Azacitidine is a pyrimidine nucleoside analog chemotherapy agent. Azacitidine for injection is indicated for the treatment of adult patients with certain myelodysplastic syndrome subtypes. It is also indicated for the treatment of pediatric patients aged 1 month and older with newly diagnosed juvenile myelomonocytic leukemia. This formulation is contraindicated in patients with advanced malignant hepatic tumors or who have experienced a hypersensitivity reaction with mannitol. Do not substitute the injectable product for oral azacitidine. Azacitidine oral tablets are indicated for the treatment of adult patients with acute myelogenous leukemia who achieved first complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy. This product should not be substituted for azacitidine for injection.
General Administration Information
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.
Route-Specific Administration
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.
Hematologic adverse events have been reported in patients who received azacitidine in clinical studies. In patients treated with azacitidine for injection, monitor complete blood counts (CBC) prior to starting azacitidine, prior to each dosing cycle, and as necessary to evaluate for response to therapy and/or toxicity. In patients with myelodysplastic syndrome (MDS), a dosage adjustment in subsequent cycles may be required based on nadir counts and hematologic response. In patients with juvenile myelomonocytic leukemia (JMML), 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 (AML) 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. Anemia (70%), thrombocytopenia (66%), leukopenia (48%), neutropenia (32%), and febrile neutropenia (16%) were reported in MDS patients who received subcutaneous azacitidine (n = 220) in pooled results from 2 clinical studies. Additionally, thrombocytopenia (70%; grade 3 or 4, 58%), neutropenia (66%; grade 3 or 4, 61%), anemia (51%; grade 3 or 4, 14%), leukopenia (18%; grade 3 or 4, 15%), and febrile neutropenia (14%; grade 3 or 4, 13%) occurred in MDS patients who received subcutaneous azacitidine plus best supportive care (n = 175) in another randomized trial. Agranulocytosis, bone marrow failure, pancytopenia, and splenomegaly were reported in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies. Anemia (39%; grade 3 or 4, 33%), thrombocytopenia (28%; grade 3 or 4, 22%), neutropenia (17%; grade 3 or 4, 11%), febrile neutropenia (11%; grade 3 or 4, 6%), and lymphadenopathy (11%; grade 3 or 4, 6%) were reported in pediatric patients (age range, 0.2 to 6.9 years) with JMML who received IV azacitidine in a clinical trial (n = 18). Neutropenia (74%), thrombocytopenia (65%), anemia (25%), and febrile neutropenia (12%; grade 3 or 4, 8%) occurred in AML patients who received oral azacitidine (n = 236) in a randomized trial; grade 3 or 4 neutropenia (49%), thrombocytopenia (21%), and anemia (4%) were worsened from baseline in azacitidine-treated patients.
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). Monitor liver function tests prior to starting azacitidine and before each cycle of therapy. Ascites was reported in 11% (grade 3 or 4, 6%) of pediatric patients (age range, 0.2 to 6.9 years) with juvenile myelomonocytic leukemia who received IV azacitidine in a clinical trial (n = 18). Cholecystitis and cholecystectomy each occurred in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies.
Nephrotoxicity (e.g., elevated serum creatinine levels, renal failure (unspecified), renal tubular acidosis (RTA)) has been reported in patients who received azacitidine for injection in combination with other chemotherapeutic agents for non-myelodysplastic (MDS) syndrome indications (off-label use); some cases resulted in death. In patients with MDS 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. RTA, defined as a fall in serum bicarbonate to less than 20 mEq/L in association with alkaline urine and hypokalemia (serum potassium less than 3 mEq/L), developed in 5 patients with chronic myeloid leukemia treated with azacitidine and etoposide. Hypokalemia (6%; grade 3 or 4, 2%) and hematuria (6%; grade 3 or 4, 2%) occurred in MDS patients who received subcutaneous azacitidine plus best supportive care (n = 175) in a multicenter, randomized trial (n = 277). Renal failure and loin pain have been reported in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies. In patients with acute myelogenous leukemia treated with oral azacitidine, 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.
Post procedural bleeding was reported in 6% of patients with myelodysplastic syndrome who received subcutaneous azacitidine (n = 220) compared with 1% of patients on observation alone (n = 92) in pooled results from 2 clinical studies.
Gastrointestinal adverse events have been reported in patients who received azacitidine in clinical studies. In patients with acute myelogenous leukemia (AML) treated with oral therapy, 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. Therapy interruption, dose or schedule reduction, or discontinuation may be necessary in patients who develop severe nausea, vomiting, or diarrhea. Nausea (65%; grade 3 or 4, 3%), vomiting (60%; grade 3 or 4, 3%), diarrhea (50%; grade 3 or 4, 5%), constipation (39%; grade 3 or 4, 1%), abdominal pain (22%; grade 3 or 4, 2%), and decreased appetite/anorexia (13%; grade 3 or 4, 1%) occurred in AML patients who received oral azacitidine (n = 236) in a randomized trial. Nausea (71%), vomiting (54%), diarrhea (36%), constipation (34%), anorexia (21%), abdominal pain (tenderness) (12%), gingival bleeding (10%), stomatitis (8%), loose stools (6%), and mouth bleeding (5%) were reported in myelodysplastic syndrome (MDS) patients who received subcutaneous azacitidine (n = 220) in pooled results from 2 clinical studies. Additionally, constipation (50%; grade 3 or 4, 1%), nausea (48%; grade 3 or 4, 2%) vomiting (27%), abdominal pain (13%; grade 3 or 4, 4%), and dyspepsia (6%) occurred in MDS patients who received subcutaneous azacitidine plus best supportive care (n = 175) in another randomized trial. Diverticulitis, GI bleeding, melena, and perirectal abscess were reported in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies. Vomiting (28%), diarrhea (22%; grade 3 or 4, 6%), constipation (22%), and abdominal pain (22%; grade 3 or 4, 11%), nausea (11%), and GI bleeding including rectal and mouth bleeding (11%) were reported in pediatric patients (age range, 0.2 to 6.9 years) with juvenile myelomonocytic leukemia who received IV azacitidine in a clinical trial (n = 18).
Dermatologic adverse events have been reported in patients with myelodysplastic syndrome who received azacitidine in clinical studies. Ecchymosis (31% vs. 15%), petechiae (24% vs. 9%), erythema (17% vs. 4%), rash (14% vs. 10%), hematoma (9% vs. 0%), urticaria (6% vs. 1%), skin nodule (5% vs. 1%), and xerosis (5% vs. 1.%) were reported more often in patients who received subcutaneous azacitidine (n = 220) compared with patients who received observation alone (n = 92) in pooled results from 2 clinical studies; injection site reaction including injection site erythema (35%), pain (23%), bruising (14%), reaction (14%), pruritus (7%), granuloma (5%), pigmentation changes (5%), and swelling (5%) were also reported with azacitidine use. Additionally, pruritus (12% vs. 2%), petechiae (11% vs. 4%), rash (10% vs. 1%), and erythema (7% vs. 3%) occurred more often in the subcutaneous azacitidine plus best supportive care (BSC) arm compared with the conventional care plus BSC arm in a multicenter, randomized trial (n = 277); grade 3 or 4 petechiae was reported in 1.1% of azacitidine-treated patients. In this study, injection site reactions including injection site erythema (43%), reaction (29%), pain (19%), hematoma (6%), rash (6%), bruising (5%), and induration (5%) were also reported with azacitidine use. Pyoderma gangrenosum, pruritic rash, skin duration, and catheter site hemorrhage occurred in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies. Rash (44%), pruritus (22%), allergic dermatitis (11%), and petechiae (11%) were reported in pediatric patients (age range, 0.2 to 6.9 years) with juvenile myelomonocytic leukemia who received IV azacitidine in a clinical trial (n = 18). In this trial, the term rash included maculopapular rash, bullous rash/dermatitis. Injection-site skin necrosis, Sweet's syndrome (acute febrile neutrophilic dermatosis), and necrotizing fasciitis (including fatal cases) have been reported with azacitidine use in postmarketing surveillance.
Musculoskeletal adverse events have been reported in patients who received azacitidine in clinical studies. Arthralgia (22%), myalgia (16%), and chest wall pain (5%) were reported in patients with myelodysplastic syndrome who received subcutaneous azacitidine (n = 220) in pooled results from 2 clinical studies. Aggravated bone pain, muscle weakness, and neck pain have been reported in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies. Musculoskeletal pain including back pain and extremity pain occurred in 11% of pediatric patients (age range, 0.2 to 6.9 years) with juvenile myelomonocytic leukemia who received IV azacitidine in a clinical trial (n = 18). Arthralgia (14%; grade 3 or 4, 1%) and extremity pain (11%; grade 3 or 4, less than 1%) occurred in patients with acute myelogenous leukemia who received oral azacitidine (n = 236) in a randomized trial.
Central nervous system adverse events have been reported in patients who received azacitidine in clinical studies. Headache (22%) and dizziness (19%) were reported in patients with myelodysplastic syndrome who received subcutaneous azacitidine (n = 220) in pooled results from 2 clinical studies. Cerebral hemorrhage, seizures, and intracranial bleeding were reported in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies. Dizziness occurred in 11% of patients with acute myelogenous leukemia who received oral azacitidine (n = 236) in a randomized trial.
Psychiatric adverse events have been reported in patients with myelodysplastic syndrome who received azacitidine in clinical studies. Anxiety (13% vs. 3%) and insomnia (11% vs. 4%) were reported more often in patients who received subcutaneous azacitidine (n = 220) compared with patients who received observation alone (n = 92) in pooled results from 2 clinical studies. Additionally, anxiety (5% vs. 1%) and insomnia (9% vs. 3%) occurred more often in the subcutaneous azacitidine plus best supportive care (BSC) arm compared with the conventional care plus BSC arm in a multicenter, randomized trial (n = 277).
Respiratory adverse events have been reported in patients with myelodysplastic syndrome who received azacitidine in clinical studies. Dyspnea was reported in 29% patients who received subcutaneous azacitidine (n = 220) compared with 12% of patients on observation alone (n = 92) in pooled results from 2 clinical studies. Additionally, dyspnea (15% vs. 5%) or exertional dyspnea (5% vs. 1%) and pharyngolaryngeal pain (6% vs. 3%) occurred more often in the subcutaneous azacitidine plus best supportive care (BSC) arm compared with the conventional care plus BSC arm in a multicenter, randomized trial (n = 277). In this study, grade 3 or 4 dyspnea was reported in 3% of azacitidine-treated patients. Hemoptysis, lung infiltration, pneumonitis, and respiratory distress occurred in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies. Cough (22%) and epistaxis (17%; grade 3 or 4, 6%) were reported in pediatric patients (age range, 0.2 to 6.9 years) with juvenile myelomonocytic leukemia who received IV azacitidine in a clinical trial (n = 18). Interstitial lung disease has been reported with azacitidine use in postmarketing surveillance.
Infection has been reported in patients who received azacitidine in clinical studies. Naso-pharyngitis (15%), upper respiratory tract infection (13%), and pneumonia (11%) were reported in patients with myelodysplastic syndrome (MDS) who received subcutaneous azacitidine (n = 220) in pooled results from 2 clinical studies. Additionally, upper respiratory tract infection (9%; grade 3 or 4, 2%), urinary tract infection (9%; grade 3 or 4, 2%), and rhinitis (6%) occurred in MDS patients who received subcutaneous azacitidine plus best supportive care (n = 175) in a multicenter, randomized trial. Limb abscess, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, streptococcal pharyngitis, systemic inflammatory response syndrome, Klebsiella pneumonia, sepsis, septic shock, Staphylococcal bacteremia and infection, and toxoplasmosis were reported in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies. Upper respiratory tract infection (44%; grade 3 or 4, 6%), febrile infection (11%; grade 3 or 4, 6%), fungal infection including candidiasis (11%; grade 3 or 4, 6%), and pneumonia (11%) were reported in pediatric patients (age range, 0.2 to 6.9 years) with juvenile myelomonocytic leukemia who received IV azacitidine in a clinical trial (n = 18). The term upper respiratory infection included influenza, nasopharyngitis, and rhinitis. Pneumonia occurred in 27% (grade 3 or 4, 9%) of patients with acute myelogenous leukemia who received oral azacitidine (n = 236) in a randomized trial; 1 patient who developed sepsis died. The term pneumonia included influenza, respiratory tract infection, lung abscess, hemoptysis, productive cough, pleural effusion, atelectasis, pleuritic pain, and rales.
Cardiovascular adverse events have been reported in patients with myelodysplastic syndrome who received azacitidine in clinical studies. Chest pain (unspecified) (16% vs. 5%) and hypotension (7% vs. 2%) were reported more often in patients who received subcutaneous azacitidine (n = 220) compared with observation alone (n = 92) in pooled results from 2 clinical studies. Additionally, hypertension occurred more often in the subcutaneous azacitidine plus best supportive care (BSC) arm (9%) compared with the conventional care plus BSC arm (4%) in a multicenter, randomized trial (n = 277); grade 3 and 4 hypertension was reported in 1% of azacitidine-treated patients. Atrial fibrillation, heart failure, congestive heart failure, cardiac arrest or respiratory arrest (cardio-respiratory arrest), congestive cardiomyopathy, and orthostatic hypotension have been reported in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies. Pericardial effusion and pericarditis have been reported with azacitidine for injection in postmarketing surveillance.
Malaise (11%) and lethargy (8%) were reported in patients with myelodysplastic syndrome (MDS) who received subcutaneous azacitidine (n = 220) in pooled results from 2 clinical studies. Fatigue (24%; grade 3 or 4, 3%) and lethargy (7%) occurred in MDS patients who received subcutaneous azacitidine plus best supportive care (n = 175) in another randomized trial. Fatigue/asthenia occurred in 44% (grade 3 or 4, 4%) of patients with acute myelogenous leukemia who received oral azacitidine (n = 236) in a randomized trial.
Fever was reported in 52% of patients with myelodysplastic syndrome (MDS) who received subcutaneous azacitidine (n = 220) compared with 30% of patients on observation alone (n = 92) in pooled results from 2 clinical studies. Additionally, fever occurred 30% (grade 3 or 4, 5%) of MDS patients who received subcutaneous azacitidine plus best supportive care (BSC) compared with 18% of patients who received conventional care plus BSC in a multicenter, randomized trial (n = 277). Fever was reported in 61% of pediatric patients (age range, 0.2 to 6.9 years) with juvenile myelomonocytic leukemia who received IV azacitidine in a clinical trial (n = 18).
Anaphylactic shock and hypersensitivity have been reported in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies.
Ocular hemorrhage been reported in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies.
Dehydration has been reported in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies.
Weight loss occurred in 8% of patients with myelodysplastic syndrome who received subcutaneous azacitidine plus best supportive care (BSC) compared with no patients who received conventional care plus BSC in a multicenter, randomized trial (n = 277); grade 3 and 4 weight loss was reported in 1% of azacitidine-treated patients. Weight loss occurred in 4% of AML patients who received oral azacitidine (n = 236) in a randomized trial.
New primary malignancy, specifically leukemia cutis, has been reported in less than 5% of patients treated with subcutaneous or IV azacitidine in clinical studies.
Tumor lysis syndrome (TLS) has been reported in postmarketing surveillance of azacitidine. 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. Hyperuricemia was reported in 17% of pediatric patients (age range, 0.2 to 6.9 years) with juvenile myelomonocytic leukemia who received IV azacitidine in a clinical trial (n = 18).
Differentiation syndrome has been reported in postmarketing experience with IV or subcutaneous azacitidine therapy.
Edema including peripheral edema (11%) and fluid retention (17%) were reported in pediatric patients (age range, 0.2 to 6.9 years) with juvenile myelomonocytic leukemia who received IV azacitidine in a clinical trial (n = 18).
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.
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).
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.
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) 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.
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.
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.
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.
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.
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 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 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 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 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.
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.
Therapeutic Drug Monitoring:
Dosage Guidance for Treatment-Related Toxicity
Myelodysplastic Syndromes (Azacitidine for injection)
Hematologic Toxicity
NOTE: All patients receive the same starting dosage on cycle 1.
In patients with baseline white blood cell (WBC) count of 3,000 cells/mm3 or greater, absolute neutrophil count (ANC) of 1,500 cells/mm3 or greater, and platelet count of 75,000 cells/mm3 or greater, subsequent dose adjustments are based on nadir counts during azacitidine therapy as follows:
ANC nadir of greater than 1,500 cells/mm3 or platelet count nadir of greater than 50,000/mm3: Give 100% of dose in the next cycle.
ANC nadir of 500 to 1,500 cells/mm3 or platelet count nadir of 25,000 to 50,000 cells/mm3: Give 67% of dose in the next cycle.
ANC nadir of less than 500 cells/mm3 or platelet count nadir less than 25,000 cells/mm3: Give 50% of dose in the next cycle.
In patients with baseline WBC of less than 3,000 cells/mm3, ANC of less than 1,500 cells/mm3, or platelet count of less than 75,000 cells/mm3, subsequent dose adjustments are based on nadir counts during azacitidine therapy and bone marrow cellularity (via biopsy) at time of nadir as follows (unless there is clear improvement in differentiation (i.e., percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, then continue the current dosage):
At nadir, WBC or platelet count is decreased by 50% to 75% from baseline value: Give 100% of dose in the next cycle for 30% to 60% bone marrow cellularity, 50% of dose in the next cycle for 15% to 30% bone marrow cellularity, and 33% of dose in the next cycle for less than 15% bone marrow cellularity. If the WBC and platelet counts are greater than 25% above the nadir and rising at day 28, start the next cycle of therapy; otherwise, re-access blood counts every 7 days. Resume therapy at 50% of the scheduled dose if WBC and platelet counts are still not at least 25% above the nadir by day 42.
At nadir, WBC or platelet count is decreased by more than 75% from baseline value: Give 75% of dose in the next cycle for 30% to 60% bone marrow cellularity, 50% of dose in the next cycle for 15% to 30% bone marrow cellularity, and 33% of dose in the next cycle for less than 15% bone marrow cellularity. If the WBC and platelet counts are greater than 25% above the nadir and rising at day 28, start the next cycle of therapy; otherwise, re-access blood counts every 7 days. Resume therapy at 50% of the scheduled dose if WBC and platelet counts are still not at least 25% above the nadir by day 42.
Juvenile Myelomonocytic Leukemia
Hematologic Toxicity
Dose reductions are not recommended within the first 3 cycles of treatment. Discontinue azacitidine therapy in patients who have an ANC less than 500 cells/mm3 at the end of cycle 3 (day 28) or on day 1 of cycle 5 or 6.
Non-Hematologic Toxicity
Consider a dose delay for 14 days or less.
Acute Myelogenous Leukemia (Azacitidine Tablets)
Neutropenia
Absolute neutrophil count (ANC) less than 500 cells/mm3 on day 1 of any cycle: Hold azacitidine therapy until the ANC is 500 cells/mm3 or greater.
ANC less than 1,000 cells/mm3 with fever (first occurrence): Hold azacitidine therapy until the ANC is 1,000 cells/mm3 or greater; resume azacitidine at the previous dose.
ANC less than 1,000 cells/mm3 with fever (occurrence in 2 consecutive cycles): Hold azacitidine therapy until the ANC is 1,000 cells/mm3 or greater; resume azacitidine at a reduced dose of 200 mg PO daily on days 1 to 14. If febrile neutropenia continues after the dose reduction, reduce the treatment duration by administering azacitidine 200 mg PO daily on days 1 to 7. Discontinue azacitidine if febrile neutropenia recurs after a dose and schedule reduction.
Thrombocytopenia
Platelets less than 50,000 cells/mm3 with bleeding (first occurrence): Hold azacitidine therapy until the platelet count is 50,000 cells/mm3 or greater; resume azacitidine at the previous dose.
Platelets less than 50,000 cells/mm3 with bleeding (occurrence in 2 consecutive cycles): Hold azacitidine therapy until the platelet count is 50,000 cells/mm3 or greater; resume azacitidine at a reduced dose of 200 mg PO daily on days 1 to 14. If thrombocytopenia with bleeding continues after the dose reduction, reduce the treatment duration by administering azacitidine 200 mg PO daily on days 1 to 7. Discontinue azacitidine if thrombocytopenia with bleeding recurs after a dose and schedule reduction.
Gastrointestinal Toxicity
Grade 3 or 4 nausea, vomiting, or diarrhea (first occurrence): Hold azacitidine therapy until the toxicity resolves to grade 1 or less; resume azacitidine at the previous dose.
Grade 3 or 4 nausea, vomiting, or diarrhea (recurrence): Hold azacitidine therapy until the toxicity resolves to grade 1 or less; resume azacitidine at a reduced dose of 200 mg PO daily on days 1 to 14. If the toxicity continues after the dose reduction, reduce the treatment duration by administering azacitidine 200 mg PO daily on days 1 to 7. Discontinue azacitidine if the toxicity continues or recurs after a dose and schedule reduction.
Other Adverse Reactions
Grade 3 or 4 toxicity (first occurrence): Hold azacitidine therapy and administer medical support; resume azacitidine at the previous dose when the toxicity resolves to grade 1 or less.
Grade 3 or 4 toxicity (recurrence): Hold azacitidine therapy until the toxicity resolves to grade 1 or less; resume azacitidine at a reduced dose of 200 mg PO daily on days 1 to 14. If the toxicity continues after the dose reduction, reduce the treatment duration by administering azacitidine 200 mg PO daily on days 1 to 7. Discontinue azacitidine if the toxicity continues or recurs after a dose and schedule reduction.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
Azacitidine for injection
Specific 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 tablet
No 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.
Patients with Renal Impairment Dosing
Azacitidine for injection
Baseline 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 tablet
No dosage adjustment is necessary in patients with mild to severe renal impairment (creatinine clearance of 15 to 89 mL/min).
*non-FDA-approved indication
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
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.
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%.
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
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) did not have a clinically relevant impact on the pharmacokinetic parameters of oral azacitidine. The effect of moderate or severe hepatic impairment (total bilirubin level greater than 1.5 times the ULN and any AST level) on the PK parameters of oral azacitidine is not known.
Renal Impairment
Azacitidine 75 mg/m2 was administered subcutaneously daily for 5 days to patients with normal renal function (creatinine clearance (CrCl) greater than 80 mL/min; n = 6) and severe renal impairment (CrCl less than 30 mL/min; n = 6). In patients with severe renal impairment, azacitidine exposure increased by approximately 70% after a single dose and by 41% after multiple administrations, resulting in exposure similar to patients with normal renal function treated with 100 mg/m2. The increase in exposure was not associated with an increase in adverse effects. Mild to moderate renal impairment (CrCl of 30 to 89 mL/min) did not have a clinically relevant impact on the pharmacokinetic (PK) parameters of oral azacitidine. The effect of severe renal impairment (CrCl of 15 to 29 mL/min) on the PK parameters of oral azacitidine is not known.
Pediatrics
The geometric mean Cmax level was 4,510 nanograms (ng)/mL (coefficient of variation (CV), 65.6%), AUC(0-24h) value was 1,550 ng x hour/mL (CV, 56.6%), half-life was 0.3 hour (CV, 59.9%), and clearance was 21.8 L/hour (CV, 102.2%) following an IV dose of azacitidine 75 mg/m2 or 2.5 mg/kg in pediatric patients with juvenile myelomonocytic leukemia (JMML). Consistent plasma azacitidine exposure was observed in pediatric patients with JMML over a body weight range of 4.6 to 18.5 kg and an age range of 0.2 to 6.9 years after recommended body surface area (BSA) or body weight-based IV dosing.
Geriatric
Age (range, 46 to 93 years) did not have a clinically relevant impact on the pharmacokinetic parameters of oral azacitidine.
Gender Differences
Gender did not have a clinically relevant impact on the pharmacokinetic parameters of oral or IV azacitidine.
Obesity
Higher body weight (range, 4.6 to 102 kg) was associated with increased azacitidine clearance following IV azacitidine administration in 6 adults and 34 pediatric patients in a population PK analysis. Weight (range, 39.3 to 129 kg) did not have a clinically relevant impact on the pharmacokinetic parameters of oral azacitidine.
Other
Tumor Type
Tumor type (MDS, JMML, AML) did not have a clinically significant impact on the pharmacokinetic (PK) parameters of IV azacitidine in a population PK analysis of 6 adults and 34 pediatric patients.