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  • CLASSES

    Small Molecule Antineoplastic DNA Methyltransferase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    A pyrimidine nucleoside analog chemotherapy agent
    Used IV or subcutaneously in adults with certain myelodysplastic syndrome subtypes; used orally in adults with acute myelogenous leukemia
    Injectable formulation contraindicated in patients with advanced malignant hepatic tumors or hypersensitivity to mannitol; oral product should not be substituted with injectable formulation

    COMMON BRAND NAMES

    ONUREG, Vidaza

    HOW SUPPLIED

    Azacitidine/Vidaza Intravenous Inj Pwd F/Susp: 100mg
    Azacitidine/Vidaza Subcutaneous Inj Pwd F/Susp: 100mg
    ONUREG Oral Tab: 200mg, 300mg

    DOSAGE & INDICATIONS

    For the treatment of myelodysplastic syndrome (MDS).
    NOTE: Azacitidine has been designated an orphan drug for this indication.
    For the treatment of MDS subtypes of refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.
    Subcutaneous dosage
    Adults

    75 mg/m2 subcutaneous once daily for 7 days repeated every 4 weeks. The dose may be increased to 100 mg/m2 subcutaneous if no beneficial response is seen after 2 treatment cycles, and no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 to 6 treatment cycles. Treatment may be continued as long as the patient continues to benefit. All patients should receive antiemetics prior to each azacitidine dose. Therapy interruption or a dose reduction may be necessary if a patient develops severe treatment-related toxicity. In a phase III trial (n = 191), patients were randomized to azacitidine 75 mg/m2 subcutaneous once daily for 7 days on days 1, 29, 57, and 85 or supportive care; patients who received supportive care were allowed to cross-over if their disease worsened. Patients were reassessed after 4 cycles, and those with a complete response (CR) continued for 3 more cycles, those with a partial response (PR) or stable disease continued until CR or progressive disease. Quality of life (QOL) was also assessed in this study. Responses occurred in 60% of patients receiving azacitidine (7% CR, 16% PR, and 37% with improvement in symptoms) compared with only 5% of patients in the observation arm demonstrating improvement. Median time to leukemic transformation was 21 months in the azacitidine arm compared with 13 months in the supportive care arm. QOL assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially treated with azacitidine.

    Intravenous dosage
    Adults

    75 mg/m2 IV once daily for 7 days repeated every 4 weeks. The dose may be increased to 100 mg/m2 IV if no beneficial response is seen after 2 treatment cycles, and no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 to 6 treatment cycles. Treatment may be continued as long as the patient continues to benefit. All patients should receive antiemetics prior to each azacitidine dose. Therapy interruption or a dose reduction may be necessary if a patient develops severe treatment-related toxicity.

    For the treatment of acute myelogenous leukemia (AML).
    NOTE: Azacitidine has been designated an orphan drug by the FDA for the treatment of AML.
    For the treatment of newly diagnosed AML in elderly patients who are ineligible for a hematopoietic stem-cell transplant†.
    Subcutaneous dosage
    Adults 65 years and older

    75 mg/m2 subcutaneously daily for 7 days repeated every 28 days for at least 6 cycles was evaluated in a randomized, phase 3 trial (n = 488; the AZA-AML-001 trial).

    For the treatment of newly-diagnosed AML in adults who are age 75 years or older or who have comorbidities that make them ineligible for intensive induction chemotherapy, in combination with venetoclax†.
    NOTE: Venetoclax is FDA approved in combination with azacitidine for this indication.
    Subcutaneous dosage
    Adults

    75 mg/m2 subcutaneously daily for 7 days repeated every 28 days starting on day 1 of cycle 1 in combination with venetoclax. The oral venetoclax dose is increased during a ramp-up phase as follows: 100 mg on day 1; 200 mg on day 2; 400 mg on day 3; and 400 mg once daily on day 4 and beyond. Continue treatment until disease progression. At a median follow-up time of 20.5 months (range, less than 0.1 to 30.7 months), the median overall survival (OS) time was significantly longer in patients with previously untreated acute myelogenous leukemia who received azacitidine plus venetoclax compared with azacitidine plus placebo (14.7 months vs. 9.6 months; hazard ratio (HR) = 0.66; 95% CI, 0.52 to 0.85; p less than 0.001) in a prespecified interim analysis of a randomized (2:1), double-blind, phase 3 trial (n = 431; the VIALE-A trial). The complete remission plus complete remission with partial hematologic recovery was significantly higher in the azacitidine plus venetoclax arm compared with azacitidine plus placebo arm (64.7% vs. 22.8%; p less than 0.001). In a subgroup of patients with IDH1 or IDH2 mutations at baseline (n = 89), the 12-month OS rate was higher with azacitidine plus venetoclax compared with azacitidine plus placebo (66.8% vs. 35.7%; HR = 0.35; 95% CI, 0.2 to 0.6; p less than 0.001). Eligible patients (median age, 76 years; range, 49 to 91 years) in this trial were aged 75 years or older (approximately 60%) and/or had coexisting conditions that prevented the use of intensive chemotherapy (i.e., standard induction therapy).

    Intravenous dosage
    Adults

    75 mg/m2 IV daily for 7 days repeated every 28 days starting on day 1 of cycle 1 in combination with venetoclax. The oral venetoclax dose is increased during a ramp-up phase as follows: 100 mg on day 1; 200 mg on day 2; 400 mg on day 3; and 400 mg once daily on day 4 and beyond. Continue treatment until disease progression. At a median follow-up time of 20.5 months (range, less than 0.1 to 30.7 months), the median overall survival (OS) time was significantly longer in patients with previously untreated acute myelogenous leukemia who received azacitidine plus venetoclax compared with azacitidine plus placebo (14.7 months vs. 9.6 months; hazard ratio (HR) = 0.66; 95% CI, 0.52 to 0.85; p less than 0.001) in a prespecified interim analysis of a randomized (2:1), double-blind, phase 3 trial (n = 431; the VIALE-A trial). The complete remission plus complete remission with partial hematologic recovery was significantly higher in the azacitidine plus venetoclax arm compared with azacitidine plus placebo arm (64.7% vs. 22.8%; p less than 0.001). In a subgroup of patients with IDH1 or IDH2 mutations at baseline (n = 89), the 12-month OS rate was higher with azacitidine plus venetoclax compared with azacitidine plus placebo (66.8% vs. 35.7%; HR = 0.35; 95% CI, 0.2 to 0.6; p less than 0.001). Eligible patients (median age, 76 years; range, 49 to 91 years) in this trial were aged 75 years or older (approximately 60%) and/or had coexisting conditions that prevented the use of intensive chemotherapy (i.e., standard induction therapy).

    For the treatment of AML in patients who achieved first complete remission (CR) or CR with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy.
    Oral dosage
    Adults

    300 mg orally daily on days 1 to 14 repeated every 28 days until disease progression. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop severe toxicity. Administer an antiemetic agent 30 minutes prior to each dose for the first 2 cycles; the antiemetic may be stopped after 2 cycles if the patient has no nausea and vomiting. At a median follow-up of 41.2 months, the median overall survival (OS) time was significantly increased in patients not eligible for a hematopoietic stem-cell transplant who received oral azacitidine compared with placebo (24.7 months vs. 14.8 months; p less than 0.001) in a randomized, double-blind, phase 3 trial (QUAZAR AML-001 trial; n = 472). Patients (median age, 68 years; range, 55 to 86 years) in this trial had achieved a CR or CR with incomplete blood count recovery to induction therapy with cytarabine-based regimens in combination with an anthracycline or similar agent; 80% of patients had received at least 1 cycle of consolidation therapy. The median OS times were higher with oral azacitidine compared with placebo in patients with measurable residual disease (MRD)-positive (14.6 months vs. 10.4 months; HR = 0.69; 95% CI, 0.51 to 0.93) and MDR-negative (30.1 months vs. 24.3 months; HR = 0.81; 95% CI, 0.59 to 1.12) status at baseline/screening in an exploratory analysis (n = 463) from the QUAZAR AML-001 trial. The benefit of oral azacitidine therapy versus placebo on OS regardless of baseline MRD status was confirmed in a multivariate analysis (HR = 0.74; 95% CI, 0.59 to 0.92). Additionally, patients who received oral azacitidine were more likely to convert from MRD-positive to MRD-negative status during treatment and had a longer overall duration of MRD negativity compared with patients who received placebo.

    For the treatment of newly-diagnosed AML with an IDH1 mutation in patients who are 75 years of age or older or who have comorbidities that preclude use of intensive induction chemotherapy, in combination with ivosidenib†.
    NOTE: Ivosidenib is FDA approved in combination with azacitidine for this indication.
    Subcutaneous dosage
    Adults

    75 mg/m2 subcutaneously once daily on days 1 to 7, every 28 days, in combination with ivosidenib (500 mg PO once daily until disease progression); alternatively, azacitidine may be administered once daily on days 1 to 5 and days 8 to 9, every 28 days. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, double-blind phase 3 clinical trial, patients with newly diagnosed, IDH1-positive AML who were 75 years or older or had comorbidities precluding the use of intensive induction chemotherapy were randomized to treatment with azacitidine plus ivosidenib (n = 72) or azacitidine plus placebo (n = 74). The primary endpoint of event-free survival duration was the same in each group (0.03 months). However, a secondary endpoint of complete remission (CR) was significantly higher in the ivosidenib group compared with the placebo group (34% vs. 11%), for a median duration not estimable versus 11 months, respectively; the rate of CR plus CR with partial hematologic recovery (CR+CRh) was also significantly higher in the ivosidenib arm (37% vs. 13%). Treatment with azacitidine plus ivosidenib significantly improved another secondary endpoint of median overall survival compared with azacitidine plus placebo (24 months vs. 7.9 months).

    Intravenous dosage
    Adults

    75 mg/m2 IV once daily on days 1 to 7, every 28 days, in combination with ivosidenib (500 mg PO once daily until disease progression); alternatively, azacitidine may be administered once daily on days 1 to 5 and days 8 to 9, every 28 days. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, double-blind phase 3 clinical trial, patients with newly diagnosed, IDH1-positive AML who were 75 years or older or had comorbidities precluding the use of intensive induction chemotherapy were randomized to treatment with azacitidine plus ivosidenib (n = 72) or azacitidine plus placebo (n = 74). The primary endpoint of event-free survival duration was the same in each group (0.03 months). However, a secondary endpoint of complete remission (CR) was significantly higher in the ivosidenib group compared with the placebo group (34% vs. 11%), for a median duration not estimable versus 11 months, respectively; the rate of CR plus CR with partial hematologic recovery (CR+CRh) was also significantly higher in the ivosidenib arm (37% vs. 13%). Treatment with azacitidine plus ivosidenib significantly improved another secondary endpoint of median overall survival compared with azacitidine plus placebo (24 months vs. 7.9 months).

    For the treatment of juvenile myelomonocytic leukemia (JMML).
    NOTE: The FDA has designated azacitidine as an orphan drug for the treatment of JMML.
    For the treatment of newly diagnosed JMML.
    Intravenous dosage
    Infants

    2.5 mg/kg IV daily for 7 days repeated every 28 days for a minimum of 3 cycles. Continue treatment for a maximum of 6 cycles in responding patients.  After 3 cycles of azacitidine therapy for the treatment of newly diagnosed juvenile myelomonocytic leukemia (median age, 2.1 years; range, 0.2 to 6.9 years), 11 of 18 patients (61%) achieved a clinical partial remission (cPR) and 6 of 16 (38%) transfusion-dependent patients no longer required transfusions in a multicenter, phase 2 (AZA-JMML-001) trial. Seven patients who had intermediate- or low-methylation signatures in genome-wide DNA-methylation studies all had a cPR. Additionally, 17 patients (94%) received an allogeneic hematopoietic stem cell transplantation (HSCT); 14 of these patients (82%) were leukemia-free at a median follow-up of 23.8 (range, 7 to 39.3) months after HSCT. At a median follow-up of 26.9 (range, 18.2 to 44.4) months, 16 patients (90%) were alive.  

    Children weighing less than 10 kg

    2.5 mg/kg IV daily for 7 days repeated every 28 days for a minimum of 3 cycles. Continue treatment for a maximum of 6 cycles in responding patients.  After 3 cycles of azacitidine therapy for the treatment of newly diagnosed juvenile myelomonocytic leukemia (median age, 2.1 years; range, 0.2 to 6.9 years), 11 of 18 patients (61%) achieved a clinical partial remission (cPR) and 6 of 16 (38%) transfusion-dependent patients no longer required transfusions in a multicenter, phase 2 (AZA-JMML-001) trial. Seven patients who had intermediate- or low-methylation signatures in genome-wide DNA-methylation studies all had a cPR. Additionally, 17 patients (94%) received an allogeneic hematopoietic stem cell transplantation (HSCT); 14 of these patients (82%) were leukemia-free at a median follow-up of 23.8 (range, 7 to 39.3) months after HSCT. At a median follow-up of 26.9 (range, 18.2 to 44.4) months, 16 patients (90%) were alive.

    Children and Adolescents weighing 10 kg or more

    75 mg/m2 IV daily for 7 days repeated every 28 days for a minimum of 3 cycles. Continue treatment for a maximum of 6 cycles in responding patients.  After 3 cycles of azacitidine therapy for the treatment of newly diagnosed juvenile myelomonocytic leukemia (median age, 2.1 years; range, 0.2 to 6.9 years), 11 of 18 patients (61%) achieved a clinical partial remission (cPR) and 6 of 16 (38%) transfusion-dependent patients no longer required transfusions in a multicenter, phase 2 (AZA-JMML-001) trial. Seven patients who had intermediate- or low-methylation signatures in genome-wide DNA-methylation studies all had a cPR. Additionally, 17 patients (94%) received an allogeneic hematopoietic stem cell transplantation (HSCT); 14 of these patients (82%) were leukemia-free at a median follow-up of 23.8 (range, 7 to 39.3) months after HSCT. At a median follow-up of 26.9 (range, 18.2 to 44.4) months, 16 patients (90%) were alive.  

    For the treatment of chronic myelogenous leukemia (CML)† in accelerated phase or blast crisis in combination with mitoxantrone.
    Intravenous infusion dosage
    Adults

    150 mg/m2/day IV for 5 days has been studied. In a phase II study, 40 patients with CML in accelerated phase or blast crisis were treated with azacitidine 150 mg/m2/day IV infusion for 5 days plus mitoxantrone (12 mg/m2/day IV for 3 days). The overall response rate was 23% including 5 complete responders, 2 partial responses and 2 with hematologic improvement.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    IV or subcutaneous dosing: 100 mg/m2 daily for 7 days per cycle.Oral dosing: 300 mg daily for 14 days per cycle.

    Geriatric

    IV or subcutaneous dosing: 100 mg/m2 daily for 7 days per cycle.Oral dosing: 300 mg daily for 14 days per cycle.

    Adolescents

    75 mg/m2 IV daily for 7 days per cycle.

    Children

    Less than 10 kg: 2.5 mg/kg IV daily for 7 days per cycle.10 kg or more: 75 mg/m2 IV daily for 7 days per cycle.

    Infants

    2.5 mg/kg IV daily for 7 days per cycle.

    Neonates

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Azacitidine for injectionSpecific guidelines for dosage adjustments in hepatic impairment are not available. Azacitidine has not been evaluated in patients with myelodysplastic syndrome or juvenile myelomonocytic leukemia and hepatic impairment; use is contraindicated in patients with advanced hepatic malignancy.Oral tabletNo dosage adjustment is necessary in patients with mild hepatic impairment (total bilirubin level of the upper limit of normal (ULN) or less and AST level greater than the ULN OR total bilirubin level of 1 to 1.5 times the ULN and any AST level). Specific guidelines for dosage adjustments in moderate (total bilirubin level of 1.5 to 3 times the ULN) or severe (total bilirubin level greater than 3 times the ULN) hepatic impairment are not available. Azacitidine has not been evaluated in patients with severe hepatic impairment.

    Renal Impairment

    Azacitidine for injectionBaseline renal impairment: No azacitidine dosage adjustment is necessary in cycle 1 in patients with renal impairment.Serum bicarbonate levels less than 20 mEq/L during therapy: Give 50% of dose in the next cycle.Elevated BUN or serum creatinine level during therapy: Delay the next cycle of therapy until value(s) return to normal or baseline; give 50% of dose in the next cycle.Oral tabletNo dosage adjustment is necessary in patients with mild to severe renal impairment (creatinine clearance of 15 to 89 mL/min).

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.
    Hazardous Drugs Classification
    NIOSH 2016 List: Group 1
    NIOSH (Draft) 2020 List: Table 1
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
    If azacitidine powder comes in contact with the skin, wash the skin immediately with soap and water. If it comes in contact with mucous membranes, flush thoroughly with water.
    Emetic Risk
    Moderate
    Administer routine antiemetic prophylaxis prior to treatment.

    Oral Administration
    Oral Solid Formulations

    Take azacitidine with or without food at about the same time each day.
    Swallow tablets whole; do not cut, crush, or chew tablets.
    If a dose is missed or not taken at the usual time, take the dose as soon as possible on the same day; resume the normal schedule the following day. Do not take 2 doses on the same day.
    If a patient vomits after a dose, do not take another dose on the same day; resume the normal schedule the following day.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Azacitidine is available as a single-use, 100-mg lyophilized powder vial; it is administered intravenously (IV) or subcutaneously.
    Do not substitute injectable azacitidine for oral azacitidine.
    Vial reconstitution concentrations are different for IV (10 mg/mL) and subcutaneous (25 mg/mL) routes; use caution when calculating the volume to be administered.
    There are several generic products for azacitidine 100-mg lyophilized powder vials, including mannitol-free formulations; refer to the manufacturer package insert for specific instructions regarding reconstitution and storage.

    Intravenous Administration

    Reconstitution:
    Inject 10 mL of Sterile Water for injection into the azacitidine 100-mg vial for a final vial concentration of 10 mg/mL.
    Shake or roll the vial vigorously until all powder is dissolved; the solution should be clear.
    Dilution:
    Add the calculated amount of azacitidine into a 50 to 100 mL infusion bag of either 0.9% Sodium Chloride injection or Lactated Ringer's injection; discard any unused drug remaining in the vial.
    For pediatric patients with juvenile myelomonocytic leukemia, dilute the admixture to a final concentration between 0.9 and 4 mg/mL.
    Do NOT dilute with 5% Dextrose solutions, Hespan, or solutions that contain bicarbonate as these solutions may cause increased rates of azacitidine degradation.
    Storage following reconstitution: The solution is stable at room temperature (25 degrees C or 77 degrees F) for up to 1 hour after reconstitution.
    Intravenous (IV) Infusion:
    Administer the azacitidine admixture IV over 10 to 40 minutes; complete the infusion within 1 hour of azacitidine vial reconstitution.

    Subcutaneous Administration

    Reconstitution:
    Slowly inject 4 mL of Sterile Water for injection into the azacitidine 100-mg vial for a final vial concentration of 25 mg/mL.
    Shake or roll the vial vigorously until a uniform suspension occurs; the suspension will be cloudy.
    Do not filter the suspension after reconstitution as this may remove the active substance.
    If the dose requires using more than one 100-mg vial, divide the dose equally between 2 syringes; due to retention in the vial and needle, it may not be feasible to withdraw all the contents from the vial.
    Discard any unused drug remaining in the vial.
    Storage following reconstitution (mannitol-containing formulations): If used immediately, store at room temperature for up to 1 hour. For delayed use, place the vial or syringe in the refrigerator. When reconstituted with Sterile Water for injection that was NOT refrigerated, the solution in the vial or a syringe is stable for up to 1 hour if stored at room temperature (25 degrees C or 77 degrees F) or for up to 8 hours under refrigeration (2 to 8 degrees C or 36 to 46 degrees F). When reconstituted with Sterile Water for injection that was refrigerated, the solution in the vial or a syringe is stable for up to 22 hours if stored in the refrigerator.
    Storage following reconstitution (mannitol-free formulations): If used immediately, store at room temperature for up to 1 hour. For delayed use, place the vial or syringe in the refrigerator. When reconstituted with Sterile Water for injection that was NOT refrigerated, the solution in the vial or a syringe is stable for up to 2 hours if stored at room temperature (25 degrees C or 77 degrees F) or for up to 12 hours under refrigeration (2 to 8 degrees C or 36 to 46 degrees F). When reconstituted with Sterile Water for injection that was refrigerated, the solution in the vial or a syringe is stable for up to 30 hours if stored in the refrigerator.
    Subcutaneous Injection:
    Allow refrigerated syringe(s) to warm to room temperature for up to 30 minutes prior to administration.
    Immediately prior to administration, vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved.
    Administer the azacitidine suspension subcutaneously; inject in 2 different sites if 2 syringes are required.
    Rotate sites for each injection (thigh, abdomen, or upper arm). Give new injections at least one inch from an old site; do not inject in a site that is tender, bruised, red, or hard.

    STORAGE

    ONUREG:
    - Avoid extreme temperatures
    - Protect from direct sunlight
    - Store and dispense in original container
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Vidaza:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard reconstituted product if not used within 1 hour
    - Discard unused portion. Do not store for later use.
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Mannitol hypersensitivity

    Azacitidine is contraindicated in patients with a known hypersensitivity to azacitidine.  Azacitidine for injection products that contain mannitol are contraindicated in patients with mannitol hypersensitivity.

    Hepatic disease, hepatotoxicity, hypoalbuminemia

    Azacitidine for injection is contraindicated in patients with advanced hepatic malignancies. Monitor liver function tests prior to starting azacitidine and before each cycle of therapy. Hepatotoxicity may occur in patients with severe hepatic impairment. Use azacitidine with caution in patients with myelodysplastic syndrome or juvenile myelomonocytic leukemia and hepatic disease/hepatic impairment as these patients were not studied in clinical trials. Progressive hepatic coma and death have been reported in azacitidine-treated patients with extensive tumor burden due to metastatic disease, particularly in patients with hypoalbuminemia (i.e., baseline albumin level less than 30 grams/L).

    Anemia, neutropenia, thrombocytopenia

    Myelosuppression (e.g., anemia, neutropenia, and thrombocytopenia) and febrile neutropenia have been reported with azacitidine therapy. In patients treated with azacitidine for injection, monitor complete blood counts (CBC) prior to starting azacitidine, prior to each cycle of therapy, and as necessary to evaluate for response to therapy and/or toxicity. In patients with myelodysplastic syndrome, a dosage adjustment in subsequent cycles may be required based on nadir counts and hematologic response. In patients with juvenile myelomonocytic leukemia, dose reductions are not recommended within the first 3 cycles of treatment; discontinue azacitidine therapy in patients who have a neutrophil count less than 0.5 X 109 cells/L at the end of cycle 3 or on day 1 of cycle 5 or 6. In patients with acute myelogenous leukemia treated with oral therapy, monitor CBCs every other week for the first 2 cycles and prior to the start of each cycle thereafter. Therapy interruption, dose or schedule reduction, or discontinuation may be necessary in patients who develop severe hematologic toxicity. Increase monitoring to every other week for the 2 cycles after any dose reduction for myelosuppression. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.

    Geriatric, renal failure, renal impairment

    Nephrotoxicity (e.g., elevated serum creatinine levels, renal failure, renal tubular acidosis) has been reported in patients who received azacitidine for injection in combination with other chemotherapeutic agents for non-myelodysplastic syndrome (MDS) indications; some cases resulted in death. In patients with MDS or juvenile myelomonocytic leukemia (JMML) treated with azacitidine for injection, monitor serum creatinine levels and electrolytes prior to starting azacitidine and prior to each cycle of therapy. Therapy interruption and/or a dose reduction may be necessary in patients who develop signs of nephrotoxicity. Use caution in geriatric patients or patients with renal impairment and closely monitor renal function. Patients with MDS or JMML and renal impairment were excluded from clinical trials. In patients with acute myelogenous leukemia treated with oral therapy, monitor patients with severe renal impairment (creatinine clearance, 15 to 29 mL/min) more frequently for signs of renal toxicity. Therapy interruption, dose or schedule reduction, or discontinuation may be necessary in patients who develop severe nephrotoxicity.

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) has been reported in patients with myelodysplastic syndrome who received azacitidine for injection. TLS may occur despite prophylaxis with allopurinol. Assess all patients for baseline TLS risk; monitor for TLS (e.g., serum electrolytes, uric acid levels, serum creatinine levels) and treat as appropriate.

    Myelodysplastic syndrome (MDS), treatment outside of a clinical trial

    The safety and effectiveness of azacitidine oral tablets for treatment of myelodysplastic syndrome (MDS) have not been established (off-label use). The AZA-MDS-003 trial was halted early when a higher incidence of early fatal and/or serious adverse reactions (e.g., sepsis) were reported in patients who received oral azacitidine compared with placebo. Therefore, oral azacitidine is not recommended in patients with MDS for treatment outside of a clinical trial.

    Pregnancy

    Azacitidine may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies; there are no data on the use of azacitidine in pregnant women. Females of reproductive potential should avoid pregnancy during treatment with azacitidine. Advise pregnant women of the potential risk to the fetus. Fetal death and anomalies were observed following the administration of a single intraperitoneal dose of azacitidine (at a dose that was less than the recommended human daily dose) in pregnant rats. Fetal anomalies included exencephaly/encephalocele, micromelia, club foot, syndactyly, oligodactyly, micrognathia, gastroschisis, edema, and rib abnormalities.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during azacitidine treatment. Pregnancy testing should be performed prior to starting azacitidine in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for 6 months after azacitidine therapy. Women who become pregnant while receiving azacitidine should be apprised of the potential hazard to the fetus. Additionally, male patients with a female partner of reproductive potential should use effective contraception during and for 3 months after azacitidine therapy due to the risk of male-mediated teratogenicity. Based on data in animals, infertility may occur in male or females treated with azacitidine.

    Breast-feeding

    It is not known if azacitidine or its metabolites are secreted in human milk or if it has effects on the breast-fed child or on milk production. Due to the risk of serious adverse reactions in a breast-fed child, women should discontinue breast-feeding during azacitidine therapy and for 1 week after the last dose.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 0-61.0
    thrombocytopenia / Delayed / 0-58.0
    anemia / Delayed / 4.0-33.0
    leukopenia / Delayed / 0-15.0
    abdominal pain / Early / 0-11.0
    infection / Delayed / 0-9.0
    lymphadenopathy / Delayed / 0-6.0
    ascites / Delayed / 0-6.0
    diarrhea / Early / 0-6.0
    epistaxis / Delayed / 0-6.0
    agranulocytosis / Delayed / 0-5.0
    pancytopenia / Delayed / 0-5.0
    cholecystitis / Delayed / 0-5.0
    renal failure (unspecified) / Delayed / 0-5.0
    seizures / Delayed / 0-5.0
    intracranial bleeding / Delayed / 0-5.0
    atrial fibrillation / Early / 0-5.0
    heart failure / Delayed / 0-5.0
    cardiomyopathy / Delayed / 0-5.0
    respiratory arrest / Rapid / 0-5.0
    cardiac arrest / Early / 0-5.0
    anaphylactic shock / Rapid / 0-5.0
    fever / Early / 0-5.0
    ocular hemorrhage / Delayed / 0-5.0
    new primary malignancy / Delayed / 0-5.0
    asthenia / Delayed / 0-4.0
    fatigue / Early / 0-4.0
    vomiting / Early / 0-3.0
    nausea / Early / 0-3.0
    dyspnea / Early / 3.0-3.0
    hematuria / Delayed / 2.0-2.0
    hypokalemia / Delayed / 2.0-2.0
    renal tubular acidosis (RTA) / Delayed / 0-1.0
    anorexia / Delayed / 0-1.0
    constipation / Delayed / 0-1.0
    petechiae / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    hypertension / Early / 1.0-1.0
    weight loss / Delayed / 0-1.0
    coma / Early / Incidence not known
    skin necrosis / Early / Incidence not known
    acute febrile neutrophilic dermatosis / Delayed / Incidence not known
    necrotizing fasciitis / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    differentiation syndrome / Delayed / Incidence not known

    Moderate

    erythema / Early / 7.0-17.0
    hyperuricemia / Delayed / 0-17.0
    fluid retention / Delayed / 0-17.0
    chest pain (unspecified) / Early / 16.0-16.0
    edema / Delayed / 0-11.0
    hematoma / Early / 9.0-9.0
    stomatitis / Delayed / 8.0-8.0
    hypotension / Rapid / 7.0-7.0
    bleeding / Early / 6.0-6.0
    splenomegaly / Delayed / 0-5.0
    melena / Delayed / 0-5.0
    bone pain / Delayed / 0-5.0
    hemoptysis / Delayed / 0-5.0
    pneumonitis / Delayed / 0-5.0
    orthostatic hypotension / Delayed / 0-5.0
    dehydration / Delayed / 0-5.0
    bullous rash / Early / Incidence not known
    candidiasis / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known

    Mild

    rash / Early / 10.0-44.0
    injection site reaction / Rapid / 5.0-43.0
    ecchymosis / Delayed / 31.0-31.0
    pruritus / Rapid / 12.0-22.0
    headache / Early / 22.0-22.0
    cough / Delayed / 0-22.0
    dizziness / Early / 11.0-19.0
    myalgia / Early / 16.0-16.0
    pharyngitis / Delayed / 15.0-15.0
    anxiety / Delayed / 5.0-13.0
    musculoskeletal pain / Early / 0-11.0
    insomnia / Early / 9.0-11.0
    malaise / Early / 11.0-11.0
    lethargy / Early / 7.0-8.0
    dyspepsia / Early / 6.0-6.0
    urticaria / Rapid / 6.0-6.0
    rhinitis / Early / 6.0-6.0
    xerosis / Delayed / 5.0-5.0
    weakness / Early / 0-5.0
    maculopapular rash / Early / Incidence not known
    back pain / Delayed / Incidence not known
    influenza / Delayed / Incidence not known

    DRUG INTERACTIONS

    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Decitabine; Cedazuridine: (Major) Avoid the concomitant use of decitabine; cedazuridine with drugs that are metabolized by the enzyme cytidine deaminase (CDA), such as azacitidine; the cytotoxicity of azacitidine may be increased. Cedazuridine is a CDA inhibitor. CDA is one of the enzymes responsible for the metabolism of azacitidine to form inactive metabolites.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Azacitidine may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies; there are no data on the use of azacitidine in pregnant women. Females of reproductive potential should avoid pregnancy during treatment with azacitidine. Advise pregnant women of the potential risk to the fetus. Fetal death and anomalies were observed following the administration of a single intraperitoneal dose of azacitidine (at a dose that was less than the recommended human daily dose) in pregnant rats. Fetal anomalies included exencephaly/encephalocele, micromelia, club foot, syndactyly, oligodactyly, micrognathia, gastroschisis, edema, and rib abnormalities.

    It is not known if azacitidine or its metabolites are secreted in human milk or if it has effects on the breast-fed child or on milk production. Due to the risk of serious adverse reactions in a breast-fed child, women should discontinue breast-feeding during azacitidine therapy and for 1 week after the last dose.

    MECHANISM OF ACTION

    Azacitidine is a pyrimidine analog for cytosine. Upon phosphorylation, azacitidine may be incorporated into RNA or DNA. Once incorporated into tRNA, azacitidine inhibits tRNA methyltransferases and interferes with tRNA methylation and processing, which leads to inhibition of protein synthesis. As regards DNA, azacitidine acts as an irreversible inhibitor of DNA methyltransferase, which can lead to cell differentiation and/or apoptosis. Following incorporation into DNA, azacitidine leads to inhibition of DNA methylation due to irreversible binding of DNA methyltransferase to the azacitidine adduct in DNA. Azacitidine inhibition of DNA methyltransferase is dose- and time-dependent. Animal studies have indicated increased response when smaller doses of azacitidine were given over a period of time versus larger doses given less frequently. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis.
     
    Normally, DNA methyltransferase methylates cytosine in newly formed DNA. Methylation usually suppresses gene transcription and gene deletion. In some cancer cells, hypermethylation blocks the activity of tumor suppressor genes, which regulate cell division and differentiation to prevent malignant transformation. When suppressor gene activity is blocked, cell division becomes unregulated, leading to the formation of neoplastic cells. Hypermethylation is thought to be an early step in malignant transformation of cells. Hypomethylation may restore normal gene function to those genes critical for differentiation and proliferation. Azacitidine induces cytotoxicity in rapidly dividing cells that are no longer responsive to normal cell growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.

    PHARMACOKINETICS

    Azacitidine is administered orally, as a subcutaneous injection, or as an intravenous (IV) infusion. The primary route of elimination is urinary excretion. Following IV administration of radiolabeled azacitidine in 5 patients, the cumulative urinary excretion was 85% and fecal excretion over 3 days was less than 1% of the total reactivity. Following subcutaneous administration of radiolabeled azacitidine, the mean urinary excretion was 50%. The mean elimination half-life of total radioactivity (azacitidine and its metabolites) was about 4 hours following IV or subcutaneous administration. Following oral administration of azacitidine 300 mg once daily, less than 2% of the dose was recovered unchanged in the urine. Azacitidine is metabolized via hydrolysis and deamination mediated by cytidine deaminase.
    Affected cytochrome P450 isoenzymes or drug transporters: None
    In vitro, azacitidine is not a P-glycoprotein (P-gp) substrate and it does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2E1, P-gp, breast cancer resistance protein, organic anion transporters (OAT)-1 and OAT3, organic anion transporting polypeptides (OATP)-1B1 and OATP1B3, or organic cation transporter (OCT)-2 or induce CYP1A2, CYP2C19, and CYP3A at clinically relevant concentrations. The concomitant administration of azacitidine and omeprazole resulted in a non-significant azacitidine AUC increase of 19%.

    Oral Route

    The mean oral bioavailability of azacitidine is approximately 11% relative to subcutaneous administration. Following a single oral dose of azacitidine 300 mg, the mean Cmax value was 145 ng/mL (coefficient of variation (CV), 64%), the mean AUC value was 242 ng x hour/mL (CV, 65%), and the median Tmax value was 1 hour. The systemic exposure of azacitidine is approximately dose proportional over the dose range of 120 mg to 600 mg once daily (0.4 to 2 times the recommended dosage). No accumulation was observed following azacitidine 300 mg once daily. In vitro, serum protein binding of oral azacitidine is about 6% to 12%; the blood-to-plasma ratio is about 0.3. The mean apparent volume of distribution is 881 L (CV, 67%), the mean terminal half-life is about 0.5 hours (CV, 27%), and the apparent clearance is 1,240 L/hour (CV, 64%).
    Effects of food: The AUC value decreased by 21% when oral azacitidine was administered with a high-fat, high calorie meal (800 to 1,000 calories, 50% fat); this decrease in exposure was not considered clinically relevant and azacitidine may be taken with or without food.

    Intravenous Route

    Following a single IV dose of azacitidine 75 mg/m2, the mean volume of distribution was 76 +/- 26 L in patients with myelodysplastic syndrome (n = 6).

    Subcutaneous Route

    Azacitidine is rapidly absorbed after subcutaneous administration. The bioavailability of subcutaneous azacitidine is approximately 89% compared with IV azacitidine (based on AUC). In 21 patients with cancer, subcutaneous azacitidine administration resulted in AUC and Cmax values that were dose proportional over a dose range of 25 mg/m2 to 100 mg/m2. Multiple dosing at the recommended dose-regimen does not result in drug accumulation. In patients with myelodysplastic syndrome (n = 6), the Cmax was 750 +/- 403 nanograms/mL, the Tmax was 0.5 hour, the mean apparent clearance was 167 +/- 49 liters/hour, and the mean half-life after was 41 +/- 8 minutes following a single-dose of azacitidine 75 mg/m2 given as a subcutaneous injection.