Azacitidine

Azacitidine is an antineoplastic medicine belonging to the nucleoside metabolic inhibitor and hypomethylating agent class. It is a cytidine analogue that can become incorporated into RNA and DNA and inhibits DNA methyltransferase activity, leading to changes in abnormal gene regulation and cellular growth. These effects can help restore the expression of genes involved in normal blood-cell development and can reduce the proliferation of abnormal bone-marrow cells. Injectable azacitidine is used primarily for adults with selected myelodysplastic syndromes and chronic myelomonocytic leukemia, while regulatory indications vary by jurisdiction and may include selected acute myeloid leukemia populations. In the United States, injectable azacitidine is also approved for pediatric patients aged one month and older with newly diagnosed juvenile myelomonocytic leukemia. The medicine is administered by subcutaneous injection or intravenous infusion, with the conventional adult starting regimen consisting of daily treatment for seven consecutive days followed by a treatment-free period within a four-week cycle. Treatment is generally continued for multiple cycles and for as long as clinical benefit continues. Because azacitidine can suppress bone-marrow function and affect the kidneys, liver and other organs, regular blood counts and laboratory monitoring are important throughout treatment.

Azacitidine was developed as a cytidine analogue with both cytotoxic and epigenetic effects on abnormal hematopoietic cells. The U.S. Food and Drug Administration initially approved injectable azacitidine in May 2004 for specified adult myelodysplastic syndrome subtypes, including refractory anemia, refractory anemia with ringed sideroblasts in defined circumstances, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation and chronic myelomonocytic leukemia. In May 2022, FDA approved an additional indication for pediatric patients aged one month and older with newly diagnosed juvenile myelomonocytic leukemia. In the European Union, Vidaza received marketing authorisation on 17 December 2008 for adults who are not eligible for hematopoietic stem cell transplantation with specified higher-risk myelodysplastic syndromes, chronic myelomonocytic leukemia and selected acute myeloid leukemia populations. Indian CDSCO records document approval of azacitidine 100 mg lyophilized powder for injection for intravenous or subcutaneous use in adult patients with selected myelodysplastic syndrome subtypes in August 2016, with regulatory conditions including specialist prescribing and post-marketing study requirements. Key clinical development programmes include CALGB 9221 and AZA-001, which established the clinical role of azacitidine in myelodysplastic syndromes and higher-risk disease.

Azacitidine is used for selected hematologic malignancies involving abnormal bone-marrow cell production. Injectable azacitidine is indicated in adults with specified myelodysplastic syndrome subtypes and chronic myelomonocytic leukemia, with the exact classification and eligibility criteria differing between regulatory jurisdictions. European authorization also includes selected adults with acute myeloid leukemia who are not eligible for hematopoietic stem cell transplantation, including specified patients with AML arising from myelodysplastic disease and older adults with newly diagnosed AML. In the United States, the injectable product has a separate pediatric indication for newly diagnosed juvenile myelomonocytic leukemia. Azacitidine may be used as a single antineoplastic therapy or as part of a broader treatment strategy depending on disease characteristics and clinical circumstances. Treatment decisions should consider disease classification, bone-marrow findings, cytogenetic and molecular features, transplant eligibility, blood counts, organ function, previous therapy and the approved indication applicable to the specific product and jurisdiction.

Injectable azacitidine is administered either by subcutaneous injection or intravenous infusion under the supervision of an experienced healthcare professional. For adults, the conventional starting regimen is 75 mg per square metre of body surface area daily for seven consecutive days, followed by a three-week treatment-free period, creating a four-week treatment cycle. Treatment is generally continued for at least six cycles when clinically appropriate and then continued for as long as the patient continues to benefit. Depending on response and toxicity, dose delays, reductions or modifications may be required, particularly when blood counts fall significantly or renal toxicity develops. Patients should receive appropriate antiemetic treatment before administration because nausea and vomiting are common. Complete blood counts, liver chemistry and serum creatinine should be assessed before treatment and monitored throughout therapy. Injectable azacitidine should not be substituted for oral azacitidine because the products have different indications, dosing schedules and clinical uses.

Common side effects of injectable azacitidine include nausea, vomiting, anemia, thrombocytopenia, neutropenia, leukopenia, fever, diarrhea, constipation, injection-site reactions, fatigue and bruising. Patients may also experience weakness, decreased appetite, headache, dizziness, cough, shortness of breath or changes in electrolyte levels. Injection-site redness, pain or swelling can occur following subcutaneous administration. Blood-count abnormalities are particularly important because treatment can temporarily reduce normal bone-marrow activity and may increase susceptibility to infection or bleeding. The frequency and severity of adverse effects vary according to disease type, treatment duration, route of administration, combination therapy and individual patient characteristics. Supportive treatment, monitoring, dose modification and treatment delays may be used to manage adverse reactions under medical supervision.

Important serious risks associated with azacitidine include severe or prolonged myelosuppression, serious infections, bleeding, renal toxicity, hepatic toxicity, tumor lysis syndrome and embryo-fetal toxicity. Neutropenia can increase the risk of bacterial, fungal or viral infections, while thrombocytopenia can increase bleeding risk and anemia can contribute to fatigue and reduced exercise tolerance. Renal toxicity can occur and requires particular attention in patients with pre-existing kidney impairment or those receiving other potentially nephrotoxic medicines. Patients with severe pre-existing hepatic impairment may have increased susceptibility to toxicity. Tumor lysis syndrome can occur when treatment causes rapid destruction of malignant cells, particularly in patients with high disease burden, and requires appropriate risk assessment and monitoring. Azacitidine can cause fetal harm, and appropriate pregnancy prevention measures are required. Serious adverse events may require treatment interruption, dose modification or discontinuation according to clinical severity.

Before starting azacitidine, healthcare professionals should confirm the hematologic diagnosis and assess baseline blood counts, liver function, renal function, electrolyte levels and overall treatment suitability. Complete blood counts should be monitored frequently because neutropenia, thrombocytopenia and anemia are common and may become severe. Renal function should be monitored throughout treatment, particularly in patients with pre-existing renal impairment or those receiving medicines that may affect kidney function. Liver function should also be assessed, especially in patients with underlying hepatic disease. Medication review should include anticoagulants, antiplatelet medicines and other treatments that can increase bleeding or infection risk. Conventional CYP-mediated drug interactions are not the main concern with injectable azacitidine, but concomitant medicines should still be reviewed for overlapping toxicities and effects on renal or hepatic function. Patients should avoid breastfeeding during treatment and for the period specified by the applicable prescribing information. Effective contraception should be used during treatment, with the required duration after treatment differing for females and males according to the applicable product information.

Prescribers should confirm the precise hematologic diagnosis, disease classification, treatment intent and applicable regulatory indication before initiating azacitidine. Baseline assessment should include complete blood count, renal and hepatic function, electrolytes, infection status and tumor-burden considerations relevant to tumor lysis risk. Patients should be counselled that blood counts can initially worsen and that treatment benefit may require several cycles; premature discontinuation should therefore be avoided unless clinically indicated. Pharmacists should verify that injectable azacitidine has not been confused with oral azacitidine, as their dosing schedules and indications differ. The seven-day administration schedule, treatment-free interval and antiemetic requirements should be checked carefully. Patients should be advised to report fever, unusual bleeding, severe weakness, persistent vomiting, reduced urine output, severe abdominal symptoms or signs of infection promptly. Coordination between hematology, oncology, pharmacy, nursing and laboratory teams is important for monitoring blood counts, renal function, hepatic function, treatment response and dose modifications.