Clofarabine (2 brand names, 2 dosage forms, 2 routes)
Available dosage forms: SOLUTION, INJECTABLE.
Routes of administration: INTRAVENOUS, INJECTION.
Brand Names
- CLOFARABINE
- CLOLAR
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.
Contraindications
None
Adverse Reactions
The following 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) [ 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)]
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.
Overdosage
There were no known overdoses of Clofarabine Injection. The highest daily dose administered to a human to date (on a mg/m 2 basis) has been 70 mg/m 2/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/m 2/day was not tolerated.