studies suggested that clofarabine undergoes limited metabolism and does not inhibit or induce major CYP enzymes. CYP inhibitors and inducers are unlikely to affect the metabolism of clofarabine. Clofarabine is unlikely to affect the metabolism of CYP substrates. However, no in vivo drug interaction studies have been conducted. An in vitro transporter study suggested that clofarabine is a substrate of human transporters OAT1, OAT3, and OCT1. A preclinical study using perfused rat kidney demonstrated that the renal excretion of clofarabine was decreased by cimetidine, an inhibitor of the hOCT2. Although the clinical implications of this finding have not been determined, signs of Clolar toxicity should be monitored when administered with other hOAT1, hOAT3, hOCT1 and hOCT2 substrates or inhibitors.

20231115

15

3 DOSAGE FORMS AND STRENGTHS Injection: 20 mg/20 mL (1 mg/mL) clear solution in single-dose vial Injection: 20 mg/20 mL (1 mg/mL) single-dose vial. ( 3 )

Clolar clofarabine SODIUM CHLORIDE WATER CLOFARABINE CLOFARABINE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Clofarabine has not been tested for carcinogenic potential. Clofarabine was clastogenic in the in vitro mammalian cell chromosome aberration assay (CHO cells) and in the in vivo rat micronucleus assay. Clofarabine was not mutagenic in the bacterial mutation assay (Ames test). Studies in mice, rats, and dogs have demonstrated dose-related adverse effects on male reproductive organs. Seminiferous tubule and testicular degeneration and atrophy were reported in male mice receiving intraperitoneal doses of 3 mg/kg/day (approximately 0.2-times the recommended human dose based on body surface area [BSA]). Rats receiving 25 mg/kg/day (approximately 3-times the recommended human dose based on BSA) in a 6-month intravenous study had testicular findings of bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells. In a 6-month intravenous dog study, cell degeneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed at 0.375 mg/kg/day (approximately 0.1-times the recommended human dose on a BSA basis). Ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (approximately 4-times the recommended human dose on a mg/m 2 basis), the only dose administered to female mice.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Clofarabine has not been tested for carcinogenic potential. Clofarabine was clastogenic in the in vitro mammalian cell chromosome aberration assay (CHO cells) and in the in vivo rat micronucleus assay. Clofarabine was not mutagenic in the bacterial mutation assay (Ames test). Studies in mice, rats, and dogs have demonstrated dose-related adverse effects on male reproductive organs. Seminiferous tubule and testicular degeneration and atrophy were reported in male mice receiving intraperitoneal doses of 3 mg/kg/day (approximately 0.2-times the recommended human dose based on body surface area [BSA]). Rats receiving 25 mg/kg/day (approximately 3-times the recommended human dose based on BSA) in a 6-month intravenous study had testicular findings of bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells. In a 6-month intravenous dog study, cell degeneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed at 0.375 mg/kg/day (approximately 0.1-times the recommended human dose on a BSA basis). Ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (approximately 4-times the recommended human dose on a mg/m 2 basis), the only dose administered to female mice.

NDA021673

Clolar

clofarabine

0024-5860

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 20 mL Vial Box NDC 0024-5860-01 Clolar ® clofarabine injection Must Be Diluted Prior To Intravenous Use Contains 1 (20 mL) single-dose vial Each single-dose 20 mL vial contains 20 mg clofarabine dissolved in 20 mL of sodium chloride injection, USP 0.9%, pH 4.5-7.5. Contains no preservatives. Sterile. sanofi Rx only PRINCIPAL DISPLAY PANEL - 20 mL Vial Box

Indications and Usage ( 1 ) 7/2022

Manufactured by: Teva Pharmachemie Swensweg 5 Haarlem, The Netherlands Manufactured for: Genzyme Corporation Cambridge, MA 02141 www.clolar.com ©2022 Genzyme Corporation. All rights reserved. Clolar is a registered trademark of Genzyme Corporation.

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) ] . 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) ] . Hepatic and Renal Toxicity Advise patients to avoid medications including over the counter and herbal medications, which may be hepatotoxic or nephrotoxic, during the 5 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 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) ] . Pregnancy Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a 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 6 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 3 months after the last dose [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ] . Lactation Advise females not to breastfeed during treatment with Clolar and for 2 weeks after the last dose [see Use in Specific Populations (8.2) ] . Gastrointestinal Disorders Advise 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) ] . Rash Advise patients that they may experience skin rash with Clolar. If this symptom is significant, they should seek medical attention.

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/m 2 daily for 5 days as an intravenous infusion. Dose Escalation Study in Pediatric Patients with Hematologic Malignancies The 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, A 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/m 2 /day intravenous infusion daily × 5 and escalated to 70 mg/m 2 /day intravenous infusion daily × 5. This dosing schedule was repeated every 2 to 6 weeks depending on toxicity and response. Nine of 17 ALL patients were treated with Clolar 52 mg/m 2 daily for 5 days. In the 17 ALL patients there were 2 complete remissions (12%) and 2 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/m 2 . As a result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m 2 /day for 5 days. Single-Arm Study in Pediatric ALL Clolar was evaluated in an open-label, single-arm study (NCT00042341) of 61 pediatric patients with relapsed/refractory ALL. Patients received a dose of 52 mg/m 2 intravenous infusion over 2 hours for 5 consecutive days repeated every 2 to 6 weeks for up to 12 cycles. There was no dose escalation in this study. All patients had disease that had relapsed after and/or was refractory to two or more prior therapies. Most patients, 38/61 (62%), had received >2 prior regimens and 18/61 (30%) of the patients had undergone at least 1 prior transplant. The median age of the treated patients was 12 years, 61% were male, 39% were female, 44% were White, 38% were Hispanic or Latino, 12% were Black or 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× 10 9 /L]. CRp was defined as meeting all criteria for CR except for recovery of platelet counts to ≥100 × 10 9 /L. Partial Response (PR) was also determined, defined as complete disappearance of circulating blasts, an M2 bone marrow (≥5% and ≤25% blasts), and appearance of normal progenitor cells or an M1 marrow that did not qualify for CR or CRp. Duration of remission was also evaluated. Transplantation rate was not a study endpoint. Response rates for these studies were determined by an unblinded Independent Response Review Panel (IRRP). Table 3 summarizes results for the pediatric ALL study. Responses were seen in both pre-B and T-cell immunophenotypes of ALL. The median cumulative dose was 530 mg (range 29–2815 mg) in 1 (41%), 2 (44%) or 3 or more (15%) cycles. The median number of cycles was 2 (range 1–12). The median time between cycles was 28 days with a range of 12 to 55 days. Table 3: Results in Single-Arm Pediatric ALL N=61 CR = Complete response CRp = 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 4 patients who were transplanted (duration of response, including response after transplant, in these 4 patients was 28.6 to 107.7 weeks). 10.7 (4.3 to 58.6) The median duration of CR, including patients who received transplantation, was 47.9 weeks (range 4.3 to 107.7+), where + indicates the patient was still in CR by the study end. Of 35 patients who were refractory to their immediately preceding induction regimen, 6 (17%) achieved a CR or CRp. Of 18 patients who had at least 1 prior hematopoietic stem cell transplant (HSCT), 5 (28%) achieved a CR or CRp. Among the 12 patients who achieved at least a CRp, 6 patients achieved the best response after 1 cycle of clofarabine, 5 patients required 2 courses and 1 patient achieved a CR after 3 cycles of therapy.

15 REFERENCES OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

8.5 Geriatric Use Safety and effectiveness of Clolar has not been established in geriatric patients aged 65 and older.

8.4 Pediatric Use Safety and effectiveness have been established in pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia.

8.1 Pregnancy Risk Summary In 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/m 2 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 a fetus. There are no available data on Clolar use in pregnant women to evaluate for a 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 a 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 data Intravenous administration of clofarabine to pregnant rats during organogenesis (gestation days [GD] 7–17) at doses of 1, 3 or 9 mg/kg/day (equivalent to 6, 18, 54 mg/m 2 /day) resulted in maternal toxicities at the 9 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 9 mg/kg/day (54 mg/m 2 ; 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 3 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 1 mg/kg/day (equivalent to 1.2, 3.6, 12 mg/m 2 /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 1 mg/kg/day dose (12 mg/m 2 ; 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/m 2 ; 0.1-times the recommended human dose based on BSA).

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary In 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/m 2 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 a fetus. There are no available data on Clolar use in pregnant women to evaluate for a 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 a 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 data Intravenous administration of clofarabine to pregnant rats during organogenesis (gestation days [GD] 7–17) at doses of 1, 3 or 9 mg/kg/day (equivalent to 6, 18, 54 mg/m 2 /day) resulted in maternal toxicities at the 9 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 9 mg/kg/day (54 mg/m 2 ; 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 3 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 1 mg/kg/day (equivalent to 1.2, 3.6, 12 mg/m 2 /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 1 mg/kg/day dose (12 mg/m 2 ; 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/m 2 ; 0.1-times the recommended human dose based on BSA). 8.2 Lactation Risk Summary There 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 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Clolar can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating Clolar. Contraception Females Advise female patients to use effective contraception during treatment with Clolar and for 6 months after the last dose. Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Clolar and for 3 months after the last dose [see Nonclinical Toxicology (13.1) ] . Infertility Females Based on findings from animal studies, Clolar may impair female fertility [see Nonclinical Toxicology (13.1) ]. The reversibility of the effect on fertility is unknown. Males Based 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 1 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 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 a dosage recommendation in patients with CrCL less than 30 mL/min or in patients on dialysis. The pharmacokinetics of clofarabine in patients with renal impairment and normal renal function were obtained from a population pharmacokinetic analysis of three pediatric and two adult studies. In patients with CrCL 60 to less than 90 mL/min (N=47) and CrCL 30 to less than 60 mL/min (N=30), the average AUC of clofarabine increased by 60% and 140%, respectively, compared to patients with normal (N=66) renal function (CrCL greater than 90 mL/min).

16 HOW SUPPLIED/STORAGE AND HANDLING Clolar (clofarabine) injection is supplied in single-dose flint vials containing 20 mg of clofarabine in 20 mL of solution. Each box contains one Clolar vial (NDC 0024-5860-01). The 20-mL flint vials contain 20 mL (20 mg) of solution. The pH range of the solution is 4.5 to 7.5. The solution is sterile, clear and practically colorless, is preservative-free, and is free from foreign matter. Vials containing undiluted Clolar should be stored at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not freeze. Retain in carton until contents are used. Clolar is a hazardous drug. Follow applicable special handling and disposal procedures. 1

Vials containing undiluted Clolar should be stored at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not freeze. Retain in carton until contents are used. Clolar is a hazardous drug. Follow applicable special handling and disposal procedures. 1