Introduction
Onureg (azacitidine) is an oral hypomethylating agent approved for the maintenance treatment of adult patients with acute myeloid leukemia (AML) who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy. It represents a significant advancement in AML management by providing a convenient oral option for maintenance therapy.
Mechanism of Action
Azacitidine is a pyrimidine nucleoside analog of cytidine that incorporates into DNA and RNA. Its primary mechanism involves DNA hypomethylation through inhibition of DNA methyltransferases, which reverses tumor-suppressor gene silencing. Additionally, it exerts direct cytotoxicity on abnormal hematopoietic cells in the bone marrow through incorporation into nucleic acids, resulting in cell death. The dual mechanism of action makes it particularly effective in managing AML.
Indications
- Maintenance treatment of adult patients with acute myeloid leukemia (AML) who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy
- Patients must be ineligible for or unable to undergo intensive curative therapy (such as hematopoietic stem cell transplantation)
Dosage and Administration
Standard dosing: 300 mg orally once daily on days 1-14 of each 28-day cycle Administration:- Take on an empty stomach (at least 2 hours before or after meals)
- Swallow tablets whole; do not crush, break, or chew
- If a dose is missed or vomited, do not make up the dose; resume with the next scheduled dose
- Hematologic toxicity: May require dose reduction to 200 mg daily or treatment interruption
- Renal impairment: Not recommended in severe renal impairment (CrCl <30 mL/min)
- Hepatic impairment: No dosage adjustment necessary for mild to moderate impairment
Pharmacokinetics
Absorption: Bioavailability approximately 11-18% under fasting conditions; food significantly reduces absorption Distribution: Mean apparent volume of distribution ~35 L; 76-89% protein bound Metabolism: Undergoes spontaneous hydrolysis and deamination by cytidine deaminase Elimination: Half-life ~1.3 hours; primarily excreted renally (50-85%) Special populations: Exposure increased in patients with severe renal impairmentContraindications
- Hypersensitivity to azacitidine or any component of the formulation
- Patients with advanced malignant hepatic tumors
- Severe renal impairment (CrCl <30 mL/min)
Warnings and Precautions
Boxed Warning: Risk of myelosuppression- May cause neutropenia and thrombocytopenia
- Monitor complete blood counts regularly
- May require dose delays or reductions
- Increased risk of infection (bacterial, fungal, viral)
- Risk of tumor lysis syndrome, particularly in patients with high tumor burden
- Embryo-fetal toxicity: Can cause fetal harm
- Gastrointestinal toxicity: Nausea, vomiting, diarrhea, constipation
- Hepatotoxicity: Monitor liver function tests
Drug Interactions
Strong CYP inducers: Avoid concomitant use with strong CYP450 inducers (rifampin, carbamazepine, phenytoin, St. John's wort) UDP-glucuronosyltransferase inducers: May decrease azacitidine concentrations Live vaccines: Avoid during treatment due to immunosuppression Antacids/proton pump inhibitors: May alter absorption; separate administration by at least 2 hoursAdverse Effects
Very common (≥20%):- Nausea (65%)
- Vomiting (60%)
- Diarrhea (50%)
- Fatigue (44%)
- Constipation (39%)
- Pneumonia (27%)
- Abdominal pain (22%)
- Arthralgia (22%)
- Decreased appetite (21%)
- Pyrexia (20%)
- Febrile neutropenia (12%)
- Neutropenia (25%)
- Thrombocytopenia (25%)
- Anemia (13%)
- Sepsis (5%)
Monitoring Parameters
Prior to initiation:- Complete blood count with differential
- Renal function (serum creatinine, CrCl)
- Liver function tests
- Pregnancy test in women of reproductive potential
- CBC with differential weekly until stable, then at least monthly
- Renal and hepatic function periodically
- Signs/symptoms of infection
- Gastrointestinal toxicity
- Tumor lysis syndrome monitoring in high-risk patients
- Secondary malignancies (theoretical risk)
- Response assessment per standard AML guidelines
Patient Education
- Take exactly as prescribed on an empty stomach
- Do not crush, chew, or break tablets
- Report signs of infection (fever, chills, cough) immediately
- Report unusual bleeding or bruising
- Use effective contraception during treatment and for at least 6 months after final dose
- Inform all healthcare providers about Onureg use
- Maintain adequate hydration to help prevent tumor lysis syndrome
- Manage gastrointestinal side effects with antiemetics and antidiarrheals as prescribed
- Do not receive live vaccines during treatment
References
1. FDA Prescribing Information: ONUREG® (azacitidine) tablets 2. Wei AH, Döhner H, Pocock C, et al. Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med. 2020;383(26):2526-2537. 3. National Comprehensive Cancer Network (NCCN) Guidelines: Acute Myeloid Leukemia (Version 3.2022) 4. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel. Blood. 2022;140(12):1345-1377. 5. ClinicalTrials.gov: QUAZAR AML-001 Maintenance Trial (NCT01757535)