Clofarabine

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.

Injection: 20 mg/20 m L (1 mg/m L) clear colorless solution in single-dose vial Injection: 20 mg/20 m L (1 mg/m L) single-dose vial. ( 3 )

None. None. ( 4 )

Myelosuppression: May be severe and prolonged. Monitor complete blood counts and platelet counts during clofarabine injection therapy. ( 5.1 ) Hemorrhage: Serious and fatal cerebral, gastrointestinal and pulmonary hemorrhage. Monitor platelets and coagulation parameters and treat accordingly. ( 5.2 ) Infections: Severe and fatal sepsis as a result of bone marrow suppression. Monitor for signs and symptoms of infection; discontinue clofarabine injection and treat promptly. ( 5.3 ) Tumor Lysis syndrome: Anticipate, monitor for signs and symptoms and treat promptly. ( 5.4 ) Systemic Inflammatory Response Syndrome (SIRS) or Capillary Leak Syndrome: Monitor for and discontinue clofarabine injection immediately if suspected. ( 5.5 ) Venous Occlusive Disease of the Liver: Monitor for and discontinue clofarabine injection if suspected. ( 5.6 ) Hepatotoxicity: Severe and fatal hepatotoxicity. Monitor liver function, for signs and symptoms of hepatitis and hepatic failure. Discontinue clofarabine injection immediately for Grade 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 injection. ( 5.8 ) Enterocolitis: Serious and fatal enterocolitis, occurring more frequently within 30 days of treatment and with combination chemotherapy. Monitor patients for signs and symptoms of enterocolitis and treat promptly. ( 5.9 ) Skin Reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases. Discontinue for exfoliative or bullous rash, or if SJS or TEN is suspected. ( 5.10 ) 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 injection causes myelosuppression which may be severe and prolonged. Febrile neutropenia occurred in 55% and non-febrile neutropenia in an additional 10% of pediatric patients in clinical trials. At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia. Myelosuppression is usually reversible with interruption of clofarabine injection treatment and appears to be dose- dependent. Monitor complete blood counts [ see Dosage and Administration( 2.4 ) ].

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 injection increases the risk of infection, including severe and fatal sepsis, and opportunistic infections. At baseline, 48% of the pediatric patients had one or more concurrent infections. A total of 83% of patients experienced at least one infection after clofarabine injection treatment, including fungal, viral and bacterial infections. Monitor patients for signs and symptoms of infection, discontinue clofarabine injection, and treat promptly.

5.4 Tumor Lysis Syndrome Administration of clofarabine injection may result in tumor lysis syndrome associated with the break-down metabolic products from peripheral leukemia cell death. Monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome and initiate preventive measures including adequate intravenous fluids and measures to control uric acid.

5.5 Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome Clofarabine injection may cause 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 respiratory distress, hypotension, pleural and pericardial effusion, and multiorgan failure. Close monitoring for this syndrome and early intervention may reduce the risk. Immediately discontinue clofarabine injection and provide appropriate supportive measures. The use of prophylactic steroids (e.g., 100 mg/m 2 hydrocortisone on Days 1 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 clofarabine injection can be considered with a 25% dose reduction.

5.6 Venous Occlusive Disease of the Liver Patients who have previously received a hematopoietic stem cell transplant (HSCT) are at higher risk for veno-occlusive disease (VOD) of the liver following treatment with clofarabine (40 mg/m 2 ) when used in combination with etoposide (100 mg/m 2 ) and cyclophosphamide (440 mg/m 2 ). Severe hepatotoxic events have been reported in a 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 clofarabine injection if VOD is suspected.

5.7 Hepatotoxicity Severe and fatal hepatotoxicity, including hepatitis and hepatic failure, has occurred with the use of clofarabine injection. In clinical studies, Grade 3-4 liver enzyme elevations were observed in pediatric patients during treatment with clofarabine injection at the following rates: elevated aspartate aminotransferase (AST) occurred in 36% of patients; elevated alanine aminotransferase (ALT) occurred in 44% of patients. AST and ALT elevations typically occurred within 10 days of clofarabine injection administration and returned to Grade 2 or less within 15 days. Grade 3 or 4 elevated bilirubin occurred in 13% of patients, with 2 events reported as Grade 4 hyperbilirubinemia (2%), one of which resulted in treatment discontinuation and one patient had multiorgan failure and died. Eight patients (7%) had Grade 3 or 4 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 clofarabine injection immediately for Grade 3 or greater liver enzyme and/or bilirubin elevations [see Dosage and Administration ( 2.4 )].

5.8 Renal Toxicity Clofarabine injection may cause acute renal failure. In clofarabine injection treated patients in clinical studies, Grade 3 or 4 elevated creatinine occurred in 8% of patients and acute renal failure was reported as Grade 3 in three patients (3%) and Grade 4 in two patients (2%). Patients with infection, sepsis, or tumor lysis syndrome may be at increased risk of renal toxicity when treated with clofarabine injection. Hematuria occurred in 13% of clofarabine injection treated patients overall. Monitor patients for renal toxicity and interrupt or discontinue clofarabine injection as necessary [see Dosage and Administration ( 2.4 )] .

5.9 Enterocolitis Fatal and serious cases of enterocolitis, including neutropenic colitis, cecitis, and C. difficile colitis, have occurred during treatment with clofarabine. This has occurred more frequently within 30 days of treatment, and in the setting of combination chemotherapy. Enterocolitis may lead to necrosis, perforation, hemorrhage or sepsis complications. Monitor patients for signs and symptoms of enterocolitis and treat promptly.

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 ) ]. […]

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 Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at1-800-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/m 2 daily x5. 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 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 (Med DRA 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 Infections and Infestations (continued) 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 . . ¹ Patients with more than one adverse reaction (Med DRA preferred term) within a SOC are counted only once in the SOC totals. Patients with more thanone occurrence of the same adverse reaction (Med DRA preferred term) are counted only once within that reaction and at the highest severity grade. 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 clofarabine injection administration at 52 mg/m 2 among pediatric patients with ALL and AML (N=115). Table 2: Incidence of Treatment-Emergent Laboratory Abnormalities after Clofarabine Injection 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 clofarabine injection. 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).

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 to 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 to 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 2 weeks after the last dose.

8.3 Females and Males of Reproductive Potential Clofarabine 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 clofarabine. Contraception Females 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 3 months after the last dose [see Nonclinical Toxicology ( 13.1) ] . Infertility Females Based on findings from animal studies, clofarabine 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, clofarabine 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 clofarabine injection has not been established in geriatric patients aged 65 and older.

8.6 Renal Impairment Reduce the clofarabine starting dose by 50% in patients with CrCL of 30 to 60 m L/min. There is insufficient information to make a dosage recommendation in patients with CrCL less than 30 m L/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 m L/min (N = 47) and Cr CL 30 to less than 60 m L/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 m L/min).

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 .