Usage
- Azacitidine is prescribed for the treatment of myelodysplastic syndromes (MDS), certain types of acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML).
- It is classified as an antineoplastic antimetabolite, specifically a pyrimidine nucleoside analog.
- It hypomethylates DNA and RNA, incorporates into RNA and DNA, and inhibits DNA, RNA and protein synthesis ultimately resulting in cytotoxic effects on abnormal hematopoietic cells in the bone marrow. Azacitidine also appears to be a DNA methylation inhibitor, causing hypomethylation of DNA.
Alternate Names
- 5-azacytidine
- Vidaza (injection)
- Onureg (oral)
How It Works
- Pharmacodynamics: Azacitidine’s primary effect is to inhibit DNA methyltransferase, leading to decreased DNA methylation and promoting differentiation of malignant hematopoietic cells into more mature forms. At higher doses, it incorporates into RNA and DNA, inhibiting protein synthesis and further promoting cellular cytotoxicity.
- Pharmacokinetics:
- Absorption: Subcutaneous administration results in almost complete bioavailability, similar to intravenous infusion. Oral administration has lower bioavailability.
- Metabolism: Rapidly metabolized, primarily by cytidine deaminase, with minimal cytochrome P450 involvement.
- Elimination: Renal excretion is the primary pathway for drug and metabolites.
- Mode of Action: Inhibits DNA methyltransferases, leading to hypomethylation of DNA, which affects gene expression in cells. Additionally, at higher doses azacitidine incorporates into DNA and RNA and inhibits protein synthesis, leading to cytotoxicity in rapidly dividing abnormal cells.
- Receptor Binding/Enzyme Inhibition: Azacitidine specifically inhibits DNA methyltransferases, enzymes responsible for DNA methylation.
Dosage
Standard Dosage
Adults:
- MDS, CMML (Vidaza, Subcutaneous/Intravenous): 75 mg/m² daily for 7 days, repeated every 4 weeks. Dose escalation to 100 mg/m² may be considered if no benefit after 2 cycles and toxicity limited to nausea and vomiting.
- AML Maintenance (Onureg, Oral): 300 mg once daily on Days 1-14 of each 28-day cycle.
Children:
- Limited data exists for Vidaza in pediatric patients. Dose adjustments made individually based on tolerance, response, and hematological values. The use of Vidaza in children is not approved in every country.
Special Cases:
- Elderly Patients: Close monitoring for hematologic toxicity is crucial, especially in those with renal impairment, but no initial dose adjustment is generally recommended. Dosage is adjusted based on response and toxicity.
- Patients with Renal Impairment: Administer with caution. No initial dose modification required but close monitoring for toxicity is vital. Dosage reduction may be necessary based on serum creatinine, blood urea nitrogen (BUN), and serum bicarbonate levels.
- Patients with Hepatic Dysfunction: Administer with caution. Monitor closely for adverse events. No initial dose reduction, with adjustments made based on response and toxicity. Contraindicated in patients with advanced malignant hepatic tumors.
- Patients with Comorbid Conditions: Patients with cardiac or pulmonary disease should be monitored closely due to potential for increased cardiac events.
Clinical Use Cases
- Azacitidine is not indicated for use in the context of intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. It is primarily used for long-term management of MDS, AML, and CMML.
Dosage Adjustments
- Dose adjustments are necessary based on hematologic toxicity (neutropenia, thrombocytopenia, anemia), renal function, and serum bicarbonate levels. Detailed dose modification guidelines are available in the prescribing information and summarized protocols for different scenarios.
Side Effects
Common Side Effects
- Nausea, vomiting, diarrhea, constipation, fatigue, injection site reactions (pain, redness, swelling), fever, loss of appetite, headache, dizziness, insomnia, and myalgia/arthralgia.
Rare but Serious Side Effects
- Severe myelosuppression (neutropenia, thrombocytopenia, anemia), increased risk of infections, bleeding, renal toxicity, hepatic dysfunction, tumor lysis syndrome, interstitial lung disease, and Sweet’s syndrome.
Long-Term Effects
- Prolonged use can potentially lead to chronic myelosuppression and increased risk of secondary malignancies.
Adverse Drug Reactions (ADR)
- Severe neutropenia with infections, severe thrombocytopenia with bleeding, acute renal failure, severe hepatic dysfunction, cardiac events, and severe allergic reactions.
Contraindications
- Hypersensitivity to azacitidine or mannitol.
- Advanced malignant hepatic tumors.
- Active severe infection.
- Breastfeeding.
Drug Interactions
- Clinically significant drug interactions involving CYP450 enzymes are unlikely due to azacitidine’s minimal interaction with these enzymes. Concomitant use with other myelosuppressive agents can worsen bone marrow suppression. Many other potential drug interactions may occur so it’s crucial to refer to a comprehensive drug interaction database when considering concomitant medication use.
Pregnancy and Breastfeeding
- Pregnancy: Contraindicated. Azacitidine is teratogenic and embryotoxic in animals. Effective contraception is required during and for several months after treatment for both men and women.
- Breastfeeding: Contraindicated due to the risk of serious adverse reactions in the nursing infant.
Drug Profile Summary
- Mechanism of Action: Hypomethylating agent, DNA and RNA synthesis inhibitor.
- Side Effects: Myelosuppression, nausea, vomiting, diarrhea, fatigue.
- Contraindications: Hypersensitivity, advanced liver cancer, breastfeeding.
- Drug Interactions: Many potential interactions, consult a database.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Variable, based on indication, patient characteristics, and response.
- Monitoring Parameters: Complete blood count, renal and liver function tests, serum bicarbonate.
Popular Combinations
- Venetoclax with azacitidine for AML.
- Ivosidenib with azacitidine for IDH1-mutated AML.
Precautions
- General Precautions: Monitor blood counts closely, renal and liver function tests, and serum bicarbonate. Manage adverse effects promptly.
- Specific Populations: Caution in elderly patients, patients with renal or hepatic impairment, and those with cardiac/pulmonary disease. Avoid in pregnancy and breastfeeding.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Azacitidine?
A: The dosage varies depending on the condition being treated, route of administration, and patient-specific factors. Consult the prescribing information for detailed guidance.
Q2: What are the most common side effects of Azacitidine?
A: Nausea, vomiting, diarrhea, constipation, fatigue, injection site reactions, and myelosuppression are common.
Q3: How is Azacitidine administered?
A: Available as an injection for subcutaneous or intravenous administration (Vidaza) and as an oral formulation (Onureg).
Q4: What are the contraindications for using Azacitidine?
A: Hypersensitivity to azacitidine, advanced malignant hepatic tumors, and breastfeeding are absolute contraindications.
Q5: Can Azacitidine be used in patients with renal impairment?
A: Administer with caution and monitor closely. No initial dose reduction is required, but later adjustments may be necessary based on lab values.
Q6: How does Azacitidine work at the molecular level?
A: Inhibits DNA methyltransferases, leading to hypomethylation and affecting gene expression. At higher doses, it incorporates into DNA/RNA causing cytotoxicity.
Q7: Is it safe to use Azacitidine during pregnancy or while breastfeeding?
A: No, it is contraindicated in both pregnancy and breastfeeding due to risks to the fetus or infant.
Q8: What monitoring is required during Azacitidine treatment?
A: Complete blood counts, renal and liver function tests, and serum bicarbonate levels should be monitored regularly.
Q9: Are there any specific precautions for elderly patients receiving Azacitidine?
A: Close monitoring for hematologic and renal toxicity is especially important in the elderly.
Q10: What are the potential long-term effects of Azacitidine?
A: Chronic myelosuppression and an increased risk of secondary cancers are potential long-term risks.
