NDC 71288-128 Clofarabine

Clofarabine

NDC Product Code 71288-128

NDC 71288-128-20

Package Description: 1 VIAL, SINGLE-DOSE in 1 CARTON > 20 mL in 1 VIAL, SINGLE-DOSE

NDC Product Information

Clofarabine with NDC 71288-128 is a a human prescription drug product labeled by Meitheal Pharmaceuticals Inc.. The generic name of Clofarabine is clofarabine. The product's dosage form is injection and is administered via intravenous form.

Labeler Name: Meitheal Pharmaceuticals Inc.

Dosage Form: Injection - A sterile preparation intended for parenteral use; five distinct classes of injections exist as defined by the USP.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Clofarabine Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • CLOFARABINE 1 mg/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.
  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Nucleic Acid Synthesis Inhibitors - [MoA] (Mechanism of Action)
  • Nucleoside Metabolic Inhibitor - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Meitheal Pharmaceuticals Inc.
Labeler Code: 71288
FDA Application Number: ANDA213461 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 10-23-2020 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Clofarabine Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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.

  • Administer the recommended pediatric dose of 52 mg/m2 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 × 109/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.
  • 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 (8.7)].

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 ToxicityIf a patient experiences a Grade 4 neutropenia (ANC <0.5 × 109/L) lasting ≥4 weeks, reduce dose by 25% for the next cycle.
  • Non-hematologic ToxicityWithhold 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 are noted. Re-institute clofarabine injection 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 clofarabine injection 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 per mL and 0.4 mg per mL. Use within 24 hours of preparation. Store diluted clofarabine injection at room temperature (15° to 30ºC).
Discard unused portion in vial.

3 Dosage Forms And Strengths

Injection: 20 mg per 20 mL (1 mg per mL) clear solution in single-dose vial

4 Contraindications

None.

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 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 and provide appropriate supportive measures. The use of prophylactic steroids (e.g., 100 mg/m2 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 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/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). 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 if VOD is suspected.

5.7 Hepatotoxicity

Severe and fatal hepatotoxicity, including hepatitis and hepatic failure, has occurred with the use of clofarabine. In clinical studies, Grade 3-4 liver enzyme elevations were observed in pediatric patients during treatment with clofarabine 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 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 immediately for Grade 3 or greater liver enzyme and/or bilirubin elevations [see Dosage and Administration (2.4)].

5.8 Renal Toxicity

Clofarabine may cause acute renal failure. In clofarabine 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. Hematuria occurred in 13% of clofarabine treated patients overall. Monitor patients for renal toxicity and interrupt or discontinue clofarabine 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)].

5.11 Embryo-Fetal Toxicity

Based on findings from animal reproductive studies and the drug's mechanism of action, clofarabine can cause fetal harm when administered to a pregnant woman. Intravenous doses of clofarabine in rats and rabbits administered during organogenesis at doses that were below the maximum recommended human dose of 52 mg/m2 based on body surface area (mg/m2) caused an increase in resorptions, malformations, and variations. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment with clofarabine and for at least 6 months after the last dose. 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 Use in Specific Populations (8.1)].

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)]

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/m2 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/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)
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 Class¹Adverse Reaction(MedDRA Preferred Term)¹ALL/AML(All Grades,N=115)Worst Grade(NCI Common Terminology Criteria)¹345N%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 InfestationsBacteremia
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 NutritionDisorders
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 UrinaryDisorders
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/m2 among pediatric patients with ALL and AML (N=115).
Table 2: Incidence of Treatment-Emergent Laboratory Abnormalities after Clofarabine Administration
ParameterAny GradeGrade 3 or higherAnemia (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 postapproval 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).

Other

Risk SummaryIn 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/m2 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/m2/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/m2; 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/m2/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/m2; 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/m2; 0.1-times the recommended human dose based on BSA).

Risk SummaryThere 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.

Pregnancy TestingPregnancy 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, 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.

Drug-Drug InteractionsIn 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 clofarabine toxicity should be monitored when administered with other hOAT1, hOAT3, hOCT1 and hOCT2 substrates or inhibitors.

Dose Escalation Study in Pediatric Patients with Hematologic MalignanciesThe safety and efficacy of clofarabine 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 clofarabine was 11.25 mg/m2/day intravenous infusion daily × 5 and escalated to 70 mg/m2/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 clofarabine 52 mg/m2 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/m2. As a result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m2/day for 5 days.

Single-Arm Study in Pediatric ALLClofarabine was evaluated in an open-label, single-arm study of 61 pediatric patients with relapsed/refractory ALL. Patients received a dose of 52 mg/m2 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 Caucasian, 38% were Hispanic, 12% were 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 × 109/L and absolute neutrophil count (ANC) ≥1 × 109/L]. CRp was defined as meeting all criteria for CR except for recovery of platelet counts to ≥100 × 109/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 29-2,815 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
CR = Complete response
CRp = Complete response without platelet recovery
1 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).
N=61     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)110.7 (4.3 to 58.6)
Six (9.8%) patients achieved a PR; the clinical relevance of a PR in this setting is unknown.
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.

Hematologic ToxicityAdvise 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)].

InfectionAdvise 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 ToxicityAdvise patients to avoid medications including over the counter and herbal medications, which may be hepatotoxic or nephrotoxic, during the 5 days of clofarabine 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 SyndromeAdvise 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)].

PregnancyAdvise 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 clofarabine and for at least 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 clofarabine and for at least 3 months after the last dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

LactationAdvise females not to breastfeed during treatment with clofarabine and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

Gastrointestinal DisordersAdvise patients that they may experience nausea, vomiting, and/or diarrhea with clofarabine. If these symptoms are significant, they should seek medical attention [see Warnings and Precautions (5.9)].

RashAdvise patients that they may experience skin rash with clofarabine. If this symptom is significant, they should seek medical attention.
meitheal®Mfd. for Meitheal PharmaceuticalsChicago, IL 60631 (USA)©2020 Meitheal Pharmaceuticals Inc.
March 2020

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 has not been established in geriatric patients aged 65 and older.

8.6 Adults With Hematologic Malignancies

Safety and effectiveness have not been established in adults.

8.7 Renal Impairment

Reduce the clofarabine 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).

10 Overdosage

There were no known overdoses of clofarabine. The highest daily dose administered to a human to date (on a mg/m2 basis) has been 70 mg/m2/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/m2/day was not tolerated.

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-purin-6-amine. Its molecular formula is C10H11ClFN5O3 with a molecular weight of 303.68 Daltons.
The molecular structure of clofarabine is:
Clofarabine Injection (1 mg per 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.

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 clofarabine 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/m2 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/m2 and 172 L/m2, 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.

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/m2 basis), the only dose administered to female mice.

14 Clinical Studies

Seventy-eight (78) pediatric patients with ALL were exposed to clofarabine. Seventy (70) of the patients received the recommended pediatric dose of clofarabine 52 mg/m2 daily for 5 days as an intravenous infusion.

15 References

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

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:
NDCClofarabine Injection (1 mg per mL)Package Factor71288-128-20
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 And Handling

Storage ConditionsVials 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 cytotoxic drug. Follow applicable special handling and disposal procedures.1Discard unused portion.
Sterile, Nonpyrogenic, Preservative-free.The container closure is not made with natural rubber latex.

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