Clofarabine

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. 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. (1)

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 .

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 mL/min 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 x 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 higher increases in creatinine or bilirubin

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 Amneal Pharmaceuticals at 1-877-835-5472 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 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 52 mg/m 2 daily × 5. The median number of cycles was 2. The median cumulative amount of clofarabine 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 1 Adverse Reaction (MedDRA Preferred Term) 1 ALL/AML (All Grades, N=115) Worst Grade (NCI Common Terminology Criteria) 1 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 Staphyl

5 WARNINGS AND PRECAUTIONS Myelosuppression: May be severe and prolonged. Monitor complete blood counts and platelet counts during clofarabine 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 a result of bone marrow suppression. Monitor for signs and symptoms of infection; discontinue clofarabine and treat promptly. (5.3) Tumor Lysis syndrome: Anticipate, monitor for signs and symptoms and treat promptly. (5.4) Systemic Inflammatory Response Syndrome (SIRS) or Capillary Leak Syndrome: Monitor for and discontinue clofarabine immediately if suspected. (5.5) Venous Occlusive Disease of the Liver: Monitor for and discontinue clofarabine if suspected. (5.6) Hepatotoxicity: Severe and fatal hepatotoxicity. Monitor liver function, for signs and symptoms of hepatitis and hepatic failure. Discontinue clofarabine immediately for Grade 3 or greater liver enzyme and/or bilirubin elevations. (5.7) Renal Toxicity: Increased creatinine and acute renal failure; monitor renal function and interrupt or discontinue clofarabine. (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. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.11) 5.1 Myelosuppression Clofarabine causes myelosuppression which may be severe and prolonged. Febrile neutropenia occurred in 55% and non-febrile neutropenia in an additional 10% of pediatric patients in clinical trials. At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia. Myelosuppression is usually reversible with interruption of clofarabine 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 Clofarabine increases the risk of infection, including severe and fatal sepsis, and opportunistic infections. At baseline, 48% of the pediatric patients had one or more concurrent infections. A total of 83% of patients experienced at least one infection after clofarabine treatment, including fungal, viral and bacterial infections. Monitor patients for signs and symptoms of infection, discontinue clofarabine, and treat promptly. 5.4 Tumor Lysis Syndrome Administration of clofarabine may result in tumor lysis syndrome associated with the break-down metabolic products from peripheral leukemia cell death. Monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome and initiate preventive measures including adequate intravenous fluids and measures to control uric acid. 5.5 Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome Clofarabine may cause a cytokine release syndrome (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that may progress to the systemic inflammatory response syndrome (SIRS) with capillary leak syndrome and organ impairment which may be fatal. Monitor patients frequently for these conditions. In clinical trials, SIRS was reported in two patients (2%); capillary leak syndrome was reported in four patients (4%). Symptoms included rapid onset of respira

4 CONTRAINDICATIONS None. None. (4)

10 OVERDOSAGE There were no known overdoses of clofarabine. 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.