Cytarabine

Cytarabine is an antineoplastic agent belonging to the pharmacological class of antimetabolites.

The FDA has approved Cytarabine for treating acute non-lymphocytic leukaemia, acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL), and the blast phase of chronic myelocytic leukaemia (CML).

Cytarabine rapidly absorbs systemically post-injection, achieving therapeutic concentrations. It broadly distributes, crosses the placenta and blood-brain barrier and metabolises via phosphorylation and deamination, forming an inactive metabolite. Primarily excreted via urine, including 10% as an unchanged drug.

The most common side effects of Cytarabine are rash, skin ulcer, nausea, vomiting, and hair loss.

Cytarabine is available in the form of an injectable solution.

The molecule is available in India, the United States, Canada, the United Kingdom, Australia, Germany, France, Japan, China, Brazil and South Africa.

Cytarabine is an antineoplastic agent belonging to the pharmacological class of antimetabolites.

Cytarabine works by directly damaging and incorporating it into DNA. Numerous types of growing mammalian cells in culture are cytotoxic to Cytarabine. It demonstrates cell phase selectivity by predominantly destroying S-phase cells conducting DNA synthesis and, in some cases, preventing G1-phase cells from entering the S-phase. Cytarabine works by inhibiting DNA polymerase. However, the exact mode of action is still unknown. Reports of a limited yet significant cytarabine incorporation into DNA and RNA have also been reported.

Injectable solutions: To be administered parenterally as applicable.

As physician recommends, take the medication with or without food. Dosage and frequency depend on the specific medical condition.

Blood cancer

Blood cancer: Inhibiting cancer cell growth, Cytarabine, a vital chemotherapy component, suppresses abnormal proliferation effectively. Widely used in treating acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), it disrupts DNA synthesis in cancer cells, preventing replication and inducing apoptosis. Cytarabine's efficacy extends to managing chronic myeloid leukaemia (CML). Despite potential side effects, it actively targets and controls blood cancers, significantly improving patient outcomes.

• For both adult and pediatric patients with acute non-lymphocytic leukaemia, cytarabine injection is indicated in combination with other approved anti-cancer medications to induce remission.
• Acute non-lymphocytic leukaemia and the blast phase of chronic myelocytic leukaemia have both been observed to benefit from their use.
• Meningeal leukaemia should be prevented and treated with intrathecal administration of Cytarabine Injection (preservative-free formulations only).

Parenterally: Cytarabine is administered parenterally, typically through intravenous infusion or injection. Before administration, the lyophilized powder is reconstituted with a suitable diluent. The resulting solution is meticulously mixed to ensure homogeneity. The preferred site for IV administration is a large vein. The infusion rate depends on the dosage, typically 20 minutes to several hours. Intrathecal administration involves injecting the drug into the cerebrospinal fluid via lumbar puncture. Strict adherence to aseptic techniques is imperative to minimize infection risk. Regular monitoring of vital signs and blood counts is crucial during and after Cytarabine administration.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Injectable solutions: 20mg/mL, 100mg/mL

Cytarabine is available in the form of Injectable solutions.

Dose Adjustment in Adult Patients:

Acute Non-lymphocytic Leukemia

Remission induction

IV

If necessary, start a second course of treatment 2-4 weeks after starting the first course. 100–200 mg/m2/day IV continuous infusion for 5–10 days OR 100 mg/m2/dose IV continuous infusion q12hr for seven days

IT

Intrathecal 5-75 mg/m2 every 2–7 days until CNS findings return to normal

Maintenance of remission: 70–200 mg/m2/day IV given every month for two to five days.

IM administration for maintenance of remission: a single dosage of 1-4 mg/kg for maintenance given at intervals of 1-4 weeks

Leukemia Meningeal

Intrathecal (IT) 30 mg/m2 every four days until average CSF results plus one extra dose

Refractory IV Leukemia

IV infusion (3 g/sq.meter; 1-3 hours) every 12 hours times four to twelve doses

Repeat every two and three weeks.

While taking Cytarabine, follow the vital dietary guidelines and precautions. Patients should prioritize a well-balanced diet, emphasising hydration and obtaining nutrients from fruits, vegetables, and lean proteins like fish, poultry, and lean meats. It is vital to avoid grapefruit and its products to prevent potential interactions. Patients must restrict alcohol intake and abstain from tobacco use to minimize possible adverse effects. Avoiding spicy or high-fibre foods that might worsen gastrointestinal symptoms is recommended.

The dietary restriction should be individualized as per patient requirements.

Hypersensitivity: Anyone who has previously experienced hypersensitivity to Cytarabine.

• Avoid using solutions containing benzyl alcohol intrathecally or in neonates.
• Cytarabine, a potent bone marrow suppressant, requires cautious initiation in individuals with pre-existing drug-induced bone marrow suppression. Close medical supervision is essential during treatment, especially in induction therapy, with daily monitoring of leucocyte and platelet counts.
• Frequent bone marrow examinations are necessary after peripheral blood blasts disappear, and facilities for managing potentially fatal complications of bone marrow suppression, such as infections and haemorrhages, should be available.
• Anaphylaxis leading to acute cardiopulmonary arrest has been reported immediately after intravenous injection.
• Experimental cytarabine injection schedules may cause severe and sometimes fatal CNS, GI, and pulmonary toxicities, including reversible corneal toxicity, hemorrhagic conjunctivitis, cerebral and cerebellar dysfunction, gastrointestinal ulceration, sepsis, liver damage, pulmonary oedema, bowel necrosis, and necrotizing colitis. Prophylaxis with a local corticosteroid eye drop may prevent or reduce some reactions.
• Severe skin rash leading to desquamation has been rarely reported, with complete alopecia more commonly observed in experimental high-dose therapy than in standard treatment programs using cytarabine injection.

• Cardiomyopathy cases resulting in death have been reported following experimental high-dose therapy with Cytarabine in combination with cyclophosphamide for bone marrow transplant preparation.

• A syndrome of sudden respiratory distress progressing to pulmonary oedema and radiographically pronounced cardiomegaly has been reported following experimental high-dose therapy with Cytarabine for relapsed leukaemia treatment; this syndrome can be fatal.

• Intrathecal (IT) and intravenous (IV)cytarabine injection at conventional doses in childhood acute myelogenous leukaemia patients has led to delayed progressive ascending paralysis, resulting in death in one patient.

• Close monitoring is essential for patients receiving therapy, including frequent platelet and leucocyte counts and mandatory bone marrow examinations. Consider suspending or modifying therapy if drug-induced marrow depression causes a platelet count under 50,000 or polymorphonuclear granulocyte count under 1000/mm³.

• Formed element counts in peripheral blood may continue to fall after drug cessation and reach the lowest values after drug-free intervals of 12 to 24 days. Restart therapy when definite signs of marrow recovery appear on successive bone marrow studies.

• Patients whose drug is withheld until achieving "normal" peripheral blood values may escape from control. Nausea and vomiting may occur for several hours post-injection when large intravenous doses are administered quickly; this tends to be less severe with a slower infusion.
• A significant fraction of an administered dose is detoxified by the human liver, with patients having renal or hepatic function impairment having a higher likelihood of CNS toxicity after high-dose cytarabine injection treatment.

• Exercise caution and consider reduced doses in patients with poor liver or kidney function. Regular checks of bone marrow, liver, and kidney functions should be conducted in patients receiving cytarabine injections.

• Cytarabine, like other cytotoxic drugs, may induce hyperuricemia due to rapid lysis of neoplastic cells. Monitor the patient's blood uric acid level, and be prepared to use supportive and pharmacologic measures as necessary to control this problem.

• Acute pancreatitis has been reported in those patients receiving injection by continuous infusion and in patients previously treated with L-asparaginase.

It is unsafe to consume Cytarabine with alcohol.

It is not recommended for use during breastfeeding.

It is not recommended for use during pregnancy.

The adverse reactions related to Cytarabine can be categorized as

•Common Adverse Effects: Nausea, vomiting, diarrhoea, fever, fatigue, anaemia, headache, and pain at the injection site.

•Less Common Adverse Effects: Confusion, dizziness, stomach pain, skin ulcers, hair loss, decreased white blood cell count, abnormal liver function, and pneumonia.

•Rare Adverse Effects: Loss of appetite, dark-coloured urine, weakness, anal ulcers, infection, low blood platelets, sepsis, and stomatitis (inflammation of the mouth).

The clinically relevant drug interactions of Cytarabine are briefly summarized here.

Patients receiving beta-acetyldigoxin and chemotherapy regimens, including vincristine, cyclophosphamide, and prednisone with or without cytarabine injection or procarbazine, observed reversible decreases in steady-state plasma digoxin concentrations and renal glycoside excretion. Steady-state plasma digitoxin concentrations did not change. Therefore, monitoring plasma digoxin levels may be indicated in patients on similar combination chemotherapy regimens, and digitoxin utilization may be considered as an alternative.

An in-vitro interaction study between gentamicin and Cytarabine demonstrated cytarabine-related antagonism for K. pneumoniae strains. A lack of prompt therapeutic response may suggest re-evaluating antibacterial therapy in patients on Cytarabine with gentamicin for a K. pneumoniae infection.

Clinical evidence in one patient indicated possible inhibition of fluorocytosine efficacy during cytarabine injection therapy, possibly due to competitive inhibition of its uptake.

The common side effects of Cytarabine include loss of appetite, diarrhoea, dark-coloured urine, dizziness, confusion, stomach pain, and weakness. Pain at the injection site, skin ulcers, hair loss, anal ulcers, anaemia, decreased white blood cell count, fever, infection, abnormal liver function, low blood platelets, pneumonia, sepsis, and stomatitis (inflammation of the mouth).

• Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

When given to a pregnant woman, cytarabine injection can harm the developing foetus. In neonatal hamsters, Cytarabine results in aberrant cerebellar development; in rat fetuses, it is teratogenic. Pregnant women have not been the subject of sufficient, well-monitored studies. It is best to counsel women who are capable of bearing children not to get pregnant.

A survey of the literature revealed 32 documented instances of cytarabine injections given during pregnancy, either by themselves or in conjunction with other cytotoxic drugs:

There were eighteen healthy babies born. There was first-trimester exposure in four of them. Five babies were born too soon or weighed too little. Following up on twelve of the eighteen normal infants, ages six weeks to seven years, revealed no anomalies. A seemingly healthy baby passed away from gastroenteritis after ninety days.

There have been two documented examples of congenital abnormalities: one had deformities of the extremities and ears, while the other had malformations of the upper and lower distal limbs. First-trimester exposure occurred in both of these patients.

Pancytopenia, transitory reduction of WBC, hematocrit, or platelets; abnormal electrolyte levels; transient eosinophilia; and one case of elevated lgM levels and hyperpyrexia potentially due to sepsis were among the seven infants with varied issues throughout the neonatal period. Furthermore, six of the seven babies were born too soon. After 21 days of sepsis, the pancytopenia youngster passed away.

In five cases, therapeutic abortions were performed. Although the fetuses were otherwise normal, two of them had abnormalities related to the Trisomy C chromosome in the chorionic tissue, and one had an enlarged spleen.

A patient taking Cytarabine should be informed about the possible risk to the fetus and the wisdom of continuing the pregnancy due to the potential for anomalies with cytotoxic medication, especially during the first trimester. If therapy is started in the second or third trimester, there is a distinct but significantly lower risk. While patients treated during all three trimesters of pregnancy have given birth to healthy babies, monitoring such infants would be advisable.

• Nursing Mothers

It is unknown if this medication is eliminated in human milk. It is essential to consider the amount of the drug to the mother when deciding whether to stop breastfeeding or stop taking it altogether because many drugs are excreted in human milk and because Cytarabine can cause significant adverse effects in nursing infants.

• Pediatric Use

Clinical trials and FDA evaluations determine the safety and efficacy of cytarabine injection in pediatric patients. Healthcare providers use the drug to treat various pediatric conditions, including leukaemia. Continuous monitoring and evaluation of pediatric patients receiving cytarabine injections are crucial in maintaining safety and efficacy.

Dose Adjustment in Kidney Impairment Patients:

Renal Impairment: Based on the degree of renal dysfunction, cytarabine injection requires dose adjustment.

Dose Adjustment in Hepatic Impairment Patients:

Hepatic Impairment: Cytarabine injection requires dose adjustment based on the degree of hepatic dysfunction.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Cytarabine.

Signs and Symptoms

Overconsumption of Cytarabine could lead to Irreversible CNS toxicity, myelosuppression, and death. Severe arachnoiditis, including encephalopathy.

Management

There is no specific antidote; management involves supportive care and symptom-specific interventions. Consideration should be given to symptomatic treatment, including hematopoietic growth factors and blood component transfusions. Due to the drug's myelosuppressive effects, monitoring blood counts is essential. If necessary, delay subsequent doses until hematopoietic recovery occurs. Hemodialysis may be considered for severe cases, although its effectiveness is limited.

Continuous observation and appropriate, timely medical interventions to address specific symptoms or complications are recommended.

Pharmacodynamics:

A variety of leukaemia types are treated with antineoplastic Cytarabine. Antimetabolites pose as purines or pyrimidines, subsequently used as DNA building blocks. They inhibit normal development and division during the "S" phase of the cell cycle by preventing these chemicals from being integrated into DNA. Cytarabine undergoes intracellular metabolism to produce cytosine arabinoside triphosphate, the active triphosphate form of the drug. Then, this metabolite damages DNA by various processes, including incorporation into DNA, inhibition of alpha-DNA polymerase, and suppression of DNA repair via an influence on beta-DNA polymerase. The most significant mechanism is the latter one. The S phase of the cell cycle is targeted explicitly by cytotoxicity.

Pharmacokinetics:

• Absorption: Cytarabine undergoes rapid systemic absorption post-injection, swiftly reaching therapeutic concentrations crucial for effectively targeting leukaemia cells throughout the body.

• Distribution: The drug exhibits broad distribution, crossing the placenta and the blood-brain barrier. Cerebrospinal fluid (CSF) levels reach 40-50% of the plasma level, emphasizing its ability to access critical sites. The volume of distribution ranges from 3 to 11.9 L/kg, and plasma protein binding is limited to 13%.

• Metabolism: Cytarabine's metabolic pathway involves phosphorylation, transforming it into an active form. Subsequently, it undergoes deamination in the liver and kidneys, forming the inactive uracil arabinoside (ARA-U). This intricate process influences the drug's bioavailability and overall efficacy.

• Excretion: The primary route of elimination for Cytarabine is through urine, primarily as an inactive metabolite, with approximately 10% excreted as the unchanged drug. This renal excretion mechanism is crucial in the drug's clearance from the body. The initial elimination half-life is rapid, lasting around 10 minutes intravenously. Elimination half-lives vary, lasting 1-3 hours intravenously and extending to a more prolonged duration of 100-263 hours intrathecally.

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