Skip to Content

AzaCITIDine

Medically reviewed by Drugs.com. Last updated on Aug 18, 2020.

Pronunciation

(ay za SYE ti deen)

Index Terms

  • 5-Azacytidine
  • 5-AZC
  • AZA-CR
  • Azacytidine
  • Ladakamycin
  • Onureg

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension Reconstituted, Injection:

Generic: 100 mg (1 ea)

Suspension Reconstituted, Injection [preservative free]:

Vidaza: 100 mg (1 ea)

Generic: 100 mg (1 ea)

Tablet, Oral:

Onureg: 200 mg, 300 mg

Brand Names: U.S.

  • Onureg
  • Vidaza

Pharmacologic Category

  • Antineoplastic Agent, Antimetabolite
  • Antineoplastic Agent, DNA Methylation Inhibitor

Pharmacology

Azacitidine (a hypomethylating agent) is a pyrimidine nucleoside analog of cytidine that inhibits DNA/RNA methyltransferases; it is incorporated into DNA and RNA and inhibits DNA and RNA methyltransferases, reduces DNA and RNA methylation, alters DNA gene expression (including re-expression of genes that regulate tumor suppression and cell differentiation), and decreases RNA stability and decreases protein synthesis.

Absorption

SubQ: Rapid and complete

Distribution

Vd: IV: 76 ± 26 L; does not cross blood-brain barrier; Oral: Vz/F: 881 L.

Metabolism

Hepatic; spontaneous hydrolysis and deamination (mediated by cytidine deaminase) to several metabolites.

Excretion

IV, SubQ: Urine (50% to 85%); feces (<1%); Oral: Urine (<2% as unchanged drug).

Time to Peak

SubQ: 30 minutes; Oral: 1 hour.

Half-Life Elimination

IV, SubQ: ~4 hours; Oral: ~0.5 hours.

Protein Binding

Oral: 6% to 12%.

Special Populations: Renal Function Impairment

The AUC was increased by ~70% after a single SubQ dose and by 41% after multiple SubQ doses in patients with severe renal impairment (CrCl <30 mL/minute) compared to patients with normal renal function. This increase in exposure did not correlate with increased adverse effects.

Use: Labeled Indications

Acute myeloid leukemia (tablet): Treatment (maintenance) of acute myeloid leukemia in adults who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.

Myelodysplastic syndromes (injection): Treatment of myelodysplastic syndromes (MDS) in patients with the following French-American-British (FAB) classification subtypes: 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.

Off Label Uses

Acute myeloid leukemia in patients requiring low-intensity therapy (injection)

Data from a phase 3 randomized trial support the use of azacitidine in the management of patients requiring low-intensity therapy for acute myeloid leukemia (AML) [Fenaux 2010]. Data from a phase 3 study support the use of azacitidine (in combination with venetoclax) for previously untreated AML in patients ≥75 years of age and/or with comorbidities who are ineligible for standard induction therapy [DiNardo 2020].

Contraindications

Hypersensitivity to azacitidine or any component of the formulation; hypersensitivity to mannitol (injection only); advanced malignant hepatic tumors (injection only).

Dosing: Adult

Note: Azacitidine is associated with a moderate emetic potential (ASCO [Hesketh 2020; MASCC/ESMO [Roila 2016]); antiemetics are recommended to prevent nausea and vomiting. Do not substitute azacitidine tablets for azacitidine injection (or vice versa); indications and dosing regimens are different.

Acute myeloid leukemia (tablet): Oral: 300 mg once daily on days 1 to 14 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity. If ANC is <500/mm3 prior to the start of a cycle, delay the treatment cycle until ANC is ≥500/mm3.

Antiemetic prophylaxis: During the first 2 oral azacitidine cycles, administer an antiemetic 30 minutes prior to each dose; antiemetic prophylaxis may be omitted after 2 cycles if there has been no nausea and vomiting.

Missed dose: If an oral azacitidine dose is missed or not administered at the usual time, administer the dose as soon as possible on the same day and resume the normal schedule the following day; do not administer 2 doses on the same day. If the oral azacitidine dose is vomited, do not administer another dose on the same day; resume the normal schedule the following day.

Acute myeloid leukemia in patients requiring low-intensity therapy (injection; off-label use):

IV, SubQ: Adults ≥75 years of age and/or with comorbidities: 75 mg/m2/day on days 1 to 7 of a 28-day treatment cycle (in combination with venetoclax); continue until disease progression or unacceptable toxicity (DiNardo 2020).

SubQ: 75 mg/m2/day for 7 days of a 28-day treatment cycle for at least 6 cycles; treatment may be continued as long as patient continues to benefit or until disease progression or unacceptable toxicity (Fenaux 2010). Dose reductions and/or therapy interruption may be required for hematologic toxicity; refer to protocol for details.

Myelodysplastic syndromes (injection): IV, SubQ: Initial cycle: 75 mg/m2/day for 7 days of a 28-day treatment cycle. Subsequent cycles: 75 mg/m2/day for 7 days every 4 weeks; dose may be increased to 100 mg/m2/day if no benefit is observed after 2 cycles and no toxicity other than nausea and vomiting have occurred. Patients should be treated for a minimum of 4 to 6 cycles; treatment may be continued as long as patient continues to benefit.

Dosage adjustment based on serum electrolytes: If serum bicarbonate falls to <20 mEq/L (unexplained decrease): Reduce dose by 50% for next treatment course.

Note: Alternate (off-label) schedules (which have produced hematologic response) have been used for convenience in community oncology centers (Lyons 2009): SubQ:

75 mg/m2/day for 5 days (Monday to Friday), 2 days rest (Saturday, Sunday), then 75 mg/m2/day for 2 days (Monday, Tuesday); repeat cycle every 28 days or

50 mg/m2/day for 5 days (Monday to Friday), 2 days rest (Saturday, Sunday), then 50 mg/m2/day for 5 days (Monday to Friday); repeat cycle every 28 days or

75 mg/m2/day for 5 days (Monday to Friday), repeat cycle every 28 days.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing. Due to the potential for decreased renal function in the elderly, select dose carefully and closely monitor renal function.

Dosing: Pediatric

Note: Dosing and frequency may vary by protocol and/or treatment phase; refer to specific protocol.

Acute myeloid leukemia (AML): Limited data available; efficacy results variable:

SubQ: Children ≥2 years and Adolescents: 75 mg/m2/dose once daily for 7 days; dosing from a patient population (n=53) that included adults up to 84 years; the minimum age of subjects in the trial was 5 years, although minimum inclusion criteria was 2 years; used in combination with tretinoin and valproic acid for refractory or relapsed cases with clinical activity observed (Soriano 2007)

IV: Dosing regimens variable: Children and Adolescents: 300 mg/m2/dose once daily for 2 consecutive days has been used for induction and intensive consolidation therapy in various combinations in newly diagnosed patients (Ravindranath 2005; Ribiero 2005). Note: Frequency of use of azacitidine therapy for AML (newly diagnosed) has decreased as newer therapies have replaced previous protocols.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing adjustment for toxicity: The presented dosing adjustments are based on experience in adult patients. Refer to specific protocol for management in pediatric patients if available.

Hematologic toxicity:

Adult:

For baseline WBC ≥3,000/mm3, ANC ≥1,500/mm3, and platelets ≥75,000/mm3:

Nadir count: ANC <500/mm3 or platelets <25,000/mm3: Administer 50% of dose during next treatment course

Nadir count: ANC 500/mm3 to 1,500/mm3 or platelets 25,000 to 50,000/mm3: Administer 67% of dose during next treatment course

Nadir count: ANC >1,500/mm3 or platelets >50,000/mm3: Administer 100% of dose during next treatment course

For baseline WBC <3,000/mm3, ANC <1,500/mm3, or platelets <75,000/mm3 : Adjust dose as follows based on nadir counts and bone marrow biopsy cellularity at the time of nadir, unless clear improvement in differentiation at the time of the next cycle:

WBC or platelet nadir decreased 50% to 75% from baseline and bone marrow biopsy cellularity at time of nadir 30% to 60%: Administer 100% of dose during next treatment course

WBC or platelet nadir decreased 50% to 75% from baseline and bone marrow biopsy cellularity at time of nadir 15% to 30%: Administer 50% of dose during next treatment course

WBC or platelet nadir decreased 50% to 75% from baseline and bone marrow biopsy cellularity at time of nadir <15%: Administer 33% of dose during next treatment course

WBC or platelet nadir decreased >75% from baseline and bone marrow biopsy cellularity at time of nadir 30% to 60%: Administer 75% of dose during next treatment course

WBC or platelet nadir decreased >75% from baseline and bone marrow biopsy cellularity at time of nadir 15% to 30%: Administer 50% of dose during next treatment course

WBC or platelet nadir decreased >75% from baseline and bone marrow biopsy cellularity at time of nadir <15%: Administer 33% of dose during next treatment course

Note: If a nadir defined above occurs, administer the next treatment course 28 days after the start of the preceding course as long as WBC and platelet counts are >25% above the nadir and rising. If a >25% increase above the nadir is not seen by day 28, reassess counts every 7 days. If a 25% increase is not seen by day 42, administer 50% of the scheduled dose.

Electrolyte disturbances: Adult: If serum bicarbonate falls to <20 mEq/L (unexplained decrease): Reduce dose by 50% for next treatment course

Dosing: Adjustment for Toxicity

Azacitidine injection:

Hematologic toxicity: Myelodysplastic syndromes:

For baseline WBC ≥3,000/mm3, ANC ≥1,500/mm3, and platelets ≥75,000/mm3:

Nadir count: ANC <500/mm3 or platelets <25,000/mm3: Administer 50% of dose during next treatment course.

Nadir count: ANC 500/mm3 to 1,500/mm3 or platelets 25,000 to 50,000/mm3: Administer 67% of dose during next treatment course.

Nadir count: ANC >1,500/mm3 or platelets >50,000/mm3: Administer 100% of dose during next treatment course.

For baseline WBC <3,000/mm3, ANC <1,500/mm3, or platelets <75,000/mm3: Adjust dose as follows based on nadir counts and bone marrow biopsy cellularity at the time of nadir, unless clear improvement in differentiation at the time of the next cycle:

WBC or platelet nadir decreased 50% to 75% from baseline and bone marrow biopsy cellularity at time of nadir 30% to 60%: Administer 100% of dose during next treatment course.

WBC or platelet nadir decreased 50% to 75% from baseline and bone marrow biopsy cellularity at time of nadir 15% to 30%: Administer 50% of dose during next treatment course.

WBC or platelet nadir decreased 50% to 75% from baseline and bone marrow biopsy cellularity at time of nadir <15%: Administer 33% of dose during next treatment course.

WBC or platelet nadir decreased >75% from baseline and bone marrow biopsy cellularity at time of nadir 30% to 60%: Administer 75% of dose during next treatment course.

WBC or platelet nadir decreased >75% from baseline and bone marrow biopsy cellularity at time of nadir 15% to 30%: Administer 50% of dose during next treatment course.

WBC or platelet nadir decreased >75% from baseline and bone marrow biopsy cellularity at time of nadir <15%: Administer 33% of dose during next treatment course.

Note: If a nadir defined above occurs, administer the next treatment course 28 days after the start of the preceding course as long as WBC and platelet counts are >25% above the nadir and rising. If a >25% increase above the nadir is not seen by day 28, reassess counts every 7 days. If a 25% increase is not seen by day 42, administer 50% of the scheduled dose.

Azacitidine tablets:

Recommended Azacitidine Tablet Dosage Modifications

Adverse reaction

Severity

Recommended azacitidine dosage modification

Hematologic toxicity

Neutrophils <500/mm3 on day 1 of cycle

Interrupt azacitidine treatment; resume at the same dose after neutrophils return to ≥500/mm3.

Neutrophils <1,000/mm3 with fever at any time

First occurrence: Interrupt azacitidine treatment; resume at the same dose after neutrophils return to ≥1,000/mm3.

Occurrence on 2 consecutive cycles: Interrupt azacitidine treatment; resume at a reduced dose of 200 mg after neutrophils return to ≥1,000/mm3. If a patient continues to experience neutropenic fever following dose reduction, reduce the treatment duration by 7 days. If neutropenic fever recurs after dose and schedule reduction, discontinue oral azacitidine

Platelets <50,000/mm3 with bleeding

First occurrence: Interrupt azacitidine treatment; resume at the same dose after platelets return to ≥50,000/mm3.

Occurrence on 2 consecutive cycles: Interrupt azacitidine treatment; resume at a reduced dose of 200 mg after platelets return to ≥50,000/mm3. If thrombocytopenia with bleeding continues following dose reduction, reduce the treatment duration by 7 days. If thrombocytopenia with bleeding recurs after dose and schedule reduction, discontinue oral azacitidine.

GI toxicity

Grade 3 or 4 nausea and vomiting

Interrupt azacitidine treatment; once toxicity has resolved to ≤ grade 1, resume azacitidine at the same dose. If toxicity recurs, interrupt azacitidine treatment until resolved to ≤ grade 1 and resume azacitidine at reduced dose of 200 mg. If nausea/vomiting continue after dose reduction, reduce the treatment duration by 7 days. If nausea/vomiting continue or recur after dose and schedule reduction, discontinue oral azacitidine.

Grade 3 or 4 diarrhea

Interrupt azacitidine treatment; once toxicity has resolved to ≤ grade 1, resume azacitidine at the same dose. If toxicity recurs, interrupt azacitidine treatment until resolved to ≤ grade 1 and resume azacitidine at reduced dose of 200 mg. If diarrhea continues after dose reduction, reduce the treatment duration by 7 days. If diarrhea continues or recurs after dose and schedule reduction, discontinue oral azacitidine.

Other adverse reactions

Grade 3 or 4

Interrupt azacitidine treatment and provide supportive care; once toxicity has resolved to ≤ grade 1, resume azacitidine at the same dose. If toxicity recurs, interrupt azacitidine treatment until resolved to ≤ grade 1 and resume azacitidine at reduced dose of 200 mg. If the toxicity continues after dose reduction, reduce the treatment duration by 7 days. If the toxicity continues or recurs after dose and schedule reduction, discontinue oral azacitidine.

Reconstitution

If reconstituted solution comes in contact with skin, wash immediately and thoroughly with soap and water; if comes in contact with mucous membranes, flush thoroughly with water.

IV: Reconstitute vial with 10 mL SWFI to form a 10 mg/mL solution; vigorously shake or roll vial until solution is dissolved and clear. Mix in 50 to 100 mL of NS or lactated Ringer's injection for infusion.

SubQ: Slowly add 4 mL SWFI to each vial, resulting in a concentration of 25 mg/mL. Vigorously shake or roll vial until a suspension is formed (suspension will be cloudy). The manufacturer recommends dividing doses requiring more than one vial equally into 2 syringes. Do not filter after reconstitution (may remove active drug). Resuspend contents of syringe by vigorously rolling between palms immediately prior to administration.

Discard unused portion (does not contain preservatives); do not save unused portions for later administration.

Administration

Azacitidine is associated with a moderate emetic potential (ASCO [Hesketh 2020; MASCC/ESMO [Roila 2016]); antiemetics are recommended to prevent nausea and vomiting.

Oral: Swallow whole; do not split, crush, or chew tablets. Administer at approximately the same time each day, with or without food. During the first 2 cycles, administer an antiemetic 30 minutes prior to each dose; antiemetic prophylaxis may be omitted after 2 cycles if there has been no nausea and vomiting.

IV: Infuse over 10 to 40 minutes; infusion must be completed within 1 hour of (vial) reconstitution.

SubQ: The manufacturer recommends equally dividing doses requiring more than one vial into 2 syringes and injecting into 2 separate sites. Rotate sites for each injection (thigh, abdomen, or upper arm). Administer subsequent injections at least 1 inch from previous injection sites; do not inject into tender, bruised, red, or hard areas. Allow refrigerated suspensions to come to room temperature (up to 30 minutes) prior to administration. Resuspend by vigorously rolling the syringe between the palms until a cloudy suspension is achieved.

If azacitidine suspension (injection) comes in contact with the skin, immediately wash with soap and water. If it comes into contact with mucous membranes, flush thoroughly with water.

Storage

Vial: Prior to reconstitution, store intact vials at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

IV solution: Solutions for IV administration have very limited stability and must be prepared immediately prior to each dose. Administration must be completed within 1 hour of (vial) reconstitution.

SubQ suspension: Following reconstitution, suspension may be stored at room temperature for up to 1 hour prior to immediate administration (administer within 1 hour of reconstitution). If administration is delayed, refrigerate reconstituted suspension immediately (either in vial or syringe); may be stored for up to 8 hours (if reconstituted with room temperature SWFI) or up to 22 hours (if reconstituted with refrigerated SWFI). After removal from refrigerator, may be allowed up to 30 minutes to reach room temperature prior to immediate administration.

Tablets: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store and dispense in original bottle (with 2 desiccant canisters); keep bottle closed tightly.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Cedazuridine: May increase the serum concentration of Cytidine Deaminase Substrates. Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Inebilizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Chest pain (16%)

Dermatologic: Ecchymoses (31%), erythema of skin (7% to 17%), pruritus (12%), skin rash (10% to 14%)

Gastrointestinal: Abdominal pain (13% to 22%), abdominal tenderness (12%), anorexia (21%), constipation (34% to 50%), decreased appetite (13%), diarrhea (36% to 50%), nausea (48% to 71%), vomiting (27% to 60%)

Hematologic & oncologic: Anemia (25% to 70%; grades 3/4: 4% to 14%), febrile neutropenia (7% to 16%; grades 3/4: 11% to 13%), leukopenia (18% to 48%; grades 3/4: 15%), neutropenia (32% to 74%; grades 3/4: 49% to 61%), petechia (11% to 24%; more common with IV administration), thrombocytopenia (65% to 70%; grades 3/4: 21% to 58%)

Local: Bruising at injection site (5% to 14%), erythema at injection site (35% to 43%), injection site reaction (14% to 29%), pain at injection site (19% to 23%)

Nervous system: Anxiety (5% to 13%), dizziness (11% to 19%), fatigue (≤44%), headache (22%), insomnia (9% to 11%), malaise (11%)

Neuromuscular & skeletal: Arthralgia (14% to 22%), asthenia (≤44%), limb pain (11%), myalgia (16%)

Respiratory: Dyspnea (5% to 29%), nasopharyngitis (15%), pneumonia (8% to 27%), upper respiratory infection (9% to 13%)

Miscellaneous: Fever (30% to 52%)

1% to 10%:

Cardiovascular: Atrial fibrillation (<5%), cardiac failure (<5%), chest wall pain (5%), congestive cardiomyopathy (<5%), hypertension (9%), hypotension (7%), orthostatic hypotension (<5%), septic shock (<5%)

Dermatologic: Cellulitis (<5%), cutaneous nodule (5%), pruritic rash (<5%), pyoderma gangrenosum (<5%), rash at injection site (6%), skin discoloration at injection site (5%), skin sclerosis (<5%), urticaria (6%), xeroderma (5%)

Endocrine & metabolic: Dehydration (<5%), hypokalemia (6%; more common with IV administration), weight loss (4% to 8%)

Gastrointestinal: Cholecystectomy (<5%), cholecystitis (<5%), diverticulitis of the gastrointestinal tract (<5%), dyspepsia (6%), gastrointestinal hemorrhage (<5%), gingival hemorrhage (10%), loose stools (6%), melena (<5%), stomatitis (8%)

Genitourinary: Abscess of rectum and/or peri-rectal area (<5%), hematuria (6%), urinary tract infection (9%)

Hematologic & oncologic: Agranulocytosis (<5%), bone marrow failure (<5%), hematoma (9%), leukemia cutis (<5%), oral hemorrhage (5%), pancytopenia (<5%), postprocedural hemorrhage (6%), splenomegaly (<5%)

Hypersensitivity: Anaphylactic shock (<5%), hypersensitivity reaction (<5%)

Infection: Bacterial infection (<5%), blastomycosis (<5%), limb abscess (<5%), neutropenic sepsis (<5%), sepsis (<5%, including Klebsiella sepsis), staphylococcal bacteremia (<5%), staphylococcal infection (<5%), systemic inflammatory response syndrome (<5%), toxoplasmosis (<5%)

Local: Catheter site hemorrhage (<5%), hematoma at injection site (6%), induration at injection site (5%), injection site granuloma (5%), injection site infection (<5%), itching at injection site (7%), swelling at injection site (5%)

Nervous system: Aggravated bone pain (<5%), cerebral hemorrhage (<5%), flank pain (<5%), intracranial hemorrhage (<5%), lethargy (7% to 8%), myasthenia (<5%), seizure (<5%)

Neuromuscular & skeletal: Neck pain (<5%)

Ophthalmic: Subconjunctival hemorrhage (<5%)

Renal: Renal failure syndrome (<5%)

Respiratory: Hemoptysis (<5%), Klebsiella pneumoniae infection (<5%), pharyngolaryngeal pain (6%), pneumonitis (<5%), pulmonary infiltrates (<5%), respiratory distress (<5%), rhinitis (6%), streptococcal pharyngitis (<5%)

Miscellaneous: Physical health deterioration (<5%)

Frequency not defined:

Hepatic: Hepatic coma

Nervous system: Rigors (more common with IV administration)

Postmarketing:

Dermatologic: Sweet's syndrome

Hematologic & oncologic: Differentiation syndrome, tumor lysis syndrome

Infection: Necrotizing fasciitis

Local: Tissue necrosis at injection site

Respiratory: Interstitial pulmonary disease

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Neutropenia, thrombocytopenia, and anemia commonly occur; neutropenic fever has been reported. Monitor blood counts. Hematologic toxicity may require treatment interruption, dose reduction, and/or discontinuation. If appropriate, consider supportive care with hematopoietic growth factors.

• Hepatotoxicity: May cause hepatotoxicity in patients with preexisting hepatic impairment. Progressive hepatic coma leading to death has been reported in patients with extensive tumor burden due to metastatic disease, especially those with a baseline albumin <30 g/L. Patients with hepatic impairment were excluded from clinical studies for myelodysplastic syndrome (MDS). Use is contraindicated in patients with advanced malignant hepatic tumors. Monitor liver function tests prior to therapy initiation and before each cycle.

• GI toxicity: Azacitidine is associated with a moderate emetic potential (ASCO [Hesketh 2020]; MASCC/ESMO [Roila 2016]; POGO [Dupuis 2011]) antiemetics are recommended to prevent nausea and vomiting.

• Hepatitis B virus reactivation: The American Society of Clinical Oncology hepatitis B screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends hepatitis B virus (HBV) screening with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), total Ig or IgG, and antibody to hepatitis B surface antigen (anti-HBs) prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

• Injection-site reactions: Injection site reactions commonly occurred with SubQ azacitidine administration.

• Nephrotoxicity: Renal toxicities, including serum creatinine elevations, renal tubular acidosis (serum bicarbonate decrease to <20 mEq/L associated with alkaline urine and serum potassium <3 mEq/L), and renal failure (some fatal), have been reported with intravenous azacitidine when used in combination with other chemotherapy agents. Monitor serum creatinine and electrolytes prior to therapy initiation and before each cycle. Withhold or reduce the dose with unexplained decreases in serum bicarbonate <20 mEq/L or if elevations in BUN or serum creatinine occur. Patients with renal impairment may be at increased risk for renal toxicity. Monitor closely for toxicity in patients with severe renal impairment (azacitidine and metabolites are excreted renally).

• Tumor lysis syndrome: May cause serious or fatal tumor lysis syndrome (TLS). TLS has occurred in patients despite receiving antihyperuricemic therapy (eg, allopurinol). Assess TLS risk at baseline and monitor for TLS symptoms; treat accordingly.

Disease-related concerns:

• Myelodysplastic syndromes: In a clinical trial of patients with RBC transfusion-dependent anemia and thrombocytopenia due to MDS, patients were randomized to receive oral azacitidine (300 mg once daily for 21 days every 28 days) versus placebo; patients received oral azacitidine for a median of 5 cycles. Enrollment was discontinued early in the trial due to a higher incidence of early fatal and/or serious adverse reactions in the azacitidine arm; sepsis was the most frequent fatal adverse reaction. Safety and efficacy of oral azacitidine for treatment of MDS have not been established, and treatment of MDS with oral azacitidine outside of a clinical trial is not recommended.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Do not substitute: Do not substitute azacitidine tablets for azacitidine injection (or vice versa); indications and dosages are different. Treatment of patients using IV or SubQ azacitidine at the recommended tablet dosage may result in a fatal adverse reaction; treatment of patients using azacitidine tablets at the doses recommended for IV or SubQ azacitidine may not be effective.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Monitoring Parameters

Monitor LFTs, electrolytes, CBC with differential and platelets prior to each cycle at a minimum and as clinically indicated (injection). For oral azacitidine, monitor blood counts every other week for 2 cycles, then prior to each cycle; increase to every other week for 2 cycles after any myelosuppression-related dose reduction. Monitor renal function (BUN and serum creatinine) at baseline, prior to each cycle, and more frequently if indicated. Hepatitis B virus screening with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), total Ig or IgG, and antibody to hepatitis B surface antigen (anti-HBs) prior to beginning systemic anticancer therapy (ASCO [Hwang 2020]). Also monitor for hematologic response, nausea/vomiting, and for injection-site reactions. Monitor adherence (tablets).

Reproductive Considerations

Evaluate pregnancy status prior to therapy. Females of reproductive potential should use effective contraception during therapy and for at least 6 months after the last azacitidine dose. Males with female partners of reproductive potential should use effective contraception during therapy and for at least 3 months after the last azacitidine dose.

Pregnancy Considerations

Based on its mechanism of action and data from animal reproduction studies, in utero exposure to azacitidine may cause fetal harm. Information related to the use of azacitidine for the treatment of acute myeloid leukemia (AML) in pregnancy is limited (Alrajhi 2019; Mahdi 2018).

The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy (ESMO [Peccatori 2013]). Guidelines are also available for the treatment of AML in pregnancy (BCSH [Ali 2015]). The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). If chemotherapy is indicated, it should not be administered in the first trimester but may begin in the second trimester. There should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation (Ali 2015; ESMO [Peccatori 2013]).

A pregnancy registry is available for all cancers diagnosed during pregnancy at Cooper Health (1-877-635-4499).

Patient Education

What is this drug used for?

Injection:

• It is used to treat a health problem called myelodysplastic syndrome (MDS).

• It may be given to you for other reasons. Talk with the doctor.

Tablets:

• It is used to treat a type of leukemia.

• This drug is not approved to treat myelodysplastic syndrome (MDS). If you have MDS, talk with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

All products:

• Constipation, diarrhea, stomach pain, upset stomach, throwing up, or feeling less hungry

• Feeling dizzy, tired, or weak

Injection:

• Mouth irritation or mouth sores

• Trouble sleeping

• Headache

• Irritation where the shot is given

• Dry skin

• Nose or throat irritation

• Muscle or joint pain

• Anxiety

• Weight loss

Tablet:

• Joint pain

• Pain in arms or legs

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

All products:

• Infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal

• Bleeding like throwing up or coughing up blood; vomit that looks like coffee grounds; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a cause or that get bigger; or bleeding you cannot stop

• Tumor lysis syndrome like fast or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, diarrhea, or not able to eat; or feel sluggish

• Chest pain or pressure

• Shortness of breath

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Injection:

• Liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes

• Kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain

• Low potassium like muscle pain or weakness, muscle cramps, or a heartbeat that does not feel normal

• High or low blood pressure like very bad headache or dizziness, passing out, or change in eyesight

• Necrotizing fasciitis like warm skin with red or purple areas of swelling that spread quickly; ulcers, blisters, black spots on the skin; or any other skin changes.

• Pinpoint red spots on the skin

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.