Azacitidine is a nucleoside metabolic inhibitor used for the treatment of patients diagnosed with specific subtypes of myelodysplastic syndrome (MDS) according to the French-American-British (FAB) classification. These include refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS), particularly when associated with neutropenia, thrombocytopenia, or when blood transfusion is required. It is also indicated for patients with refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).

Azacitidine is a pyrimidine nucleoside analog of cytidine that acts by inhibiting DNA and RNA methyltransferases. After entering the cell, Azacitidine undergoes enzymatic conversion into nucleotide triphosphates and becomes incorporated into both DNA and RNA. Incorporation into DNA results in inhibition of DNA methyltransferase activity, leading to reduced DNA methylation and modification of gene expression. This includes the reactivation of genes involved in tumor suppression and cell differentiation. When incorporated into RNA, Azacitidine inhibits RNA methyltransferases, reduces RNA methylation, decreases RNA stability, and ultimately reduces protein synthesis. In laboratory studies, Azacitidine demonstrated antileukemic activity by decreasing the viability of leukemia cells and inducing apoptosis in acute myeloid leukemia (AML) cell lines. In animal tumor models, the drug also reduced tumor burden and improved survival outcomes.

Do not substitute Azacitidine for intravenous or subcutaneous Azacitidine. The indications and dosing regimen for Azacitidine differ from that of intravenous or subcutaneous Azacitidine.

Recommended Dosage: The recommended dosage of Azacitidine is 300 mg orally once daily with or without food on Days 1 through 14 of each 28-day cycle. Continue Azacitidine until disease progression or unacceptable toxicity. Administer an antiemetic 30 minutes prior to each dose of Azacitidine for the first 2 cycles. Antiemetic prophylaxis may be omitted after 2 cycles if there has been no nausea and vomiting. If the absolute neutrophil count (ANC) is less than 0.5 Gi/L on Day 1 of a cycle, do not administer Azacitidine (Azacitidine). Delay the start of the cycle until the ANC is 0.5 Gi/L or more.

Instruct patients on the following:

• Do not split, crush, or chew Azacitidine tablets.
• Take a dose about the same time each day.
• If a dose of Azacitidine is missed, or not taken at the usual time, take the dose as soon as possible on the same day, and resume the normal schedule the following day. Do not take 2 doses on the same day.
• If a dose is vomited, do not take another dose on the same day. Resume the normal schedule the following day. Azacitidine is a hazardous drug. Follow applicable special handling and disposal procedures.

Monitoring and Dosage Modifications for Adverse Reactions: Monitor complete blood count every other week for the first 2 cycles and prior to the start of each cycle thereafter. Increase monitoring to every other week for the 2 cycles after any dose reduction for myelosuppression.

Azacitidine is contraindicated in patients who have a known history of severe hypersensitivity or allergic reactions to Azacitidine or any of its components. Patients with such reactions should not receive this medication.

Clinically significant adverse reactions associated with Azacitidine include myelosuppression, which may lead to decreased levels of blood cells. Additional adverse reactions have been reported following the post-approval use of intravenous or subcutaneous Azacitidine. Since these reactions are reported voluntarily from populations of uncertain size, their exact frequency and direct relationship with the drug cannot always be precisely determined.

Reported adverse reactions include:

• Hypersensitivity reactions
• Interstitial lung disease
• Tumor lysis syndrome
• Sweet’s syndrome (acute febrile neutrophilic dermatosis)
• Necrotizing fasciitis, including some fatal cases
• Differentiation syndrome

Pregnancy: Based on its mechanism of action and findings from animal studies, Azacitidine may cause harm to a developing fetus when administered during pregnancy. There are no adequate data on the use of Azacitidine in pregnant women to assess drug-related risk. In animal studies, Azacitidine demonstrated teratogenic effects and caused embryo-fetal death at doses lower than the recommended human daily dose on a mg/m² basis. Pregnant women should be informed about the potential risks to the fetus. The background risk of major birth defects and miscarriage in the indicated population is unknown. However, in the general U.S. population, the estimated risk of major birth defects is 2% to 4%, and miscarriage occurs in approximately 15% to 20% of clinically recognized pregnancies.

Lactation: There is no available information on whether Azacitidine is present in human breast milk, its effects on the breastfed infant, or its impact on milk production. Due to the possibility of serious adverse reactions in breastfed infants, women are advised not to breastfeed during treatment with Azacitidine and for at least 1 week after the final dose.

Risk of Substitution with Other Azacitidine Products: Azacitidine oral formulation should not be substituted for intravenous or subcutaneous Azacitidine products. Significant differences exist in their pharmacokinetic properties, recommended dosing, and administration schedules. Using oral Azacitidine at the dosage intended for injectable formulations may result in severe or even fatal adverse reactions. Conversely, administering oral Azacitidine at doses designed for injectable products may lead to reduced therapeutic effectiveness. Therefore, substitution between oral and injectable Azacitidine formulations should be avoided.

Myelosuppression: Severe myelosuppression, including Grade 3 or 4 neutropenia and thrombocytopenia, has been reported in patients receiving Azacitidine. Approximately 49% of patients developed neutropenia and 22% experienced thrombocytopenia, while febrile neutropenia occurred in about 12% of patients. Dose reductions were required in a small proportion of patients, and less than 1% discontinued treatment because of these complications. Regular monitoring of complete blood counts is recommended, and dose adjustments should be made when necessary. Supportive care, including hematopoietic growth factors, may be required if significant myelosuppression occurs.

Increased Early Mortality in Patients with Myelodysplastic Syndromes: In the AZA-MDS-003 clinical study involving patients with transfusion-dependent anemia and thrombocytopenia caused by myelodysplastic syndromes, an increased rate of early fatal or serious adverse events was observed in patients receiving Azacitidine compared with placebo. The most commonly reported fatal event was sepsis. Due to these findings, the safety and effectiveness of Azacitidine for treating myelodysplastic syndromes have not been fully established, and its use for this condition outside controlled clinical trials is not recommended.

Embryo-Fetal Toxicity: Based on its mechanism of action and animal study findings, Azacitidine may cause harm to a developing fetus when administered during pregnancy. In animal studies, administration of Azacitidine resulted in fetal death and congenital abnormalities at doses lower than the recommended human dose. Women of reproductive potential should use effective contraception during treatment and for at least 6 months after the last dose. Male patients with female partners of reproductive potential should also use effective contraception during treatment and for at least 3 months after the final dose.

Pediatric Use: The safety and effectiveness of Azacitidine in pediatric patients have not yet been established.

Geriatric Use: Among patients enrolled in the QUAZAR study, approximately 72% were aged 65 years or older, and 12% were aged 75 years or older. No significant differences in safety or effectiveness were observed between elderly and younger patients.

Renal Impairment: Patients with severe renal impairment (creatinine clearance 15–29 mL/min) should be monitored closely for adverse reactions, and dosage modifications should be made if necessary. However, dose adjustment is generally not required for patients with mild to severe renal impairment (CrCl 15–89 mL/min).

Hepatic Impairment: Azacitidine has not been adequately studied in patients with severe hepatic impairment. Therefore, a recommended dosage has not been established for patients with moderate hepatic impairment. No dose adjustment is generally required for patients with mild hepatic impairment.

During clinical trials, one case of Azacitidine overdose was reported. A patient who received approximately 290 mg/m² intravenously, which is nearly four times the recommended starting dose, experienced symptoms such as diarrhea, nausea, and vomiting. The symptoms resolved without long-term complications, and the correct dose was resumed the following day. In cases of overdose, patients should be carefully monitored with appropriate blood tests and provided supportive treatment as needed. There is currently no specific antidote for Azacitidine overdose.

Cytotoxic Chemotherapy

Store below 25°C in a cool, dry place. Protect from light and keep out of reach of children.