Clofarabine

Indications and Usage ( 1 ) 7/2022

1 INDICATIONS AND USAGE Clofarabine Injection 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. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Clofarabine Injection. Clofarabine injection 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. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Clofarabine Injection. ( 1 )

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 to 6 weeks. ( 2.1 ) • Provide supportive care, such as intravenous infusion fluids, antihyperuricemic treatment, and alkalinization of urine throughout the 5 days of Clofarabine Injection administration to reduce the risk of tumor lysis and other adverse reactions. ( 2.1 ) • Discontinue Clofarabine Injection 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 Clofarabine Injection administration to reduce the effects of tumor lysis and other adverse reactions. • Discontinue Clofarabine Injection if hypotension develops during the 5 days of administration. • Monitor renal and hepatic function during the 5 days of Clofarabine Injection administration [see Warnings and Precautions ( 5.7 , 5.8 )] . • Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Clofarabine Injection. 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 Clofarabine Injection is moderately emetogenic. • Consider the use of prophylactic steroids to mitigate Systemic Inflammatory Response Syndrome (SIRS) or capillary leak syndrome (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema). • Minimize exposure to drugs with known renal toxicity during the 5 days of Clofarabine Injection administration since the risk of renal toxicity may be increased. • 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 Clofarabine Injection if a patient develops a clinically significant infection, until the infection is controlled, then restart at the full dose. • Withhold Clofarabine Injection for a Grade 3 non-infectious non-hematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting controlled by antiemetic therapy). Re-institute Clofarabine Injection administration at a 25% dose reduction when resolution or return to baseline. • Discontinue Clofarabine Injection administration for a Grade 4 non-infectious non-hematologic toxicity. • Discontinue Clofarabine Injection 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 Clofarabine Injection administration if Grade 3 or high …

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

4 CONTRAINDICATIONS None. • None. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Myelosuppression [ see Warnings and Precautions (5.1) ] Hemorrhage [ see Warnings and Precautions (5.2) ] Serious Infections [ see Warnings and Precautions (5.3) ] Hyperuricemia (Tumor Lysis) [ see Warnings and Precautions (5.4) ] Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome [ see Warnings and Precautions (5.5) ] Venous Occlusive Disease of the Liver [ see Warnings and Precautions (5.6) ] Hepatotoxicity [ see Warnings and Precautions (5.7) ] Renal Toxicity [ see Warnings and Precautions (5.8) ] Enterocolitis [ see Warnings and Precautions (5.9) ] Skin Reactions [ see Warnings and Precautions (5.10) ] 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 Fosun Pharma USA Inc. at 1-866-611-3762 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Clofarabine Injection in 115 pediatric patients with relapsed or refractory Acute Lymphoblastic Leukemia (ALL) (70 patients) or Acute Myelogenous Leukemia (AML) (45 patients). In total, 115 pediatric patients treated in clinical trials received the recommended dose of Clofarabine Injection 52 mg/m2 daily × 5. The median number of cycles was 2. The median cumulative amount of Clofarabine Injection received by pediatric patients during all cycles was 540 mg. Most common adverse reactions (≥25%): vomiting, nausea, diarrhea, febrile neutropenia, pruritus, headache, bacteremia, pyrexia, rash, tachycardia, abdominal pain, chills, fatigue, anorexia, pain in extremity, hypotension, epistaxis, and petechiae. Table 1 lists adverse reactions by System Organ Class, including severe or life-threatening (NCI CTC Grade 3 or Grade 4), reported in ≥5% of the 115 patients in the 52 mg/m2/day dose group (pooled analysis of pediatric patients with ALL and AML). More detailed information and follow-up of certain events is given below. Table 1: Most Commonly Reported (≥5% Overall) Adverse Reactions by System Organ Class (N=115 pooled analysis) System Organ Class1 Preferred Term1 ALL/AM (N=115) Worst NCI Common Terminology Criteria Grade1 3 4 5 N % N % N % N % Blood and Lymphatic System Disorders Febrile neutropenia 63 55 59 51 3 3 Neutropenia 11 10 3 3 8 7 . . Cardiac Disorders Pericardial effusion 9 8 . . 1 1 . . Tachycardia 40 35 6 5 . . . . Gastrointestinal Disorders Abdominal pain 40 35 8 7 . . . . Abdominal pain upper 9 8 1 1 . . . . Diarrhea 64 56 14 12 . . . . Gingival or mouth bleeding 20 17 8 7 1 1 . . Nausea 84 73 16 14 1 1 . . Oral mucosal petechiae 6 5 4 4 . . . . Proctalgia 9 8 2 2 . . . . Stomatitis 8 7 1 1 . . . . Vomiting 90 78 9 8 1 1 . . General Disorders and Administration Site Conditions Asthenia 12 10 1 1 1 1 . . Chills 39 34 3 3 . . . . Fatigue 39 34 3 3 2 2 . . Irritability 11 10 1 1 . . . . Mucosal inflammation 18 16 2 2 . . . . Edema 14 12 2 2 . . . . Pain 17 15 7 6 1 1 . . Pyrexia 45 39 16 14 . . . . Hepatobiliary Disorder Jaundice 9 8 2 2 . . . . Infections and Infestations Bacteremia 10 9 10 9 . . . . Candidiasis 8 7 1 1 . . . . Catheter related infection 14 12 13 11 . . . . Cellulitis 9 8 7 6 . . . . Clostridium colitis 8 7 6 5 . . . . Herpes simplex 11 10 6 5 . . . . Herpes zoster 8 7 6 5 . . . . Oral candidiasis 13 11 2 2 . . . . Pneumonia 11 10 6 5 1 1 1 1 1 Patients with more than one preferred term within a SOC are counted only once in the SOC totals. Patients …

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 Clofarabine 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 Clofarabine, and for at least 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating Clofarabine. Contraception Females Clofarabine 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 Clofarabine 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 Clofarabine and for at least 3 months after the last dose [see Nonclinical Toxicology ( 13.1 )] . Infertility Females Based on findings from animal studies, Clofar …

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 .

11 DESCRIPTION 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-purine-6-amine. Its molecular formula is C 10 H 11 Cl FN 5 O 3 with a molecular weight of 303.68 Daltons. The molecular structure of clofarabine is: Clofarabine Clofarabine injection (1 mg/m L) is supplied in a 20 m L, single-dose vial. The 20 m L vial contains 20 mg clofarabine formulated in 20 m L unbuffered normal saline (comprised of Water for Injection, USP, and Sodium Chloride, USP). The p H range of the solution is 4.5 to 7.5. The solution is sterile, clear and practically colorless, and is preservative-free. clofarabine-structure

10 OVERDOSAGE There were no known overdoses of Clofarabine Injection. The highest daily dose administered to a human to date (on a mg/m 2 basis) has been 70 mg/m 2 /day x 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Clofarabine Injection is a sterile, clear and practically colorless solution, is preservative-free and is free from foreign matter. It is supplied in single-dose flint vials containing 20 mg of clofarabine in 20 mL of solution as follows: NDC Clofarabine Injection (1 mg per mL) Package Factor 71288- 128 -20 20 mg per 20 mL Single-Dose Vial 1 vial per carton The pH range of the solution is 4.5 to 7.5. Storage Conditions Vials containing undiluted Clofarabine Injection should be stored at 25°C (77°F); excursions permitted between 15° to 30°C (59° to 86°F). Do not freeze. Retain in carton until contents are used. Clofarabine Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Discard unused portion. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.