CLOFARABINE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CLOFARABINE (CLOFARABINE).
Clofarabine is a purine nucleoside antimetabolite that inhibits DNA synthesis by reducing intracellular deoxynucleotide triphosphate pools via inhibition of ribonucleotide reductase, and by terminating DNA chain elongation through incorporation into DNA, leading to apoptosis.
| Metabolism | Hepatic; primarily metabolized by deamination via cytidine deaminase to 6-ketoclofarabine, a major metabolite. Also undergoes phosphorylation intracellularly. CYP450 involvement is minimal. |
| Excretion | Renal: 49-60% as unchanged drug; biliary/fecal: minimal (<1%) |
| Half-life | Terminal elimination half-life: 5.2 hours (range 4-6 hours) in adult patients; clinically, this supports a 5-day continuous infusion schedule |
| Protein binding | 47% bound to plasma proteins (primarily albumin) |
| Volume of Distribution | Vd: 14.6 L/kg (range 10-20 L/kg); indicates extensive extravascular distribution and tissue binding |
| Bioavailability | IV: 100% (only IV route); oral: not approved |
| Onset of Action | IV: 1-2 hours after start of infusion; oral: not applicable (only IV formulation available) |
| Duration of Action | Duration of action: 24-48 hours after infusion; clinical effects (e.g., lymphopenia) persist for days to weeks due to prolonged cellular effects |
52 mg/m^2 intravenously over 2 hours daily for 5 consecutive days, repeated every 28 days.
| Dosage form | SOLUTION |
| Renal impairment | Clcr ≥ 60 mL/min: no adjustment; Clcr 30-59 mL/min: reduce dose to 39 mg/m^2; Clcr < 30 mL/min: not recommended (no data). |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 25% (monitor toxicity); Child-Pugh C: not recommended (no data). |
| Pediatric use | 52 mg/m^2 intravenously over 2 hours daily for 5 days every 28 days (same as adult dosing per body surface area; safety and efficacy established in pediatric patients 1 year and older). |
| Geriatric use | No specific dose adjustment based solely on age; monitor renal function closely due to increased risk of nephrotoxicity; use same dosing as adults with renal adjustment as per GFR. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for CLOFARABINE (CLOFARABINE).
| Breastfeeding | It is unknown whether clofarabine is excreted in human breast milk. Due to the potential for serious adverse reactions in nursing infants, breastfeeding is contraindicated during therapy and for at least 1 week after the last dose. M/P ratio is not available. |
| Teratogenic Risk | Clofarabine is embryotoxic and teratogenic in animal studies. In humans, it is classified as Pregnancy Category D. First trimester exposure is associated with major congenital malformations including neural tube defects, skeletal anomalies, and cardiovascular defects. Second and third trimester exposure may cause fetal myelosuppression, intrauterine growth restriction, and premature delivery. |
■ FDA Black Box Warning
Clofarabine causes severe bone marrow suppression, including neutropenia, anemia, thrombocytopenia, and increased risk of infection. Hemorrhage and severe infections have been reported. Monitor blood counts regularly.
| Serious Effects |
Hypersensitivity to clofarabine or any component of the formulation; severe hepatic impairment (Child-Pugh class C); severe renal impairment (creatinine clearance <30 mL/min).
| Precautions | 1) Myelosuppression: monitor CBCs; dose adjustment may be needed. 2) Infections: increased susceptibility. 3) Hemorrhagic cystitis: may occur; manage with hydration and monitoring. 4) Hepatic toxicity: monitor liver function tests; dose reduction in hepatic impairment. 5) Renal toxicity: monitor renal function; dose adjustment for creatinine clearance <60 mL/min. 6) Tumor lysis syndrome: hydrate and use prophylactic allopurinol. 7) Systemic inflammatory response syndrome (SIRS): monitor for signs; discontinue if occurs. |
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| Fetal Monitoring | Monitor complete blood counts with differential at baseline and throughout therapy. Assess hepatic (ALT, AST, bilirubin) and renal function (serum creatinine, BUN, urinalysis) frequently. Monitor for signs of infection, bleeding, and tumor lysis syndrome. Fetal ultrasound to assess growth and anatomy if exposure occurs during pregnancy. |
| Fertility Effects | Clofarabine may impair fertility in both males and females. In preclinical studies, it caused testicular atrophy and reduced spermatogenesis. In humans, reversible or permanent infertility may occur. Women of reproductive potential should use effective contraception during and for 6 months after therapy; men for 3 months. |