Azacitidine, a synthetic pyrimidine nucleoside analog of cytidine, is an antineoplastic agent.1, 2
Injectable azacitidine is used for the treatment of myelodysplastic syndrome (MDS)1, 3 and is designated an orphan drug by FDA for use in this condition.4 The drug is indicated for use in adults with the following French-American-British (FAB) subtypes of MDS: refractory anemia (RA) or RA with ringed sideroblasts (RARS) if requiring blood transfusions or accompanied by neutropenia or thrombocytopenia, RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).1, 3 In patients with high-risk MDS, improved response rates (complete responses, partial responses, hematologic improvement) and improved survival have been reported with azacitidine therapy compared with conventional care (best supportive care, low-dose cytarabine, or an anthracycline-cytarabine regimen).1, 5
The current indication for injectable azacitidine in MDS is based on results of 2 randomized, open-label, phase 3 studies (Cancer and Leukemia Group B [CALGB] 92211, 3, 6 and AZA-0011, 5 ) and 2 open-label, single-arm, phase 2 studies (CALGB 8921 and 8421).1, 6
The CALGB 9221 study included patients with any of the 5 FAB subtypes of MDS or with acute myelogenous leukemia (AML), whereas the CALGB 8921 study included only patients with RAEB, RAEB-T, CMMoL, or AML and CALGB 8421 included only patients with RAEB, RAEB-T, or AML.1, 3, 6 Patients with AML were not intended to be included in any of the CALGB studies.1 Azacitidine was administered in these studies at a dosage of 75 mg/m2 daily, given as a subcutaneous injection (CALGB 8921 and 9221 studies) or as an IV infusion (CALGB 8421 study), for 7 days every 4 weeks.1, 3, 6 Dosage was increased to 100 mg/m2 daily if no beneficial effect was observed after 2 treatment cycles or was decreased and/or delayed based on hematologic or renal toxicity.1, 6 Patients who achieved a complete response with azacitidine received 3 additional cycles of the drug, while those exhibiting a partial response or improvement continued to receive the drug until either a complete response or relapse occurred.3, 6 A complete response to therapy (lasting at least 4 weeks) generally was defined as less than 5% blast cells in the bone marrow, complete blood cell count (CBC) within normal limits (if abnormal at baseline), and absence of blast cells in the peripheral circulation.1 Partial response to therapy (lasting at least 4 weeks) generally was defined as at least a 50% decrease in blast cells in the bone marrow and improvement in bone marrow dyspoiesis (for those with subtypes RAEB, RAEB-T, or CMMoL; no marrow criteria for those with RA or RARS); at least 50% restoration (in the baseline deficit from normal) of leukocytes, hemoglobin, and platelets; and absence of blast cells in the peripheral circulation.1 In addition, in patients with CMMoL and an elevated baseline leukocyte count, criteria for partial response also included at least a 75% decrease in the excess (over the upper limit of normal) leukocyte count.1
In the CALGB 9221 study, the overall response rate (complete plus partial responses) was higher (about 16 versus 0%) for patients receiving azacitidine combined with supportive care compared with those receiving supportive care alone.1, 3 These responses generally were prolonged and occurred in all 5 FAB subtypes of MDS as well as in patients with AML.1, 3 Greater than 90% of patients who responded to azacitidine initially demonstrated a hematologic response (e.g., decreased bone marrow blast cell percentages; increased platelets, hemoglobin, or leukocytes) by the fifth treatment cycle.1 All patients who previously were transfusion dependent became transfusion independent during partial or complete responses to azacitidine.1
In the CALGB 9221 study, patients receiving azacitidine had a longer median time to treatment failure than did those receiving supportive care alone (9.1 versus 3.8 months).3 In addition, among patients with high-risk MDS subtypes (RAEB, RAEB-T, and CMMoL), the median time to transformation to AML or death was longer with azacitidine therapy than with supportive care alone (19 versus 8 months).3 Within 6 months after study entry, transformation to AML occurred in 3% of patients receiving azacitidine compared with 24% of those receiving supportive care.3 Transition to AML adversely affected survival; the median additional survival time following a 12-month landmark date was 3 months in patients who underwent transformation to AML prior to the landmark date compared with 18 months in those who had not undergone such transformation.3 Following a 6-month landmark date, the median additional survival time (adjusted for the study's crossover design) was 18 months for patients receiving azacitidine compared with 11 months for those receiving supportive care alone.3
Overall response rates in the CALGB 8921 and 8421 studies were similar to those in the CALGB 9221 study, with 14% of patients in CALGB 8921 and 19% of those in CALGB 8421 achieving complete or partial responses to azacitidine.1 Response occurred regardless of MDS subtype (RAEB, RAEB-T, or CMMoL) or baseline diagnosis of AML.1
About 19% of patients in the 3 CALGB studies met criteria for improvement but did not exhibit a complete or partial response.1 In the CALGB 9221 study, approximately 24% of patients receiving azacitidine (combined with supportive care) were considered “improved,” and about 66% of these patients lost transfusion dependence.1 In comparison, only about 6% of patients receiving supportive care alone in this study were considered “improved,” and none of these patients lost transfusion dependence.1
In the AZA-001 study, 95% of patients had high-risk MDS based on FAB subtype (RAEB, RAEB-T, or CMMoL) at study entry, and 89% were classified as higher risk (intermediate-2 or high risk) based on the International Prognostic Staging System (IPSS).1, 5 Patients were randomized to receive either azacitidine (75 mg/m2 daily, given as a subcutaneous injection, for 7 days every 28 days) combined with best supportive care or conventional care (best supportive care or a standard anthracycline-cytarabine or low-dose cytarabine regimen combined with supportive care).1, 5 After a median follow-up of 21.1 months, median overall survival times were longer (24.5 versus 15 months) and 2-year survival rates were higher (50.8 versus 26.2%) for patients receiving azacitidine compared with those receiving conventional care.1, 5 Improved survival with azacitidine therapy was observed across all IPSS groups, including patients with intermediate- and poor-risk cytogenetics.5 A subgroup analysis of patients with the chromosome 7q deletion (a poor-risk karyotype) revealed a longer overall survival (13.1 versus 4.6 months) for azacitidine-treated patients compared with those receiving conventional care.5
Results from the AZA-001 study also showed that azacitidine was associated with a reduced need for red blood cell transfusions.1, 5 Among patients who were transfusion dependent at baseline, 45% of those receiving azacitidine and 11% of those receiving conventional care became transfusion independent during therapy; among those who were transfusion independent at baseline, 15% of those receiving azacitidine and 43% of those receiving conventional care became transfusion dependent during therapy.1 Patients who were transfusion dependent at baseline but became transfusion independent during azacitidine therapy remained transfusion independent for a median of 13 months.1
According to some experts, lower-risk MDS (characterized by an IPSS score indicating very low or low risk disease, and some instances of intermediate risk) is much less likely to progress to AML, and can often be managed by treating cytopenias (most often anemia) and improving quality of life.9 Azacitidine is recommended for treatment of patients with higher-risk MDS (based on an IPSS score indicating intermediate to very high risk disease) who do not have major comorbidities and who are not immediately eligible for allogeneic stem cell transplant.9 Determination of whether to treat patients with intermediate-risk MDS should be based on additional factors such as patient age, comorbidities, severity of cytopenias, somatic mutations, and effect of first-line treatment.9
Juvenile Myelomonocytic Leukemia
Injectable azacitidine is used for the treatment of newly diagnosed juvenile myelomonocytic leukemia (JMML) in pediatric patients ≥1 month of age.1 Injectable azacitidine has been designated an orphan drug by FDA for the treatment of this cancer.4
The current indication for injectable azacitidine in JMML is based on results of a phase 2, multicenter, open-label study (AZA-JMML-001) of 18 pediatric patients between 1 month and 18 years of age with JMML who received intravenous azacitidine prior to hematopoietic stem cell transplantation (HSCT).1, 7 Enrolled patients had to have a diagnosis confirmed in peripheral blood and bone marrow and either 1) a somatic gene mutation in one of the following genes: PTPN11 , KRAS , or NRAS with a fetal hemoglobin >5 times the normal value for their age, or 2) a clinical diagnosis of neurofibromatosis type 1.1 Azacitidine was administered at a dosage of 75 mg/m2 IV daily, for 7 days every 4 weeks for 3 to 6 cycles.1, 7 Patents weighing <10 kg or those <1 year of age received a dosage of 2.5 mg/kg IV daily, for 7 days every 4 weeks.1, 7 Treatment was discontinued in patients who were ready for HSCT between cycles 4 and 6, who had a neutrophil count <0.5/mm3 on cycle 3 day 28 or day 1 of cycles 5 or 6, or who experienced disease progression during treatment.1, 7
Of the enrolled patients (median age, 2.1 years), 13 had PTPN11 mutations, 3 had NRAS mutations, 1 had a KRAS mutation, and 1 had neurofibromatosis type 1.1 The primary endpoint of clinical complete remission or clinical partial remission (according to the International JMML response criteria) by 3 months, occurred in 50% (n=9) of patients (n=3, complete remission; n=6, partial remission).1 The median time to response was 1.2 months.1 The majority of patients (94%) underwent HSCT after a median of 4.6 months.1
Oral azacitidine is used for the continued treatment of acute myeloid leukemia (AML) in adults who achieved first complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy, but who are unable to complete intensive curative therapy.2 Oral azacitidine has been designated an orphan drug by FDA for the treatment of this cancer.4
Continued Treatment of AML Following Intensive Induction Chemotherapy
The current indication for oral azacitidine is based on the results of a randomized, double-blind, placebo-controlled, phase 3 trial (QUAZAR).2, 8 The QUAZAR study enrolled 472 patients 55 years of age and older who had newly diagnosed AML or secondary AML with cytogenetic characteristics indicating intermediate- or poor-risk disease.8 Patients were also required to be within 4 months of achieving a first complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy.1, 8 Eligible patients could have received consolidation therapy, but were excluded if they were eligible for HSCT at the time of screening.1 Patients were randomized to receive oral azacitidine 300 mg or placebo once daily on days 1-14 of each 28-day cycle.2, 8 Administration of oral azacitidine or placebo continued until more than 15% blasts were present or unacceptable adverse effects occurred.8
At baseline, patients were a median 68 years of a the majority of included patients were between 65 to <75 years of age, had an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1, and had intermediate cytogenetic risk.2 Most patients had primary (de novo) AML, classified as AML not otherwise specified, and experienced complete remission following intensive induction chemotherapy.2 At a median follow-up of 41.2 months, patients receiving oral azacitidine had a longer overall survival than did those receiving placebo (24.7 versus 14.8 months).2, 8 Overall survival was unchanged at an updated analysis after 55.5 months of follow-up.10
Recommendations from the National Cancer Institute (NCI) on intensive treatment of newly diagnosed AML suggest a minimum of 2 agents as combination chemotherapy consisting of cytarabine and an anthracycline or mitoxantrone.11 Addition of midostaurin or gemtuzumab ozogamicin can be considered for certain patients.11 Guidelines from the American Society of Hematology (ASH) on management of newly diagnosed AML in older adults recommend postremission therapy in patients who achieve remission following a single dose of intensive chemotherapy and who are not candidates for HSCT.12 The NCI lists the following as options for postremission treatment of AML: chemotherapy, maintenance therapy with midostaurin (for FLT3 -mutated disease) or oral azacitidine, or hematopoietic cell (bone marrow or stem cell) transplant.11
Untreated AML in Elderly Patients
Azacitidine also has been used in the treatment of previously untreated AML in geriatric patients† who were not eligible to receive standard induction therapy with an anthracycline-cytarabine regimen and in the treatment of relapsed or refractory AML in geriatric patients†.10002, 10007, 10008, 10009 Overall response rates of 49-60%, with complete response rates of 13-35%, have been reported in case series and nonrandomized studies of azacitidine in geriatric patients with AML.10002, 10007, 10008 A small, retrospective review of treatment outcomes for geriatric patients receiving azacitidine or a cytarabine-idarubicin regimen for treatment of AML found median survival times of 13 or 9 months, respectively.10009 Although efficacy of azacitidine has not been evaluated consistently and reported in a sufficient number of patients with classic FAB-defined AML (e.g., marrow blast count exceeding 30%), azacitidine may be considered a reasonable choice (accepted, with possible conditions) for initial treatment of AML in geriatric patients (older than 60 years of age) who are not candidates for standard induction therapy (i.e., because of compromised performance status or the presence of a clinically important comorbidity).10011 Improved survival and favorable overall response rates have been reported for geriatric patients with AML with normal to favorable karyotypes†;10007, 10009 therefore, use of azacitidine can be recommended (accepted) in this population.10011
Variable responses and poor survival outcomes have been reported in geriatric patients with AML with poor-risk or complex cytogenetics†;10007, 10009 therefore, use of azacitidine in this population is not fully established because of equivocal evidence.10011 In addition, because variable responses have been reported in a small number of geriatric patients with relapsed or refractory AML†, 10007, 10008 use of azacitidine in this patient population also is not fully established because of equivocal evidence.10011 Prospective, controlled studies with adequate sample sizes are lacking; additional data are needed to define the response rate, survival benefit, tolerability, and relevance of prognostic characteristics (e.g., host status, cytogenetic risk features, history of an antecedent hematologic disease) in patients receiving azacitidine or other DNA-methyltransferase inhibitors (DMITs), either as monotherapy or in combination with other targeted agents.10011
Dispensing and Administration Precautions
Azacitidine is administered orally as Onureg® or parenterally (e.g., as Vidaza® , generics) by subcutaneous injection or short IV infusion; dosage formulations are not equivalent and may not be substituted.1, 2
Tablets should be swallowed whole, and not cut, chewed or crushed.2 Oral azacitidine should be administered at the same time each day and can be administered with or without food.2
Missed doses should be taken as soon as possible on the same day, with resumption of the normal dosing schedule the following day.2 If a dose of oral azacitidine is vomited, do not repeat the dose on the same day; resume the normal schedule the following day.2
Store at 20-25°C in the original container; excursions are permitted between 15-30°C.2
Azacitidine is administered by subcutaneous injection as a suspension into the thigh, abdomen, or upper arm; injection sites should be rotated.1 Give new injections at least 1 inch away from an old site.1 Injections should not be made into areas where the skin is tender, bruised, red, or hard.1 The manufacturer states that doses exceeding 4 mL (1 vial) should be divided equally into 2 syringes and injected into 2 separate sites.1 Store unreconstituted vials of injectable azacitidine at 25°C; excursions are permitted to 15-30°C.1
Azacitidine sterile powder for injection is reconstituted for subcutaneous administration by adding 4 mL of sterile water for injection to a vial labeled as containing 100 mg of azacitidine to provide a suspension containing 25 mg/mL.1 The vial should be shaken vigorously or rolled until a uniform suspension is achieved.1 Such concentrated suspensions should not be administered IV.1 The suspension will be cloudy.1 The resultant azacitidine suspension must not be filtered after reconstitution since active drug could be removed.1
When azacitidine is reconstituted using room temperature (25°C) sterile water, the manufacturer recommends use of the resultant azacitidine suspension within 1 hour when stored at 25°C or within 8 hours if refrigerated at 2-8°C.1 When azacitidine is reconstituted using cold sterile water (2-8°C), the manufacturer recommends use of the resultant azacitidine suspension within 22 hours if stored under refrigeration at 2-8°C.1 After removal from the refrigerator, suspensions of azacitidine may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration.1 The contents of the syringe must be resuspended immediately prior to administration by vigorously rolling the syringe between the palms until a uniform, cloudy suspension is achieved.1 Commercially available azacitidine for injection contains no preservatives and is intended for single use; any unused portions of the suspension should be discarded.1
Azacitidine is also administered as a solution by IV infusion.1 Store unreconstituted vials of injectable azacitidine at 25°C; excursions are permitted to 15-30°C.1
Azacitidine sterile powder for injection is reconstituted for IV administration by adding 10 mL of sterile water for injection to a vial labeled as containing 100 mg of azacitidine to provide a solution containing 10 mg/mL.1 The vial should be vigorously shaken or rolled until complete dissolution has occurred.1 The resultant solution should be clear.1 The reconstituted (10 mg/mL) solution should be further diluted prior to IV administration.1
For the preparation of doses for adult patients with myelodysplastic syndrome, withdraw the desired dose of the reconstituted azacitidine solution from the vial and inject into a 50- to 100-mL infusion bag containing 0.9% sodium chloride injection or lactated Ringer's injection.1 For the preparation of doses for pediatric patients with juvenile myelomonocytic leukemia, withdraw the desired dose of the reconstituted azacitidine solution from the vial and inject into an infusion bag (volume up to 100 mL) of 0.9% sodium chloride injection or lactated Ringer's injection to yield a final concentration between 0.9 and 4 mg/mL.1
Azacitidine is incompatible with 5% dextrose solutions, hetastarch, or sodium bicarbonate-containing solutions; these solutions should not be used since they may potentially increase the rate of degradation of azacitidine.1
Reconstituted and diluted solutions of azacitidine may be stored at 25°C, but IV administration must be completed within 1 hour of reconstitution.1 Commercially available azacitidine for injection contains no preservatives and is intended for single use; any unused portions of the solution should be discarded.1
Azacitidine is administered as a solution by IV infusion over 10-40 minutes.1
Juvenile Myelomonocytic Leukemia (JMML)
Pediatric patients 1 month of age : For the management of newly diagnosed JMML, see Table 1 for the recommended dosage of injectable azacitidine based on age and weight.1 The dosage should be administered as an IV infusion once daily for 7 days during a 28-day cycle.1 The manufacturer recommends that patients receive a minimum of 3 treatment cycles, although additional cycles may be added up to a maximum of 6 cycles based on clinical benefit.1
Pediatric Patients with JMML | Recommended Dose |
|---|---|
Age 1 month to <1 year OR weight <10 kg | 2.5 mg/kg |
Age ≥1 year AND weight ≥10 kg | 75 mg/m2 |
Myelodysplastic Syndrome (MDS)
The recommended initial adult dosage of injectable azacitidine for the treatment of MDS for all patients, regardless of baseline hematologic laboratory values, is 75 mg/m2 given IV over 10-40 minutes or by subcutaneous injection once daily for 7 days.1 Cycles of therapy should be repeated every 4 weeks.1 The daily dosage may be increased to 100 mg/m2 if no beneficial effect is observed after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred.1 The manufacturer recommends that patients receive at least 4-6 treatment cycles, although additional treatment cycles may be needed to achieve a complete or partial response.1
Azacitidine may be continued as long as the patient is deriving benefit from therapy.1
The recommended adult dosage of oral azacitidine for maintenance treatment in adult patients with AML who have achieved a complete remission or complete remission with incomplete blood count recovery following induction chemotherapy or who are unable to complete intensive curative therapy, is 300 mg once daily from days 1—14 of each 28-day cycle.2 The drug should be continued until disease progression or unacceptable toxicity occurs.2 If the absolute neutrophil count (ANC) is <500/mm3 prior to starting a cycle, do not administer the drug and delay treatment until the ANC has recovered to ≥500/mm3.2
The manufacturer recommends administration of antiemetic prophylaxis 30 minutes prior to each dose of azacitidine for the first 2 treatment cycles; antiemetic prophylaxis may be omitted after 2 treatment cycles if no nausea or vomiting occurs.2
Dosage Modifications for Toxicity
Hematologic Toxicity in Pediatric Patients with JMML
Because of difficulties with the differentation and assessment of hematologic toxicities from the underlying disease course being treated, dosage reductions are not recommended during the first 3 treatment cycles in pediatric patients with JMML.1 Discontinuation of injectable azacitidine, however, is recommended if the ANC is <500/mm3 at the end of cycle 3, or on day 1 of cycles 5 or 6.1
Hematologic Toxicity in Adults with MDS
In adult patients with a baseline (start of treatment) white blood cell (WBC) count of at least 3000/mm3, ANC of at least 1500/mm3, and platelet count of at least 75,000/mm3, the dosage of injectable azacitidine in the next treatment cycle should be adjusted based on nadir ANC and platelet counts observed in the current cycle (see Table 2).1
Nadir ANC (per mm3) | Nadir Platelets (per mm3) | Dosage in Next Cycle (expressed as % of dose in current cycle) |
|---|---|---|
<500 | <25,000 | 50% |
500—1500 | 25,000—50,000 | 67% |
>1500 | >50,000 | 100% |
In adult patients with a baseline (start of treatment) WBC count of <3000/mm3, ANC of <1500/mm3, or platelet count of <75,000/mm3, dosage adjustments of injectable azacitidine should be based on nadir blood cell counts and bone marrow biopsy cellularity at the time of the nadir count (see Table 3), unless clear improvement in differentiation (increased percentage of mature granulocytes and higher ANC) is observed at the time of initiation of the subsequent cycle relative to the time of initiation of the previous cycle.1 If such improvement in differentiation is observed, the current dosage should be continued.1
Nadir WBC or Platelet Count (expressed as % decrease from baseline count) | Bone Marrow Biopsy Cellularity (%) at Time of Nadir Count | Dosage in Next Cycle (expressed as % of dose in previous cycle)a |
|---|---|---|
50—75 | 30-60 | 100% |
15-30 | 50% | |
<15 | 33% | |
>75 | 30-60 | 75% |
15-30 | 50% | |
<15 | 33% |
aThe next 7-day course of injectable azacitidine should be given 28 days after initiation of the previous course, provided that both the WBC and platelet counts at day 28 exceed the nadir counts by at least 25% and are increasing.1 If an increase in WBC and platelet counts of at least 25% has not occurred by day 28, these blood cell counts should be reassessed every 7 days; if increases of at least 25% do not occur by day 42, patients should receive 50% of the scheduled dosage.1
Hematologic Toxicity in Adults with AML
The manufacturer recommends monitoring the CBC every 2 weeks during the first 2 treatment cycles of oral azaciditine, and prior to the start of each cycle thereafter.2 If dosage reduction of oral azacitidine is necessary to manage myelosuppressive adverse reactions, it is recommended to increase monitoring to every 2 weeks for the 2 cycles following the dosage reduction.2 See Table 4 for dosage modifications for hematologic toxicity in adult patients taking oral azacitidine for AML.2
Adverse Reaction | Severity | Dosage Modification |
|---|---|---|
Myelosuppression | ANC <500/mm3 on day 1 of cycle | Withhold azacitidine and resume at same dosage once ANC recovers to ≥500/mm3. |
ANC <1000/mm3with concomitant fever at any time | First occurrence
Occurrence during 2 consecutive cycles
| |
Platelets <50,000/mm3 with concomitant bleeding | First occurrence
Occurrence during 2 consecutive cycles
| |
GI Toxicity | Grade 3 or 4 nausea or vomiting | Temporarily withhold azacitidine and resume at the same dosage once grade 3 or 4 nausea or vomiting has resolved to grade 1 or less. If recurrent grade 3 or 4 nausea or vomiting, temporarily withhold azacitidine until toxicity has resolved to grade 1 or less, and resume at a reduced dosage of 200 mg daily. If grade 3 or 4 nausea or vomiting continues after dosage reduction, reduce the duration of treatment by 7 days. If grade 3 or 4 nausea or vomiting persists after reduction of the dosage and duration, discontinue azacitidine therapy. |
Grade 3 or 4 diarrhea | Temporarily withhold azacitidine and resume at the same dosage once grade 3 or 4 diarrhea has resolved to grade 1 or less. If recurrent grade 3 or 4 diarrhea, temporarily withhold azacitidine until toxicity has resolved to grade 1 or less, and resume at a reduced dosage of 200 mg daily. If grade 3 or 4 diarrhea continues after dosage reduction, reduce the duration of treatment by 7 days. If grade 3 or 4 diarrhea persists after reduction of the dosage and duration, discontinue azacitidine therapy. | |
Other Adverse Reactions | Grade 3 or 4 severity | Temporarily withhold azacitidine and provide clinically appropriate care. Resume at the same dosage once toxicity has resolved to grade 1 or less. If recurrent grade 3 or 4 toxicity, temporarily withhold azacitidine until toxicity has resolved to grade 1 or less, and resume at a reduced dosage of 200 mg daily. If grade 3 or 4 toxicity continues after dosage reduction, reduce the duration of treatment by 7 days. If grade 3 or 4 toxicity persists after reduction of the dosage and duration, discontinue azacitidine therapy. |
Renal Toxicity and Electrolyte Disturbances with Injectable Azacitidine
If unexplained decreases in serum bicarbonate concentrations (to <20 mEq/L) occur during subcutaneous or IV azacitidine therapy, the dosage in the next treatment cycle should be reduced by 50%.1
If unexplained elevations of blood urea nitrogen (BUN) or serum creatinine concentrations occur during subcutaneous or IV azacitidine therapy, the next cycle should be delayed until such values return to normal or baseline levels and the dosage of azacitidine should be reduced by 50% in the next treatment cycle.1
Oral : The manufacturer states that no dosage adjustment of oral azacitidine is necessary in patients with mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN], or total bilirubin 1—1.5 times ULN with any aspartate aminotransferase [AST] level).2 The manufacturer states that dosage adjustments have not been established in patients with moderate hepatic impairment (total bilirubin greater than 1.5—3 times ULN).2 Oral azaciditine has not been studied in patients with severe hepatic impairment (total bilirubin greater than 3 times ULN).2
Subcutaneous or IV : Injectable azacitidine has not been studied in adult patients with MDS or in pediatric patients with JMML and hepatic impairment.1
Oral : The manufacturer states that no dosage adjustment of oral azaciditine is necessary in patients with mild to severe renal impairment (creatinine clearance 15—89 mL/minute).2 In patients with severe renal impairment (creatinine clearance 15—29 mL/minute), the manufacturer recommends monitoring for adverse events frequently and adjusting the dosage as necessary to manage adverse events.2
Subcutaneous or IV : The manufacturer provides no specific dosage recommendations for injectable azacitidine in patients with renal impairment.1 Because azacitidine and its metabolites primarily undergo renal excretion, there is a potential for an increased risk of toxicity in patients with renal impairment and close monitoring is recommended.1 The manufacturer recommends evaluation of serum creatinine and electrolyes prior to initiation of injectable azacitidine.1 If unexplained reductions in serum bicarbonate concentrations (to less than 20 mEq/L) or elevations of BUN or serum creatinine concentrations occur, the dosage should be reduced or therapy with the drug withheld.1 Injectable azacitidine has not been studied in adult patients with MDS or pediatric patients with JMML and renal impairment.1
Oral : The manufacturer makes no specific dosage recommendations for oral azaciditine in geriatric patients.2
Subcutaneous or IV : The manufacturer makes no specific dosage recommendations for injectable azacitidine in geriatric patients; however, due to a greater likelihood of renal impairment in geriatric patients, monitoring of renal function is recommended.1
Risks of Substitution with Other Azacitidine Products
Due to large differences in the pharmacokinetics and recommended dosages, as well as differences in labeled indications, of each product, oral and injectable azacitidine must not be substituted.1, 2 Treatment with injectable azacitidine at dosages recommended for oral azacitidine may result in fatal adverse events.1, 2 Oral azacitidine given at dosages recommended for injectable azacitidine may result in a loss of therapeutic efficacy.1, 2
Anemia, neutropenia, and thrombocytopenia have occurred in adult patients with myelodysplastic syndrome (MDS) and pediatric patients with juvenile myelomonocytic leukemia (JMML) receiving injectable azacitidine.1 Complete blood cell and platelet counts should be performed prior to each treatment cycle at a minimum and frequently thereafter as needed to monitor response and toxicity.1 After administration of the recommended dosage for the first cycle in adult patients with MDS, dosage for subsequent cycles should be adjusted or delayed based on nadir blood cell counts and hematologic response.1 Because of difficulties with the differentation and assessment of hematologic toxicities from the underlying disease course being treated, dosage reductions are not recommended during the first 3 treatment cycles in pediatric patients with JMML.1
In patients who received oral azacitidine, new or worsening neutropenia and thrombocytopenia (grade 3 or 4) occurred in 49% and 22% of patients, respectively, with 12% of patients experiencing febrile neutropenia.2 Dosage reductions due to neutropenia and thrombocytopenia were necessary in 7% and 2% of patients, respectively.2 Less than 1% of patients who received oral azacitidine required treatment discontinuation because of neutropenia or thrombocytopenia.2 Monitor CBC and adjust the dosage as recommended by the manufacturer based on adverse reactions.2 If myelosuppression develops, provide appropriate supportive care, including the administration of hematopoietic growth factor.2
Increased Early Mortality with Oral Azacitidine in Patients with MDS
In a clinical study of 216 patients with MDS-related transfusion-dependent anemia or thrombocytopenia who were randomized to oral azacitidine or placebo, study enrollment was prematurely discontinued due to an increased incidence of early fatal and/or serious adverse events in patients who received oral azacitidine compared to placebo therapy.2 The 107 patients who received oral azaciditine received a median of 5 cycles of oral azacitidine 300 mg daily for 21 days of a 28-day cycle.2 Sepsis was the most commonly occurring fatal reaction.2 Safety and efficacy of oral azacitidine for the treatment of MDS have not been established.2 Use of oral azacitidine for MDS is not supported outside of enrollment into clinical trials.2
Hepatotoxicity in Patients with Severe Pre-Existing Hepatic Impairment
Because azacitidine has potential to be hepatotoxic in patients with severe pre-existing hepatic impairment, the manufacturer of injectable azacitidine states that caution is advised in patients with liver disease.1 Progressive hepatic coma and death have been reported rarely during azacitidine therapy in patients with extensive tumor burden due to metastatic disease, particularly in those with baseline serum albumin concentrations less than 3 g/dL.1 The use of injectable azacitidine is contraindicated in patients with advanced malignant hepatic tumors.1
The manufacturer of injectable azacitidine states that liver function tests should be performed prior to initiation of azacitidine and with each cycle of therapy.1
The safety and efficacy of injectable azacitidine have not been evaluated in adult patients with MDS or pediatric patients with JMML and concomitant hepatic impairment, as these patients were excluded from clinical studies.1
Renal abnormalities (e.g., elevated serum creatinine concentrations, renal tubular acidosis), renal failure, and death have been reported rarely in patients treated with IV azacitidine in combination with other antineoplastic agents (e.g., etoposide) for conditions other than myelodysplastic syndrome (e.g., chronic myelogenous leukemia).1
The manufacturer of injectable azacitidine states that serum creatinine concentration and electrolytes should be determined prior to initiation of azacitidine therapy and with each cycle.1 If unexplained reductions in serum bicarbonate concentrations to less than 20 mEq/L or elevations of BUN or serum creatinine concentrations occur, the dosage should be reduced or therapy with the drug withheld.1
Because azacitidine and its metabolites primarily undergo renal excretion, there is a potential for an increased risk of toxicity in patients with renal impairment and close monitoring is recommended with use of injectable azacitidine.1 Use of injectable azacitidine has not been studied in adult patients with MDS or pediatric patients with JMML and concomitant renal impairment.1
Despite the use of concomitant allopurinol, serious or fatal tumor lysis syndrome has occurred in patients receiving azacitidine therapy, including those with MDS.1 The manufacturer of injectable azacitidine states that patients should be assessed for baseline risk of tumor lysis syndrome and should be monitored and treated appropriately.1
Fetal/Neonatal Morbidity and Mortality
Based on animal data and its mechanism of action, may cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1, 2
Verify pregnancy status in females of reproductive potential prior to initiating azacitidine therapy and inform pregnant women of the potential fetal risk with azacitidine.1, 2 Advise females of reproductive potential to use effective contraceptives during azacitidine therapy, and for 6 months following the final dose.1, 2 Advise males with female partners of reproductive potential to use effective contraceptives during treatment, and for 3 months following the final dose.1, 2
Based on animal data and its mechanism of action, azacitidine may cause fetal harm.1, 2 No data are available on its use in pregnancy to evaluate for a drug-associated fetal risk.1, 2 Teratogenicity and embryolethality have been demonstrated in animals at doses lower than the recommended dosage in humans.1, 2 Verify pregnancy status in females of reproductive potential prior to initiating azacitidine and inform pregnant women of the potential fetal risk with azacitidine.1, 2
It is not known whether azacitidine or its metabolites are distributed into human milk.1, 2 The effects of azacitidine on the breast-fed infant and the effect on milk production are not known.1, 2 Because of the potential for serious adverse reactions to azacitidine in nursing infants, advise patients to discontinue breast-feeding during therapy with azacitidine, and for 1 week following the final dose.1, 2
Females and Males of Reproductive Potential
Azacitidine may result in fetal harm if administered during pregnancy.1, 2 Azacitidine may also impair fertility in females and males.1, 2
Confirm pregnancy status prior to initiation of therapy.1, 2 Advise females of reproductive potential to use effective contraceptives during azacitidine therapy, and for 6 months following the final dose.1, 2 Advise males with female partners of reproductive potential to use effective contraceptives during treatment, and for 3 months following the final dose.1, 2
Safety and efficacy of injectable azaciditine are established in pediatric patients 1 month of age and older with JMML.1 Safety and efficacy of injectable azacitidine in pediatric patients with JMML younger than 1 month of age have not been established.1
Safety and efficacy of injectable azacitidine have not been established in pediatric patients with MDS.1
Safety and efficacy of oral azacitidine are not established in pediatric patients.2
When the total number of patients studied in the Cancer and Leukemia Group B (CALGB) clinical trials of injectable azacitidine is considered, 62% were 65 years of age or older, while 21% were 75 years of age and older; in the AZA-001 clinical trial, 68% were 65 years of age or older, while 21% were 75 years of age and older.1 No overall differences in efficacy or safety were observed between geriatric and younger patients.1 In AZA-001, survival data for geriatric patients were consistent with overall survival results.5
In the QUAZAR clinical trial of oral azacitidine in 238 adult patients with AML, 72% of patients were 65 years of age and older and 12% were 75 years of age and older; no differences in safety in efficacy were observed in these patients compared to younger adults.2
The manufacturer of injectable azacitidine states that azacitidine and its metabolites are known to be substantially excreted by the kidneys, and the risk of azacitidine-induced toxicity may be increased in patients with impaired renal function.1 Because geriatric patients may have decreased renal function, monitor renal function in such patients.1
Manufacturer of injectable azacitidine states that azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment; use with caution in patients with liver disease.1 Safety and efficacy of injectable azacitidine in adult patients with MDS or pediatric patients with JMML who have concomitant hepatic impairment have not been established.1
Mild hepatic impairment (total bilirubin less than or equivalent to the upper limit of normal (ULN) and AST greater than ULN, or total bilirubin 1—1.5 times ULN and any AST) does not have a clinically important effect on the pharmacokinetics of oral azacitidine.2 The effects of moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN and any AST) on the pharmacokinetics of oral azacitidine are not known.2
Azacitidine and its metabolites are excreted principally in urine following IV or subcutaneous injection; patients with renal impairment should be closely monitored for toxicity.1 Safety and efficacy of injectable azacitidine in patients with MDS or pediatric patients with JMML who have concomitant renal impairment have not been established.1
The pharmacokinetics of subcutaneous azaciditine were evaluated in adult patients with cancer with severe renal impairment (creatinine clearance less than 30 mL/minute) and normal renal function (creatinine clearance greater than 80 mL/minute) at a once daily dosage of 75 mg/m2 for 5 days.1 Following single and multiple (daily for 5 days) dose subcutaneous administrations of azacitidine in patients with severe renal impairment, exposure was increased by approximately 70% and 41%, respectively.1, 2 This increased azaciditine exposure was not associated with an increase in adverse effects, and was shown to be similar to exposures in adult patients with normal renal function receiving a daily dosage of 100 mg/m2.1
No clinically meaningful differences in the pharmacokinetics of oral azacitidine have been detected in patients with mild to moderate renal impairment (creatinine clearance 30—89 mL/minute).2 The effects of severe renal impairment (creatinine clearance 15 to 29 mL/min) on the pharmacokinetics of oral azacitidine are unknown.2
Adverse effects occurring in greater than 30% of patients with MDS receiving azacitidine by subcutaneous injection include nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, and ecchymosis.1 In patients with MDS receiving the drug IV, the most common adverse effects also include petechiae, rigors, weakness, and hypokalemia.1
Adverse effects occurring in greater than 30% of pediatric patients with JMML receiving azacitidine by IV infusion include pyrexia, rash, upper respiratory infection, and anemia.1
Adverse effects occuring in 10% or greater of adult patients with acute myeloid leukemia receiving oral azacitidine include nausea, vomiting, diarrhea, fatigue or asthenia, constipation, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, and pain in the extremities.2
No formal drug interaction studies with injectable azacitidine have been performed to date.1 In vitro studies indicate that at clinically relevant concentrations, azacitidine does not inhibit cytochrome P450 (CYP) isoenzyme 1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1, and does not induce CYP1A2, CYP2C19, or CYP3A.2 Azacitidine is neither an inhibitor of, nor a substrate for P-glycoprotein (P-gp), and at clinically relevant concentrations, is not an inhibitor of breast cancer resistance protein (BCRP), organic anion transporters (OAT) 1 and OAT3, organic anion transporter polypeptides (OATP) 1B1 and OATP1B3, or organic cation transporter (OCT) 2.2
Concomitant administration of oral azacitidine with the proton pump inhibitor omeprazole increased the exposure of azacitidine by 19%, and had no effect on peak plasma concentrations.2
Azacitidine, a synthetic pyrimidine nucleoside analog of cytidine, is an antineoplastic agent.1, 2 Following cellular uptake and bioenzymatic transformation to nucleotide triphosphates, azacitidine is incorporated into DNA and RNA.2 The drug appears to exert its antineoplastic effect by inhibiting DNA methyltransferase (the enzyme responsible for methylating newly synthesized DNA in mammalian cells), thereby causing hypomethylation of DNA, and by direct cytotoxic effect on abnormal hematopoietic cells in the bone marrow.1, 2 Azacitidine also decreases RNA stability and protein synthesis.2 The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not appear to cause major suppression of DNA synthesis.1 Hypomethylation may restore normal function to genes that are critical for cellular differentiation and proliferation.1 The cytotoxic effects of azacitidine may cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms.1 Nonproliferating cells, however, are relatively insensitive to azacitidine.1 In vitro, the antileukemic activity of azaciditine was demonstrated by the induction of acute myeloid leukemia (AML) cell line apoptosis and reduced cell viability.2 During the first treatment cycle in pediatric patients with juvenile myelomonocytic leukemia (JMML), reduced global DNA methylation scores were observed in bone marrow granulocytes after treatment with azacitidine.1 Global DNA methylation was reduced to a greater extent with higher azaciditine plasma exposures in adult patients with AML who received oral azacitidine for 14 days out of a 28-day cycle.2
Azaciditine is rapidly absorbed following subcutaneous administration, and peak plasma concentrations are achieved 30 minutes after administration.1 Based on the area under the serum concentration time-curve (AUC), approximately 89% of subcutaneous azacitidine is bioavailable relative to azacitidine administered intravenously.1 In adult patients with cancer, AUC and peak plasma concentrations of subcutaneous azacitidine are approximately dose proportional over the dosage range of 25—100 mg/m2.1 Administration of multiple IV or subcutaneous doses at the recommended dosage does not result in accumulation of the drug.1 Systemic exposure of oral azacitidine is approximately dose proportional over the dosage range of 120—600 mg once daily (0.4 to 2 times the recommended dosage).2 Following repeated administration of oral azacitidine at a dosage of 300 mg once daily, accumulation of the drug does not occur.2 Relative to subcutaneous administration, the mean oral biovailability of azacitidine is 11%.2 Following oral administration of azacitidine, peak plasma concentrations are attained in a median of 1 hour.2 Administration of oral azacitidine with a high-fat, high calorie meal (approximately 800—1000 Kcal, 50% from fat), does not affect the total systemic exposure of azacitidine, but reduces peak plasma concentrations by 21%.2 Azacitidine is not metabolized by cytochrome P450 (CYP) isoenzymes;1 azacitidine undergoes spontaneous hydrolysis and deamination by cytidine deaminase.1, 2 Azaciditine and its metabolites primarily undergo elimination via urinary excretion.1 Following IV administration of a radiolabeled dose of azacitidine, cumulative excretion in the urine was 85% of the radiolabeled dose; less than 1% of the radiolabeled dose was recovered in the feces over a 3-day period.1 Following subcutaneous administration of radiolabeled azacitidine, the mean urinary excretion of radioactivity was 50%.1 Based on total radioactivity after intravenous and subcutaneous administration, the mean elimination half-lives of azacitidine (and its metabolites) between routes were similar, and were approximately 4 hours.1 The mean elimination half-life of oral azacitidine is approximately 30 minutes.2 After administration of oral azacitidine at the recommended dosage of 300 mg once daily, less than 2% of the dose is recovered in the urine as unchanged drug.2 Based on population pharmacokinetic analysis, following IV administration of either a 75 mg/m2 or 2.5 mg/kg dose of injectable azacitidine in pediatric patients with JMML, the mean geometric half-life of azaciditine is 0.3 hours.1 Based on a population pharmacokinetic analysis of adult and pediatric patients, no clinically meaningful differences were detected in the pharmacokinetics of IV azacitidine based on sex or tumor type (myelodysplastic syndrome [MDS], JMML, AML).1 Increased clearance of injectable azaciditine in adult and pediatric patients was associated with an increased baseline body weight ranging from 4.6—102 kg; however, dosing based on body surface area (BSA) or body weight resulted in consistent plasma concentrations in pediatric patients with JMML across body weights from 4.6—18.5 kg and ages of 0.2—6.9 years.1 The pharmacokinetics of injectable azaciditine have not been evaluated based on hepatic impairment, race/ethnicity, or gender.1 Following single and multiple dose subcutaneous administrations of azacitidine in patients with severe renal impairment, exposure was increased by approximately 70% and 41%, respectively.1, 2 No clinically meaningful differences in the pharmacokinetics of oral azacitidine have been detected based on age (46—93 years), sex, body weight (39.3—129 kg), mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal (ULN), or total bilirubin 1—1.5 times ULN with any AST level) , and mild to moderate renal impairment (creatinine clearance 30—89 mL/minute).2 The effects of race/ethnicity, moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN and any AST) or severe renal impairment (creatinine clearance 15—29 mL/minute) on the pharmacokinetics of oral azacitidine are not known.2
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 200 mg | Onureg® | Bristol Myers Squibb |
300 mg | Onureg® | Bristol Myers Squibb | ||
Parenteral | For injection, for IV or subcutaneous use | 100 mg* | Azacitidine injection | |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
1. Celgene Corporation. Vidaza® (azacitidine for injection) prescribing information. Summit, NJ; 2024 Jan. [Web]
2. Bristol Myers Squibb. Onureg® (azacitidine for oral use) prescribing information. Princeton, NJ; 2022 Oct. [Web]
3. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol . 2002;20(10):2429-2440.
4. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2024 May 16. [Web]
5. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol . 2009;10(3):223-232.\
6. US Food and Drug Administration Center for Drug Evaluation and Research. Azacitidine medical officer's review. 2004 May 19. From FDA website. [Web]
7. Niemeyer CM, Flotho C, Lipka DB, et al. Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial. Blood Adv . 2021;5(14):2901-2908.
8. Wei AH, Döhner H, Pocock C, et al. Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med . 2020;383(26):2526-2537.
9. Fenaux P, Haase D, Santini V, et al. Myelodysplastic syndromes: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol . 2021;32(2):142-156.
10. Wei AH, Döhner H, Sayar H, et al. Long-term survival with oral azacitidine for patients with acute myeloid leukemia in first remission after chemotherapy: Updated results from the randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial. Am J Hematol . 2023;98(4):E84-E87.
11. National Cancer Institute. Acute Myeloid Leukemia Treatment (PDQ®)-Health Professional Version. From NIH website. Accessed 2024, Jun 5, [Web]
12. Sekeres MA, Guyatt G, Abel G, et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv . 2020 11;4(15):3528-3549.
10001. Silverman L, McKenzie D, Peterson B et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol . 2006; 24: 3895-3903. [PubMed 16921040]
10002. Sudan N, Rossetti J, Shadduck R et al. Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer . 2006; 107:1839-43. [PubMed 16967444]
10003. Kaminskas E, Farrell A, Abraham S et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res . 2005; 11: 3604-3608. [PubMed 15897554]
10004. Fenaux P, Mutfi G, Santini V et al. Azacitidine treatment prolongs overall survival in higher-risk MDS patients compared with conventional care regimens: Results of the AZA-001 Phase III study. Blood . 2007; 110: Abstract No. 817.
10005. List AF, Fenaux P, Mutfi GJ et al. Effect of azacitidine (AZA) on overall survival in higher-risk myelodysplastic syndromes (MDS) without complete remission. J Clin Oncol . 2008; 26: Abstract No. 7006.
10006. Mufti GJ, Fenaux P, Hellstrom-Lindberg E. et al. Treatment of high-risk MDS patients (pts) with -7/del(7q) with azacitidine (AZA) versus conventional care regimens (CCR): effects on overall survival. J Clin Oncol . 2008; 26: Abstract No. 7033.
10007. Fabre C, Gardin G, Mbida R et al. Treatment of AML with Azacytidine (AZA): Current results of the French ATU program. Blood . 2007; 110 (11): Abstract No. 1849.
10008. Al-Ali H, Schwind S, Becket C et al. 5-Azacitidine induces hematologic responses in a high proportion of patients with acute myeloid leukemia refractory to or not eligible for intensive chemotherapy. Blood . 2006; 108: Abstract No. 1953
10009. Goldberg S, Hsu J, Orr A et al. 5-Azacitidine therapy in elderly patients with acute myelogenous leukemia yields similar survival compared to 3+ 7 induction chemotherapy with less transfusional support, bacteremias and hospital days. Blood . 2006; 108: Abstract No. 4569.
10010. Jain N, Mattiuzzi G, Cortes J et al. Benefit of anti-infectious prophylaxis in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome receiving frontline targeted therapy. Blood . 2007; 110: Abstract No. 2858.
10011. AHFS drug information off-label use determinations. McEvoy GK, ed. Azacitidine. Bethesda, MD: American Society of Health-System Pharmacists; 2008 Apr. From AHFS drug information website. [Web]