azacitidine (Rx)

Action and Spectrum

Action and Spectrum: 

azacitidine is a nucleoside analogue that is used as a chemotherapy drug for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It works by causing DNA hypomethylation, leading to abnormal gene expression and inhibition of cell division, causing the death of rapidly dividing cells. 

azacitidine is used to treat MDS and AML, particularly in patients who are not eligible for more intensive chemotherapy regimens. It can be administered orally or intravenously. The spectrum of activity of azacitidine includes the ability to induce differentiation and apoptosis of cancer cells, leading to a reduction in the size of the cancer cell population.

Drug Interaction

Adverse Reaction

Frequency defined: 

>10%: 

Chest pain 

Erythema of skin 

Skin rash 

Abdominal pain 

Constipation 

Nausea 

Vomiting 

Anemia 

Leukopenia 

Anxiety 

Dizziness 

Limb pain 

Arthralgia 

Dyspnea 

Pneumonia 

Fever 

1%-10% 

Atrial fibrillation 

Hypertension 

Orthostatic hypotension 

Septic shock 

Frequency not defined 

Hepatic coma 

rigors 

Black Box Warning

Azacitidine does not carry a formal FDA Black Box Warning 

Contraindication / Caution

Contraindications 

Azacitidine is contraindicated in patients with advanced malignant liver tumors when given intravenously or subcutaneously. It should also not be used in individuals with known hypersensitivity to azacitidine, mannitol (for IV/SC use), or any of its ingredients (for oral use). 

Cautions 

Oral azacitidine must not replace IV or SC forms, as incorrect substitution can lead to fatal toxicity or ineffective treatment. It is not recommended for MDS patients outside clinical trials, and its use during pregnancy may harm the fetus. Azacitidine can cause severe bone marrow suppression, requiring regular CBC monitoring and supportive care. Tumor lysis syndrome may occur even with preventive therapy. Patients with liver disease are at increased risk of hepatic failure, especially with low albumin. Renal toxicity, including renal failure and tubular acidosis, has been reported—renal function and electrolytes must be closely monitored, especially in at-risk patients. 

Pregnancy / Lactation

Pregnancy consideration: Based on animal studies, it may cause harm to patients who can become pregnant. 

Lactation: excretion of azacitidine in breast milk is not known. 

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 

• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 

• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women 

• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 

• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 

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

Pharmacology

Pharmacology 

Azacitidine is a pyrimidine nucleoside analog of cytidine with antineoplastic and hypomethylating properties. It is primarily used in the treatment of myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML), among other hematologic malignancies. 

Pharmacokinetics 

Absorption 

Azacitidine is quickly absorbed after subcutaneous administration, reaching peak levels (750 ng/mL) in 0.5 hours. Its bioavailability is about 89% compared to IV, with dose-proportional exposure and no accumulation on repeated dosing. 

Distribution 

After IV administration, the volume of distribution is approximately 76 liters, suggesting wide tissue distribution. Protein binding data is not available 

Metabolism 

Azacitidine is not metabolized by cytochrome P450 enzymes. It undergoes spontaneous hydrolysis and enzymatic deamination by cytidine deaminase. 

Elimination/Excretion 

The drug and its metabolites are mainly excreted in urine. In patients given radioactive azacitidine IV, 85% of the dose was recovered in urine, with less than 1% excreted in feces over 3 days. 

The mean half-life is about 41 minutes after SC dosing, while the elimination half-life for azacitidine and its metabolites is approximately 4 hours for both IV and SC routes. 

Pharmacodynamics 

Azacitidine induces DNA hypomethylation at concentrations that do not significantly inhibit DNA synthesis. This hypomethylation may help restore normal gene function involved in cell differentiation and growth. Clinical evidence in juvenile myelomonocytic leukemia shows reduced methylation in bone marrow cells after the first treatment cycle, confirming this effect. 

However, azacitidine is associated with adverse effects such as anemia, neutropenia, and thrombocytopenia in both adults with myelodysplastic syndrome and children with JMML. It also carries risks of renal toxicity, tumor lysis syndrome, fetal harm, and liver toxicity, particularly in patients with severe liver impairment. 

Adminstartion

Azacitidine can be administered via intravenous (IV), subcutaneous (SC), or oral routes. The method of administration should match the prescribed formulation, as they are not interchangeable. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: Azacitidine 

Pronounced: aza-sy-ti-din 

Why do we use azacitidine? 

Azacitidine is an antimetabolites chemotherapeutic drug. It is used to treat myelodysplastic syndrome and a certain type of leukemia.