Cytarabine - Drug Monograph

Introduction

Cytarabine (also known as ara-C or cytosine arabinoside) is a pyrimidine nucleoside analog chemotherapeutic agent that has been a cornerstone of hematologic malignancy treatment for decades. First synthesized in 1959 and approved by the FDA in 1969, cytarabine remains an essential component of induction and consolidation therapy for acute myeloid leukemia (AML) and is used in various other hematologic cancers.

Mechanism of Action

Cytarabine is a cell cycle-specific antimetabolite that primarily acts during the S-phase of cell division. After intracellular activation to its active metabolite, cytarabine triphosphate, it competitively inhibits DNA polymerase alpha, resulting in impaired DNA synthesis and repair. Additionally, cytarabine incorporates into DNA chains, causing premature chain termination and fragmentation. The drug also inhibits ribonucleotide reductase, further depleting deoxyribonucleotide pools necessary for DNA replication.

Indications

• Primary Indication: Induction and consolidation therapy for acute myeloid leukemia (AML)
• Other FDA-approved Uses:

- Acute lymphoblastic leukemia (ALL) - Chronic myeloid leukemia (CML) in blast crisis - Meningeal leukemia (intrathecal administration)

• Off-label Uses:

- Non-Hodgkin lymphoma - Myelodysplastic syndromes - Prophylaxis and treatment of central nervous system leukemia

Dosage and Administration

• Conventional dose: 100-200 mg/m²/day by continuous IV infusion for 5-10 days
• High-dose: 1-3 g/m² every 12 hours for 3-6 days
• Subcutaneous: 100-200 mg/m²/day for 5-10 days
• Intrathecal: 30-100 mg/dose 2-3 times weekly

• Renal impairment: Dose reduction recommended for CrCl <60 mL/min
• Hepatic impairment: Use with caution; consider dose reduction
• Elderly: Increased risk of toxicity; consider dose adjustment
• Pediatric: Dosing based on body surface area with careful monitoring

Pharmacokinetics

• Absorption: Poor oral bioavailability (<20%); administered parenterally
• Distribution: Widely distributed throughout body tissues and fluids, including CSF (40-50% of plasma levels)
• Metabolism: Primarily deaminated in liver, kidneys, and blood to inactive uracil arabinoside (ara-U) by cytidine deaminase
• Elimination: Half-life 1-3 hours; primarily renal excretion (80-90% as ara-U)
• CSF penetration: Excellent with systemic administration; sustained levels with intrathecal administration

Contraindications

• Hypersensitivity to cytarabine or any component of the formulation
• Active meningeal infection (for intrathecal use)
• Pregnancy (unless potential benefit justifies potential risk to fetus)

Warnings and Precautions

• Severe bone marrow suppression with resulting anemia, leukopenia, thrombocytopenia, and bleeding
• Potential for irreversible CNS toxicity with high-dose regimens

• Cytarabine syndrome: Fever, myalgia, bone pain, rash, conjunctivitis - may require corticosteroid prophylaxis
• Pulmonary toxicity: Non-cardiogenic pulmonary edema, ARDS
• Hepatotoxicity: Elevated transaminases, jaundice
• Neurotoxicity: Cerebellar syndrome (ataxia, dysarthria, nystagmus) - more common with high doses and renal impairment
• Ocular toxicity: Corneal toxicity, conjunctivitis
• Tumor lysis syndrome: Risk in patients with high tumor burden

Drug Interactions

• Live vaccines: Increased risk of adverse reactions
• Digoxin: May decrease digoxin absorption
• Methotrexate: Sequential administration may enhance cytotoxicity
• Gentamicin: Cytarabine may inhibit antibacterial activity
• Other myelosuppressive agents: Additive bone marrow toxicity

Adverse Effects

• Myelosuppression (anemia, neutropenia, thrombocytopenia)
• Nausea, vomiting, diarrhea
• Mucositis, oral ulcerations
• Fever, rash
• Elevated liver enzymes

• Cerebellar toxicity (irreversible at high doses)
• Non-cardiogenic pulmonary edema
• Severe dermatologic reactions (including Stevens-Johnson syndrome)
• Cardiomyopathy, pericarditis
• Anaphylaxis
• Pancreatitis

Monitoring Parameters

• Complete blood count: Daily during therapy, then regularly until recovery
• Renal function: Serum creatinine, BUN at baseline and periodically
• Liver function: AST, ALT, bilirubin, alkaline phosphatase baseline and regularly
• Neurologic assessment: Especially with high-dose therapy (evaluate for cerebellar signs)
• Fluid balance: Input/output, weight, signs of fluid overload
• Tumor lysis parameters: Uric acid, potassium, phosphate, calcium
• Ophthalmic examination: For high-dose or prolonged therapy

Patient Education

• Importance of frequent blood count monitoring
• Signs of infection (fever, chills) requiring immediate medical attention
• Bleeding precautions (avoid NSAIDs, report unusual bruising/bleeding)
• Nausea management strategies and antiemetic use
• Oral care to prevent mucositis
• Contraception requirements during and after treatment
• Report neurological symptoms immediately (dizziness, slurred speech, coordination problems)
• Potential for temporary hair loss
• Avoid crowds and people with infections during neutropenic periods

References

1. Package Insert: Cytarabine Injection. Various manufacturers. 2. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 2.2023. 3. Löwenberg B, et al. Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011;364(11):1027-1036. 4. Döhner H, et al. Diagnosis and management of AML in adults: 2022 ELN recommendations. Blood. 2022;140(12):1345-1377. 5. Larson RA. Cytarabine syndrome. J Clin Oncol. 2007;25(18):2671-2672. 6. Lexicomp Online. Cytarabine monograph. Wolters Kluwer Clinical Drug Information. 7. Micromedex Solutions. Cytarabine drug information. IBM Watson Health. 8. Herzig RH, et al. High-dose cytarabine therapy for refractory leukemia. Blood. 1983;62(2):361-369.