Clofarabine
Generic: CLOFARABINE
Basic Information
Manufacturer
Meitheal Pharmaceuticals Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INTRAVENOUS
FDA Set ID
54436453-882e-406b-87a3-049d150101c6
Indications & Usage
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 )
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 )
Adverse Reactions
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 Meitheal Pharmaceuticals Inc.
at 1-844-824-8426 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) ¹ 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.
System Organ Class¹ 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 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 clofarabine 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 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.
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).
( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc.
at 1-844-824-8426 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) ¹ 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.
System Organ Class¹ 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 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 clofarabine 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 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.
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).