clofarabine

Action and Spectrum

Actions and Spectrum: 

Action: 

clofarabine exerts its action by interfering with the synthesis and repair of DNA and RNA. It is converted into its active form inside the cells, where it is incorporated into the DNA and RNA strands. Once incorporated, clofarabine inhibits the activity of certain enzymes, such as DNA polymerase and ribonucleotide reductase, which are essential for DNA and RNA synthesis.  

Spectrum: 

clofarabine has a relatively narrow spectrum of activity and is primarily indicated for the treatment of acute lymphoblastic leukemia (ALL) in pediatric patients. It is specifically used in cases where the leukemia has relapsed or is refractory to other therapies. clofarabine is not typically used as a first-line treatment for ALL but is reserved for cases that have not responded to initial therapies or have relapsed after treatment. 

Drug Interaction

Adverse Reaction

Frequency defined  

>10% 

Pruritus (43%) 

Anorexia (30%) 

Abdominal pain (8-35%) 

Diarrhea (53%) 

Thrombocytopenia (81%) 

Febrile neutropenia (57%) 

Lymphopenia (82%) 

Leukopenia (88%) 

Anemia (83%) 

Nausea (75%) 

Vomiting (83%) 

1-10% 

Agitation (5%) 

Cellulitis (8%) 

Somnolence (10%) 

Lethargy (10%) 

Irritability (10%) 

Sepsis (10%) 

Herpes simplex infections (10%) 

Bacteremia (10%) 

Back pain (10%) 

Black Box Warning

Black Box Warning:  

None

Contraindication / Caution

Contraindication/Caution:  

Hypersensitivity: clofarabine should not be used in individuals with a known hypersensitivity or severe allergic reaction to the drug or any of its components.  

Severe renal impairment: clofarabine is primarily eliminated through the kidneys, and dosage adjustments are required for patients with impaired renal function. The use of this medication is not recommended for individuals with severe kidney dysfunction, specifically those with a creatinine clearance below 30 mL/min. 

Severe hepatic impairment: clofarabine is metabolized by the liver, and its pharmacokinetics may be altered in patients with severe hepatic impairment. Use caution and consider dosage adjustment in patients with moderate to severe hepatic impairment. 

Pregnancy and breastfeeding: clofarabine can cause fetal harm when administered to pregnant women. It is also not recommended during breastfeeding, as it may be excreted in human milk. 

Vaccination with live vaccines: The use of live vaccines should be avoided during clofarabine therapy due to the potential for reduced efficacy and increased risk of infections. 

Pregnancy / Lactation

Pregnancy warnings:     

Pregnancy category: AU TGA pregnancy category: D
US FDA pregnancy category: D 

Lactation: Excreted into human milk is unknown 

Pregnancy Categories:         

Category A: Studies that were well-controlled and met expectations revealed no risk to the fetus in either the first or second trimester. 

Category B: There were a lack of studies on pregnant women and no evidence of risk to the fetus in animal experiments.   

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.   

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category

Pharmacology

Pharmacology:  

clofarabine is a chemotherapy medication used in the treatment of certain types of cancer, primarily acute lymphoblastic leukemia (ALL) in both children and adults. 

Pharmacodynamics:  

Inhibition of DNA synthesis: clofarabine is converted intracellularly to its active metabolite, 5′-triphosphate (clofarabine-5′-triphosphate). This metabolite inhibits the enzyme ribonucleotide reductase, which is responsible for converting ribonucleotides to deoxyribonucleotides required for DNA synthesis. By blocking this enzyme, clofarabine disrupts the synthesis of DNA, leading to the inhibition of cancer cell growth. 

Incorporation into DNA strands: clofarabine-5′-triphosphate is also incorporated into the DNA strands during replication. It acts as a false building block, disrupting the DNA structure and interfering with its proper function. This incorporation leads to DNA strand breakage and subsequent cell death. 

Pharmacokinetics: 

Absorption 

clofarabine is administered intravenously, meaning it is injected directly into the bloodstream. As a result, it is rapidly and completely absorbed. 

Distribution 

Once absorbed, clofarabine is widely distributed throughout the body. It crosses the blood-brain barrier poorly, which means it has limited penetration into the central nervous system. 

Metabolism 

clofarabine is primarily metabolized in the liver through various enzymatic pathways. The main enzyme involved in its metabolism is cytidine deaminase, which converts clofarabine into the active metabolite, 2-chloro-2′-fluoroaraadenosine triphosphate (2-CF-ATP). This active metabolite is responsible for the cytotoxic effects of clofarabine. 

Excretion and Elimination 

The elimination of clofarabine and its metabolites primarily occurs through the kidneys. The unchanged drug and its metabolites are primarily excreted in the urine. 

Adminstartion

Administration:  

clofarabine is administered through intravenous (IV) infusion. It is typically given in a healthcare setting such as a hospital or clinic, under the supervision of a healthcare professional experienced in chemotherapy administration. During the infusion, a healthcare professional will insert a needle into a vein, usually in the arm, and connect it to an IV line.

The medication is then slowly infused into the bloodstream over a specific period, typically over 2 hours. The exact infusion time may vary based on the specific treatment regimen prescribed by your doctor. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: clofarabine 

Why do we use clofarabine?  

Acute Lymphoblastic Leukemia: clofarabine is approved for the treatment of relapsed or refractory (resistant to other treatments) ALL in pediatric patients aged 1 to 21 years. It is often used when other treatments have not been effective or have stopped working. 

Acute Myeloid Leukemia (AML): clofarabine may be used off-label or as part of clinical trials for the treatment of AML, especially in cases that have relapsed or are resistant to other therapies. 

Myelodysplastic Syndromes (MDS): clofarabine is sometimes used off-label or as part of clinical trials for the treatment of MDS. 

Stem Cell Transplantation: clofarabine may be used as part of a conditioning regimen before stem cell transplantation in certain cases of leukemia or other blood disorders. The purpose is to suppress the patient’s immune system and eradicate any remaining cancer cells before the transplantation procedure.