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CLOFARABINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Clofarabine is a purine nucleoside analog. Clofarabine inhibits the synthesis of DNA by inhibiting the ribonucleotide reductase and reducing the pools of deoxynucleotide triphosphate. It is incorporated into the DNA chain by competitive inhibition of DNA polymerase, thus terminating DNA chain elongation and inhibiting repair.

Specific Substances

    1) Cl-F-Ara-A
    2) Clofarabina
    3) Clofarabinum
    4) CaFDA
    5) CFA
    6) Clofarex
    7) 2-Chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purin-6-amine
    8) Molecular Formula: C10-H11-Cl-F-N5-O3
    9) CAS 123318-82-1
    1.2.1) MOLECULAR FORMULA
    1) C10-H11-Cl-F-N5-O3 (Prod Info CLOLAR(TM) IV injection, 2004)

Available Forms Sources

    A) FORMS
    1) Clofarabine is available commercially as 20 mL single use vials containing 20 mg clofarabine (concentration 1 mg/mL) (Prod Info Clolar(R) intravenous injection, 2014).
    B) USES
    1) Clofarabine is used for the treatment of pediatric patients (ages 1 to 21 years) with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens (Prod Info Clolar(R) intravenous injection, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Clofarabine is used for the treatment of pediatric patients (ages 1 to 21 years) with relapsed or refractory acute lymphoblastic leukemia (ALL) after at least two prior regimens.
    B) PHARMACOLOGY: Clofarabine is a purine nucleoside analog. It inhibits the synthesis of DNA by inhibiting the ribonucleotide reductase and reducing the pools of deoxynucleotide triphosphate. It is incorporated into the DNA chain by competitive inhibition of DNA polymerase, thus terminating DNA chain elongation and inhibiting repair.
    C) EPIDEMIOLOGY: Exposure may occur.
    D) WITH THERAPEUTIC USE
    1) COMMON: Commonly reported adverse reactions, with an incidence of at least 10%, include nausea, vomiting, diarrhea, abdominal pain, anorexia, anemia, leukopenia, neutropenia (including febrile neutropenia), thrombocytopenia, tachycardia, hypotension, hypertension, rash, pruritus, pyrexia, infection, edema, elevated liver enzymes, back pain, myalgia, headache, lethargy, fatigue, anxiety, flushing, hematuria, dyspnea, epistaxis, petechiae, mucosal inflammation, and palmar-plantar erythrodysesthesia syndrome.
    2) LESS FREQUENT: Adverse effects that were reported less frequently during clinical trials include stomatitis, arthralgia, pancreatitis, hyperbilirubinemia, tumor lysis syndrome, hypersensitivity reactions, pulmonary edema, acute renal failure, venous occlusive disease of the liver, and systemic inflammatory response syndrome or capillary leak syndrome manifesting with symptoms of rapid onset respiratory distress, pleural effusions, pericardial effusion and multi-organ failure. In postmarketing surveillance, there have been reports of gastrointestinal hemorrhage, including fatalities, hyponatremia, and serious, sometimes fatal, skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Effects are expected to be an extension of adverse effects reported with therapeutic use. Grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash developed in 2 pediatric patients with ALL after receiving clofarabine 70 mg/m(2)/day for 5 days, the highest daily dose administered to a human to date (on a mg/m(2) basis). The recommended pediatric dose of 52 mg/m(2)/day was not tolerated in adults with refractory and/or relapsed hematologic malignancies during a Phase 1 clinical trial.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Pyrexia was reported with clofarabine therapy.
    0.2.20) REPRODUCTIVE
    A) Clofarabine is classified as FDA pregnancy category D. At the time of this review, no data were available to assess the teratogenic potential of this agent. In animal studies, developmental toxicity (reduced fetal body weight and increased post-implantation loss) were reported.
    0.2.21) CARCINOGENICITY
    A) Clofarabine has not been tested for carcinogenic potential.

Laboratory Monitoring

    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Neutrophil nadir may not develop for 3 to 4 weeks and platelet nadir for 2 weeks or more.
    B) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    C) Monitor serum electrolytes, renal function, and hepatic enzymes.
    D) Monitor vital signs.
    E) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    F) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Treatment Overview

    0.4.4) EYE EXPOSURE
    A) Irrigate eyes with 0.9% saline or water. Perform an eye exam, including slit lamp, if irritation persists.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Wash exposed skin well with soap and water and remove contaminated clothing.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes. For severe hypotension, evaluate for sepsis, bleeding, and systemic inflammatory response syndrome. Administer intravenous fluids, 0.9% saline (1 to 1.5 L in adults, 20 mL/kg in children). Avoid large volumes of IV fluids as they may worsen capillary leak syndrome. Central venous pressure monitoring may help guide therapy. If hypotension persists, administer vasopressors.
    C) INTRATHECAL INJECTION
    1) There are no reports of inadvertent intrathecal injection with clofarabine. The following recommendations are based on experience with other antineoplastic agents. After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    E) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe bleeding or significant respiratory distress.
    F) ANTIDOTE
    1) There is no specific antidote.
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    H) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    I) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during the neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    J) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).
    K) STOMATITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. It has not been studied in the setting of chemotherapy overdose. In patients with a clofarabine overdose, consider administering palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    L) ENHANCED ELIMINATION PROCEDURE
    1) It is unknown if hemodialysis would be effective in overdose.
    M) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    N) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of clofarabine therapy. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    O) PHARMACOKINETICS
    1) Protein binding is 47%, mostly to albumin. Steady state volume of distribution is 172 L/m(2) Clofarabine is sequentially metabolized intracellularly via deoxycytidine kinase to a 5'-monophosphate metabolite, then to the active 5'-triphosphate metabolite via mono- and di-phosphokinases. 49% to 60% of the drug is excreted unchanged in urine within 24 hours. Terminal elimination half life is 5.2 hours.
    P) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression.

Range Of Toxicity

    A) TOXICITY: Two pediatric patients with acute lymphoid leukemia developed grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash after receiving clofarabine 70 mg/m(2)/day for 5 days, the highest daily dose administered to a human to date (on a mg/m(2) basis). One pediatric patient developed fatal toxic epidermal necrolysis and liver toxicity after receiving clofarabine 52 mg/m(2)/day for 5 days. For adult patients with solid tumors, the maximum tolerated dose was 2 mg/m(2)/day
    B) THERAPEUTIC DOSE (1 to 21 years of age): 52 mg/m(2) IV infusion over 2 hours daily for 5 consecutive days; repeat every 2 to 6 weeks following recovery or return to baseline organ function.

Clinical Effects

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, neutropenia was reported in 10% of patients, with grades 3 and 4 neutropenia reported in 3% and 7% of patients, respectively (Prod Info Clolar(R) intravenous injection, 2014).
    b) Neutropenia (grade 3 or 4) developed in all 8 patients treated with clofarabine 4 mg/meter(2)/day for 5 day for multiple myeloma. In these patients there were two neutrophil count nadirs, one around day 8 of therapy, the other between days 22 to 28; neutrophil recovery occurred between days 35 and 42 (Uy et al, 2006).
    B) FEBRILE NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, febrile neutropenia was reported in 55% of patients, with grades 3 and 4 febrile neutropenia reported in 51% and 3% of patients, respectively (Prod Info Clolar(R) intravenous injection, 2014).
    C) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia or acute myelogenous leukemia who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials (n=114), any grade anemia was reported in 83% of patients. Additionally, grade 3 or higher anemia was reported in 75% of patients who received clofarabine (Prod Info Clolar(R) intravenous injection, 2014).
    D) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia or acute myelogenous leukemia who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials (n=114), grade 3 or higher leukopenia was reported in 88% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    E) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia or acute myelogenous leukemia who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials (n=114), any grade thrombocytopenia was reported in 81% of patients. Additionally, grade 3 or higher thrombocytopenia was reported in 80% of patients who received clofarabine (Prod Info Clolar(R) intravenous injection, 2014).
    b) Thrombocytopenia (grade 3 or 4) developed in 3 of 8 patients treated with clofarabine 4 mg/meter(2)/day for 5 day for multiple myeloma. However, a greater than 50% decrease in platelet counts compared to baseline levels was observed in all 8 patients. The platelet nadir occurred on day 15 with recovery by day 28 (Uy et al, 2006).
    F) LYMPHOCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia or acute myelogenous leukemia who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials (n=113), grade 3 or higher lymphopenia was reported in 82% of patients (Prod Info Clolar(R) intravenous injection, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, rash was reported in 38% of patients, with grade 3 rash reported in 7% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    2) WITH POISONING/EXPOSURE
    a) Two pediatric patients with acute lymphoid leukemia developed grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash after receiving clofarabine 70 mg/m(2)/day for 5 days, the highest daily dose administered to a human to date (on a mg/m(2) basis) (Prod Info Clolar(R) intravenous injection, 2014).
    B) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, pruritus was reported in 43% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    C) ACRAL ERYTHEMA DUE TO CYTOTOXIC THERAPY
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, palmar-plantar erythrodysesthesia syndrome was reported in 16% of patients, grade 3 palmar-plantar erythrodysesthesia syndrome was reported in 7% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    D) ERYTHEMA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, erythema was reported in 11% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    E) CELLULITIS
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, cellulitis was reported in 8% of patients, with grade 3 cellulitis reported in 6% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    F) PETECHIAE
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, petechiae was reported in 26% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    G) FLUSHING
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, flushing was reported in 19% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    H) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) Toxic epidermal necrolysis (TEN), with fatalities, has been reported during postmarketing surveillance of clofarabine in patients who were receiving or had recently been treated with clofarabine and other medications (eg, allopurinol or antibiotics) known to cause TEN (Prod Info Clolar(R) intravenous injection, 2014).
    b) CASE REPORT: A 9-year-old child developed elevated liver enzymes, periorbital edema, severe oral mucositis, and generalized erythema and pustules 2 to 7 days after beginning clofarabine therapy. The patient was also receiving triple intrathecal therapy with cytarabine, methotrexate, and hydrocortisone. By day 10, the patient was severely jaundiced, and a skin biopsy indicated toxic epidermal necrolysis. Over the next 2 days, the patient's condition worsened with progressive desquamation and deteriorating liver function, resulting in death. The authors speculate that an interaction between clofarabine and methotrexate may have resulted in increased severity of similar toxicities, thereby contributing to the development of skin and liver toxicity in this patient (Johnston & Mandel, 2008).
    I) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens-Johnson syndrome (SJS), with fatalities, has been reported during postmarketing surveillance of clofarabine in patients who were receiving or had recently been treated with clofarabine and other medications (eg, allopurinol or antibiotics) known to cause SJS (Prod Info Clolar(R) intravenous injection, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, arthralgia was reported in 9% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    B) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, back pain was reported in 10% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    C) PAIN IN LIMB
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, pain in extremity was reported in 30% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    D) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, myalgia was reported in 14% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    E) BONE PAIN
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, bone pain was reported in 10% of patients (Prod Info Clolar(R) intravenous injection, 2014).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, one or more infections (bacterial, fungal, and viral) were reported in 83% of patients; however, 48% of patients had one or more concurrent infections at baseline (Prod Info Clolar(R) intravenous injection, 2014).
    b) Tuberculosis pneumonia, fungal pneumonia, pneumocystis carinii and torulopsis infections have been reported following clofarabine use (Sternberg, 2003; Kantarjian et al, 2003; Kantarjian et al, 2003a).
    B) SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, Systemic Inflammatory Response Syndrome (SIRS) was reported in 2 patients (2%) (Prod Info Clolar(R) intravenous injection, 2014).
    C) SYSTEMIC INFECTION
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, sepsis, including septic shock, was reported in 17% (any grade), 5% (grade 3), 4% (grade 4), and 8% (grade 5) of patients. Additionally, Staphylococcal sepsis was reported in 5% (any grade), 4% (grade 3), and 1% (grade 4) of patients who received clofarabine. Escherichia sepsis and fungal sepsis were each reported in 1% to 4% of patients who received clofarabine (Prod Info Clolar(R) intravenous injection, 2014).
    D) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, hypersensitivity was reported in 1% to 4% of the patients (Prod Info Clolar(R) intravenous injection, 2014).

Summary Of Exposure

    A) USES: Clofarabine is used for the treatment of pediatric patients (ages 1 to 21 years) with relapsed or refractory acute lymphoblastic leukemia (ALL) after at least two prior regimens.
    B) PHARMACOLOGY: Clofarabine is a purine nucleoside analog. It inhibits the synthesis of DNA by inhibiting the ribonucleotide reductase and reducing the pools of deoxynucleotide triphosphate. It is incorporated into the DNA chain by competitive inhibition of DNA polymerase, thus terminating DNA chain elongation and inhibiting repair.
    C) EPIDEMIOLOGY: Exposure may occur.
    D) WITH THERAPEUTIC USE
    1) COMMON: Commonly reported adverse reactions, with an incidence of at least 10%, include nausea, vomiting, diarrhea, abdominal pain, anorexia, anemia, leukopenia, neutropenia (including febrile neutropenia), thrombocytopenia, tachycardia, hypotension, hypertension, rash, pruritus, pyrexia, infection, edema, elevated liver enzymes, back pain, myalgia, headache, lethargy, fatigue, anxiety, flushing, hematuria, dyspnea, epistaxis, petechiae, mucosal inflammation, and palmar-plantar erythrodysesthesia syndrome.
    2) LESS FREQUENT: Adverse effects that were reported less frequently during clinical trials include stomatitis, arthralgia, pancreatitis, hyperbilirubinemia, tumor lysis syndrome, hypersensitivity reactions, pulmonary edema, acute renal failure, venous occlusive disease of the liver, and systemic inflammatory response syndrome or capillary leak syndrome manifesting with symptoms of rapid onset respiratory distress, pleural effusions, pericardial effusion and multi-organ failure. In postmarketing surveillance, there have been reports of gastrointestinal hemorrhage, including fatalities, hyponatremia, and serious, sometimes fatal, skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Effects are expected to be an extension of adverse effects reported with therapeutic use. Grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash developed in 2 pediatric patients with ALL after receiving clofarabine 70 mg/m(2)/day for 5 days, the highest daily dose administered to a human to date (on a mg/m(2) basis). The recommended pediatric dose of 52 mg/m(2)/day was not tolerated in adults with refractory and/or relapsed hematologic malignancies during a Phase 1 clinical trial.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Pyrexia was reported with clofarabine therapy.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, pyrexia was reported in 39% of patients, with grade 3 pyrexia reported in 14% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    2) In a study, fever of unknown origin occurred in 31% of patients receiving clofarabine (Kantarjian et al, 2003).

Heent

    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, epistaxis was reported in 27% of patients (Prod Info Clolar(R) intravenous injection, 2014).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, tachycardia was reported in 35% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    B) PERICARDIAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, pericardial effusion was reported in 12% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    b) In a series of 40 children with ALL who had MUGA scans before and after receiving clofarabine, 12 (29%) developed pericardial effusions, in 2 of them the effusion was of moderate size, and in one patient there was evidence of increased intrapericardial pressure which resolved without intervention (Jeha et al, 2006).
    C) LOW BLOOD PRESSURE
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, hypotension was reported in 29% of patients, with grades 3 and 4 hypotension reported in 11% and 8% of patients, respectively (Prod Info Clolar(R) intravenous injection, 2014).
    D) HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) In a series of 40 children with ALL who had MUGA scans before and after receiving clofarabine, 4 patients had increases in right ventricular pressure, and 7 had decreases in left ventricular systolic function. One patient, who was also septic, developed congestive heart failure (Jeha et al, 2006).
    E) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, hypertension was reported in 13% of patients, with grade 3 hypertension reported in 5% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    F) EDEMA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, edema was reported in 12% of patients (Prod Info Clolar(R) intravenous injection, 2014).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY DISTRESS
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, respiratory distress was reported in 10% of patients, with grades 3, 4, and 5 respiratory distress reported in 4%, 4%, and 1% of patients, respectively (Prod Info Clolar(R) intravenous injection, 2014).
    B) PLEURAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, pleural effusion was reported in 12% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    C) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, dyspnea was reported in 13% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    D) TACHYPNEA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, tachypnea was reported in 9% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    E) PULMONARY EDEMA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, pulmonary edema was reported in 1% to 4% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    F) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, upper respiratory tract infection was reported in 5% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    G) PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, pneumonia was reported in 10% of patients (Prod Info Clolar(R) intravenous injection, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, headache was reported in 43% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    B) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, asthenia was reported in 10% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    C) ANXIETY
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, anxiety was reported in 21% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    D) DROWSY
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, somnolence and lethargy were reported in 10% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    E) FEELING AGITATED
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, agitation was reported in 5% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    F) FEELING IRRITABLE
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, irritability was reported in 10% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    b) In a study involving 25 pediatric patients with leukemia treated with clofarabine, some patients developed irritability when the dose was infused over 1 hour; this resolved when the drug was administered over 2 hours (Jeha et al, 2004).

Reproductive

    3.20.1) SUMMARY
    A) Clofarabine is classified as FDA pregnancy category D. At the time of this review, no data were available to assess the teratogenic potential of this agent. In animal studies, developmental toxicity (reduced fetal body weight and increased post-implantation loss) were reported.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Increased incidences of malformations and variations were reported in animals administered clofarabine at doses approximately equal to the recommended human dose (Prod Info Clolar(R) intravenous injection, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info Clolar(R) intravenous injection, 2014).
    B) PREGNANCY CATEGORY
    1) The manufacturer has classified clofarabine as FDA pregnancy category D (Prod Info Clolar(R) intravenous injection, 2014).
    2) Do not administer this drug to a pregnant woman (Prod Info Clolar(R) intravenous injection, 2014).
    C) ANIMAL STUDIES
    1) Developmental toxicity was reported in animals administered clofarabine at doses approximately equal to the recommended human dose (Prod Info Clolar(R) intravenous injection, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether clofarabine is excreted in human milk. Due to the potential for adverse reactions in the nursing infant, do not nurse while being treated with clofarabine (Prod Info Clolar(R) intravenous injection, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) MALE ANIMALS
    a) Seminiferous tubule and testicular degeneration and atrophy were reported in male animals given intraperitoneal doses of clofarabine at approximately 17% of the recommended human dose on a mg/m(2) basis (Prod Info Clolar(R) intravenous injection, 2014).
    b) Studies done in male animals given IV doses of clofarabine at approximately 3 times the recommended clinical dose on a mg/m(2) basis for 6 months had bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells (Prod Info Clolar(R) intravenous injection, 2014).
    c) In a 6-month animal study, cell degeneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed at doses approximately 14% of the clinical recommended dose on a mg/m(2) basis (Prod Info Clolar(R) intravenous injection, 2014).
    2) FEMALE ANIMALS
    a) Studies done in female animals given clofarabine doses 4-fold the recommended human dose on a mg/m(2) basis revealed ovarian atrophy or degeneration and uterine mucosal apoptosis (Prod Info Clolar(R) intravenous injection, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS123318-82-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) Clofarabine has not been tested for carcinogenic potential.

Genotoxicity

    A) Clofarabine showed clastogenic activity in the in vitro mammalian cell chromosome aberration assay and the in vivo rat micronucleus assay. Clofarabine did not show evidence of mutagenic activity in the bacterial mutation assay (Ames test) (Prod Info CLOLAR(TM) IV injection, 2004).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, nausea and vomiting were reported in 73% and 78% of patients, respectively. Grade 3 nausea and vomiting were reported in 14% and 8% of patients, respectively, and grade 4 nausea and vomiting were each reported in 1% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    2) WITH POISONING/EXPOSURE
    a) Two pediatric patients with acute lymphoid leukemia developed grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash after receiving clofarabine 70 mg/m(2)/day for 5 days, the highest daily dose administered to a human to date (on a mg/m(2) basis) (Prod Info Clolar(R) intravenous injection, 2014).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, diarrhea was reported in 56% of patients, with grade 3 diarrhea reported in 12% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, abdominal pain was reported in 35% of patients, with grade 3 abdominal pain reported in 7% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    D) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal hemorrhage, including fatalities, has been reported during postmarketing surveillance of clofarabine (Prod Info Clolar(R) intravenous injection, 2014).
    E) BLEEDING GUMS
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, gingival or mouth bleeding was reported in 17% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    F) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, stomatitis was reported in 7% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    G) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, anorexia was reported in 30% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    H) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, pancreatitis was reported in 1% to 4% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    I) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, mucosal inflammation was reported in 16% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    J) RECTAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, proctalgia was reported in 8% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    K) CLOSTRIDIUM DIFFICILE COLITIS
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, clostridium colitis was reported in 7% of patients, with grade 3 clostridium colitis reported in 5% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    L) CANDIDIASIS OF MOUTH
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, oral candidiasis was reported in 7% of patients (Prod Info Clolar(R) intravenous injection, 2014).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HYPERBILIRUBINEMIA
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia or acute myelogenous leukemia who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials (n=114), any grade elevated total bilirubin was reported in 45% of patients and grade 3 or higher elevated total bilirubin was reported in 13% of patients. Additionally, hyperbilirubinemia was reported in 1% to 4% of patients who received clofarabine. Eight patients with grade 3 or 4 serum bilirubin elevations died due to sepsis and/or multiorgan failure (Prod Info Clolar(R) intravenous injection, 2014).
    2) WITH POISONING/EXPOSURE
    a) Two pediatric patients with acute lymphoid leukemia developed grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash after receiving clofarabine 70 mg/m(2)/day for 5 days, the highest daily dose administered to a human to date (on a mg/m(2) basis) (Prod Info Clolar(R) intravenous injection, 2014).
    B) JAUNDICE
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, jaundice was reported in 8% of patients (Prod Info Clolar(R) intravenous injection, 2014).
    C) AMINOTRANSFERASE ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia or acute myelogenous leukemia who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials (n=100), any grade elevated AST was reported in 74% of patients. Additionally, grade 3 or higher elevated AST was reported in 36% of patients who received clofarabine (Prod Info Clolar(R) intravenous injection, 2014).
    b) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia or acute myelogenous leukemia who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials (n=113), any grade elevated ALT was reported in 81% of patients. Additionally, grade 3 or higher elevated ALT was reported in 43% of patients who received clofarabine (Prod Info Clolar(R) intravenous injection, 2014).
    c) Most liver aminotransferase (AST and ALT) elevations were transient, usually occurring within the first 10 days of clofarabine administration and returning to grade 2 or less within 15 days (Prod Info Clolar(R) intravenous injection, 2014).
    D) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 9-year-old child developed elevated liver enzymes, periorbital edema, severe oral mucositis, and generalized erythema and pustules 2 to 7 days after beginning clofarabine therapy. The patient was also receiving triple intrathecal therapy with cytarabine, methotrexate, and hydrocortisone. By day 10, the patient was severely jaundiced, and a skin biopsy indicated toxic epidermal necrolysis. Over the next 2 days, the patient's condition worsened with progressive desquamation and deteriorating liver function, resulting in death. The authors speculate that an interaction between clofarabine and methotrexate may have resulted in increased severity of similar toxicities, thereby contributing to the development of skin and liver toxicity in this patient (Johnston & Mandel, 2008).
    E) VENO-OCCLUSIVE DISEASE OF THE LIVER
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, treatment-related veno-occlusive disease was reported in 2 patients (Prod Info Clolar(R) intravenous injection, 2014).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, any grade elevated creatinine was reported in 50% of patients. Additionally, grade 3 or higher elevated creatinine was reported in 8% of patients who received clofarabine (Prod Info Clolar(R) intravenous injection, 2014).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, grade 3 and grade 4 acute renal failure was reported in 3% and 2% of the patients, respectively (Prod Info Clolar(R) intravenous injection, 2014).
    b) CASE REPORT: A 65-year-old man experienced acute renal failure with proteinuria after receiving clofarabine 30 mg/m(2)/day for 5 days to treat relapsed acute myelogenous leukemia. On the morning following his last daily dose of clofarabine, the patient's serum creatinine concentration increased to approximately 1.4-fold over his baseline level, and within 72 hours, it peaked at 2.97 mg/dL (at least 2.8- to 3.6-fold over baseline). A 24-hour collection of his urine contained 4100 mg of protein; peripheral edema was also present. During the remaining 3 weeks of hospitalization, his serum creatinine concentration was gradually reduced to within a range of 1.29 to 1.44 mg/dL (within 1.5 times his baseline value). Concomitant medications included metformin and lisinopril, which were both discontinued at the onset of the acute kidney injury. Additionally, a 1-week course of valacyclovir was completed on day 1 of clofarabine therapy; furosemide, tobramycin and allopurinol were also administered prior to clofarabine therapy. Due to the time course of events in this case, the patient's renal failure and proteinuria were associated with the use of clofarabine (Kintzel et al, 2011).
    C) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) In a pooled analysis of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (n=70) or acute myelogenous leukemia (n=45) who received clofarabine 52 mg/m(2)/day for 5 days/cycle in clinical trials, hematuria was reported in 13% of patients (Prod Info Clolar(R) intravenous injection, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Neutrophil nadir may not develop for 3 to 4 weeks and platelet nadir for 2 weeks or more.
    B) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    C) Monitor serum electrolytes, renal function, and hepatic enzymes.
    D) Monitor vital signs.
    E) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    F) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    4.1.2) SERUM/BLOOD
    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Neutrophil nadir may not develop for 3 to 4 weeks and platelet nadir for 2 weeks or more (Uy et al, 2006).
    B) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    C) Monitor serum electrolytes, renal function, and hepatic enzymes.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs.
    b) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    c) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Neutrophil nadir may not develop for 3 to 4 weeks and platelet nadir for 2 weeks or more.
    B) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    C) Monitor serum electrolytes, renal function, and hepatic enzymes.
    D) Monitor vital signs.
    E) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    F) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: Two pediatric patients with acute lymphoid leukemia developed grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash after receiving clofarabine 70 mg/m(2)/day for 5 days, the highest daily dose administered to a human to date (on a mg/m(2) basis). One pediatric patient developed fatal toxic epidermal necrolysis and liver toxicity after receiving clofarabine 52 mg/m(2)/day for 5 days. For adult patients with solid tumors, the maximum tolerated dose was 2 mg/m(2)/day
    B) THERAPEUTIC DOSE (1 to 21 years of age): 52 mg/m(2) IV infusion over 2 hours daily for 5 consecutive days; repeat every 2 to 6 weeks following recovery or return to baseline organ function.

Therapeutic Dose

    7.2.1) ADULT
    A) UP TO THE AGE OF 21 YEARS: 52 mg/m(2) IV infusion over 2 hours daily for 5 consecutive days (Prod Info Clolar(R) intravenous injection, 2013)
    7.2.2) PEDIATRIC
    A) CHILDREN 1 YEAR OLD OR OLDER: 52 mg/m(2) IV infusion over 2 hours daily for 5 consecutive days (Prod Info Clolar(R) intravenous injection, 2013)

Minimum Lethal Exposure

    A) PEDIATRIC
    1) A 9-year-old child with acute lymphoid leukemia developed elevated liver enzymes and periorbital edema after receiving clofarabine 52 mg/m(2)/day for 5 days. The patient was also receiving triple intrathecal therapy with cytarabine, methotrexate, and hydrocortisone. Liver function deteriorated and the patient's rash worsened with progression to toxic epidermal necrolysis, resulting in death. An interaction between methotrexate and clofarabine is speculated by the authors to have contributed to the patient's symptoms due to the similar toxicities of these medications (Johnston & Mandel, 2008).

Maximum Tolerated Exposure

    A) PEDIATRIC
    1) Two pediatric patients with acute lymphoid leukemia developed grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash after receiving clofarabine 70 mg/m(2)/day for 5 days, the highest daily dose administered to a human to date (on a mg/m(2) basis) (Prod Info Clolar(R) intravenous injection, 2014).
    B) ADULT
    1) In adults with solid tumors, myelosuppression was the dose limiting toxicity and the maximum tolerated dose was 2 mg/m(2)/day for 5 days. In adults with indolent leukemias, myelosuppression was the dose limiting toxicity and the maximum tolerated dose was 3 to 4 mg/m(2)/day (Cooper et al, 2004).
    2) In adults with acute leukemia, hepatotoxicity was dose limiting, and the maximum tolerated dose was 40 mg/m(2)/day (Cooper et al, 2004).

Workplace Standards

    A) ACGIH TLV Values for CAS123318-82-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS123318-82-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS123318-82-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS123318-82-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Clofarabine is both an S-phase specific and a cell-cycle non-specific agent (Kline & Larson, 2005). It undergoes intracellular phosphorylation to the active triphosphate form by the enzyme 2'-deoxycytidine.
    B) Clofarabine triphosphate inhibits ribonucleotide reductase directly, and decreases the amount of deoxynucleoside triphosphates available intracellularly for DNA synthesis. It is also is incorporated into DNA during synthesis and repair, causing inhibition of DNA polymerase and DNA chain termination (Kline & Larson, 2005).
    C) Clofarabine is resistant to bacterial purine nucleoside phosphorylase and to acid hydrolysis, giving it the potential for administration orally, although this form is not available clinically (Kline & Larson, 2005).

Physicochemical

Physical Characteristics

    A) Clofarabine solution is clear and practically colorless (Prod Info CLOLAR(TM) IV injection, 2004).

Molecular Weight

    A) 303.68 (Prod Info CLOLAR(TM) IV injection, 2004)

References

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