Clofarabine (Monograph)

Brand name: Clolar
Drug class: Antineoplastic Agents
Chemical name: 2-Chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine
Molecular formula: C₁₀H₁₁ClFN₅O₃
CAS number: 123318-82-1

Introduction

Antimetabolite antineoplastic agent; synthetic purine nucleoside.

Uses for Clofarabine

Acute Lymphocytic Leukemia

Treatment of acute lymphocytic (lymphoblastic) leukemia (ALL) refractory to or relapsed after at least 2 prior therapies in patients 1–21 years of age. Designated an orphan drug by FDA for this use.

Current indication based on induction of complete responses; randomized studies showing increased survival or other clinical benefits have not been conducted to date.

Clofarabine Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

• Monitor respiratory status and BP during infusion, especially in patients receiving drugs that affect BP or cardiac function. (See Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome under Cautions.)

• Administer IV fluids continuously throughout the 5 days of clofarabine therapy to reduce the effects of tumor lysis and other adverse effects. Administer allopurinol if tumor lysis is expected to prevent hyperuricemia. (See Tumor Lysis Syndrome under Cautions.)

• Administration of corticosteroids (e.g., hydrocortisone 100 mg/m² on days 1–3) may prevent signs and symptoms of cytokine release or capillary leak syndrome. (See Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome under Cautions.)

Administration

Administer by IV infusion.

IV Infusion

Administer IV infusion over 2 hours.

Other drugs should not be infused through the same IV line.

Dilution

Dilute the commercially available injection for IV infusion (1 mg/mL) prior to administration.

Filter the appropriate dose through a sterile 0.2μm filter and further dilute with 5% dextrose injection or 0.9% sodium chloride injection.

Dosage

Dosage is based on the patient’s body surface area and is calculated using the actual body weight and height of the patient before starting each cycle.

Pediatric Patients

Acute Lymphocytic Leukemia

IV

1–21 years of age: 52 mg/m² by IV infusion over 2 hours daily for 5 consecutive days.

Repeat treatment cycle following recovery or return to baseline organ function, approximately every 2–6 weeks.

Discontinue infusion immediately and initiate appropriate supportive measures if early manifestations of cytokine release or capillary leak syndrome occur. Consider reinstitution of therapy, generally at a lower dosage, if patient is stable and organ function has returned to baseline levels. (See Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome under Cautions.)

Discontinue infusion immediately if substantial increases in serum creatinine or bilirubin concentrations occur. Consider reinstitution of therapy, generally at a lower dosage, once the patient is stable and organ function has returned to baseline levels.

Discontinue infusion immediately if hypotension develops. Consider reinstitution of therapy at a lower dosage if hypotension was transient and resolved without pharmacologic intervention.

Special Populations

No special population dosage recommendations at this time.

Cautions for Clofarabine

Contraindications

• No known contraindications to use of clofarabine; use with caution in patients with known hypersensitivity to the drug or any ingredient in the formulation.

Warnings/Precautions

Warnings

Administer only under supervision of clinicians qualified in use of cytotoxic therapy.

Hematologic Effects and Infectious Complications

Anticipate bone marrow suppression (usually reversible and dose dependent) with use.

Severe bone marrow suppression (neutropenia, anemia, thrombocytopenia) reported.

Increased risk of developing infectious complications, including severe sepsis and opportunistic infections.

Tumor Lysis Syndrome

Monitor for signs and symptoms of tumor lysis syndrome.

Use appropriate measures (e.g., hydration, allopurinol) to prevent hyperuricemia.

Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome

Signs and symptoms of cytokine release (i.e., tachypnea, tachycardia, hypotension, pulmonary edema) reported.

Rapid onset of respiratory distress, hypotension, capillary leak (e.g., pleural and pericardial effusions), and multiorgan failure reported.

Monitor closely and intervene early by discontinuance of the drug and supportive measures (e.g., corticosteroids, diuretics, and/or albumin).

Development of SIRS or capillary leak syndrome may be fatal. (See Dosage under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals.

Avoid pregnancy during therapy. If used during pregnancy, apprise of potential fetal hazard.

General Precautions

Adequate Patient Monitoring

Perform CBC, including platelet counts at regular intervals; more frequently in patients who develop cytopenias.

Monitor hepatic and renal function prior to therapy and throughout the 5 days of clofarabine administration.

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether clofarabine or its metabolites are distributed into milk.

Discontinue nursing because of potential risk to nursing infants.

Pediatric Use

Safety and efficacy established for treatment of relapsed or refractory ALL in patients 1–21 years of age.

Evaluated in a limited number of children with refractory acute myeloid leukemia (AML)^{† [off-label]}.

Adult Use

Safety and efficacy not established in adults >21 years of age.

Dosage of 40 mg/m² (given by IV infusion over 1–2 hours) daily for 5 days every 28 days was used in a phase II clinical trial in adults with relapsed or refractory hematologic malignancies.

Hepatic Impairment

[64] Not studied in patients with hepatic impairment; use with caution.

[64] If increases in bilirubin concentrations occur, withhold drug until hepatic function returns to baseline. Dosage adjustment may be considered.

Renal Impairment

Not studied in patients with renal impairment; use with caution.

If substantial increases in serum creatinine concentrations occur, withhold drug until renal function returns to baseline. Dosage adjustment may be considered.

Common Adverse Effects

Nausea, vomiting, diarrhea, anemia, leukopenia, thrombocytopenia, neutropenia (including febrile neutropenia), infections.

Drug Interactions

No formal drug interaction studies to date.

Interaction with drugs that induce or inhibit CYP 450 isoenzymes not expected.

Nephrotoxic Drugs

Avoid concomitant use with nephrotoxic drugs throughout the 5 days of clofarabine administration because clofarabine is eliminated by kidneys.

Hepatotoxic Drugs

Avoid concomitant use with hepatotoxic drugs because clofarabine may cause hepatotoxicity.

Clofarabine Pharmacokinetics

Distribution

Plasma Protein Binding

47% (mainly albumin) in pediatric patients.

Elimination

Metabolism

Metabolized to active 5-triphosphate metabolite.

Undergoes limited hepatic metabolism (0.2%) in pediatric patients.

Elimination Route

Excreted in urine (49–60%) as unchanged drug in pediatric patients.

Half-life

Estimated terminal half-life about 5.2 hours in pediatric patients.

Special Populations

Pharmacokinetics not studied in patients with renal or hepatic impairment.

Stability

Storage

Parenteral

Injection for IV infusion

25°C (may be exposed to 15–30°C).

Store diluted solutions at room temperature; discard after 24 hours.

Actions

• Inhibits DNA synthesis, inhibits ribonucleoside reductase, and has direct effects on mitochondria; these effects lead to depletion of intracellular deoxynucleotide triphosphate pools, inhibition of elongation of DNA strands during synthesis, and release of proapoptotic mitochondrial factors in both actively dividing and quiescent tumor cells.

Advice to Patients

• Advise patients about risk of dehydration secondary to vomiting and diarrhea.

• Importance of advising patients regarding appropriate measures to avoid dehydration.

• Advise patients to notify clinician immediately if symptoms of hypotension (e.g., dizziness, lightheadedness, fainting spell) or decreased urine output occurs.

• Importance of monitoring blood cell counts, renal and hepatic function.

• Necessity of advising women to use an effective method of contraception and to avoid breast-feeding while receiving clofarabine therapy.

• Importance of women informing a clinician immediately if they are or plan to become pregnant or plan to breast-feed. Advise pregnant women of risk to the fetus.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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