azacitidine (Rx)

Brand and Other Names:Vidaza, Onureg
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 100mg/single-dose vial (Vidaza, generic)

tablet

  • 200mg (Onureg)
  • 300mg (Onureg)

Myelodysplastic Syndromes

Vidaza only

Indicated for myelodysplastic syndromes in patients with the following French-American-British (FAB) subtypes: Refractory anemia (RA) or RA with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), chronic myelomonocytic leukemia (CMMoL)

Each cycle is 4 weeks

75 mg/m2 IV or SC qDay for 7 days; repeat cycle every 4 weeks

May increased to 100 mg/m2 if no benefit observed after 2 treatment cycles and if no toxicity other than nausea and vomiting

Treat for minimum of 4-6 cycles

Continue treatment as long as patient continues to benefit

Acute Myeloid Leukemia

Onureg only

Indicated for continued treatment of adults with acute myeloid leukemia who achieved first complete remission (CR) or CR with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy

Each cycle is 28 days

300 mg PO qDay on Days 1-14

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Hematology toxicity (SC or IV)

  • If a nadir defined below occurs, administer 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, reduce scheduled dose by 50%
  • For baseline WBC ≥3 x 10^9/L, ANC ≥1.5 x 10^9/L, and platelets ≥75 x 10^9/L
    • Nadir count: ANC <0.5 x 109/L or platelets <25 x 109/L: Administer 50% of dose during next treatment course
    • Nadir count: ANC 0.5-1.5 x 109/L or platelets 25-50 x 109/L: Administer 67% of dose during next treatment course
    • Nadir count: ANC >1.5 x 109/L or platelets >50 x 109/L: Administer 100% of dose during next treatment course
  • For baseline WBC <3 x 10^9/L, ANC <1.5 x 10^9/L, and platelets <75 x 10^9/L
    • WBC or platelet nadir decreased 50-75% from baseline and bone marrow biopsy cellularity at time of nadir 30-60%: Administer 100% of dose during next treatment course
    • WBC or platelet nadir decreased 50-75% from baseline and bone marrow biopsy cellularity at time of nadir 15-30%: Administer 50% of dose during next course
    • WBC or platelet nadir decreased 50-75% from baseline and bone marrow biopsy cellularity at time of nadir <15%: Administer 33% of dose during next course
    • WBC or platelet nadir decreased >75% from baseline and bone marrow biopsy cellularity at time of nadir 30-60%: Administer 75% of dose during next course
    • WBC or platelet nadir decreased >75% from baseline and bone marrow biopsy cellularity at time of nadir 15-30%: Administer 50% of dose during next 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 course

Dosage modifications based on serum electrolytes and renal toxicity (IV or SC)

  • If unexplained reductions in serum bicarbonate levels <20 mEq/L occur, reduce dose by 50% for next course
  • If unexplained elevations of BUN or serum creatinine occur, delay next cycle until values return to normal or baseline and reduce dose by 50% for next course

Hematology toxicity (PO)

  • Neutrophils <0.5 Gi/L on Day 1 of cycle: Interrupt treatment; resume at same dose once neutrophils ≥0.5 Gi/L
  • Neutrophils <1 Gi/L with fever at any time
    • First occurrence: Interrupt treatment; resume at same dose once neutrophils ≥1 Gi/L
    • Occurrence in 2 consecutive cycles: Interrupt treatment; after neutrophils ≥1 Gi/L, then resume at reduced dose of 200 mg; if febrile neutropenia continues after dose reduction, reduce treatment duration by 7 days; if febrile neutropenia reoccurs after dose and schedule reduction, discontinue treatment
  • Platelets <50 Gi/L with bleeding
    • First occurrence: Interrupt dose; resume at same dose once platelets ≥50 Gi/L
    • Occurrence in 2 consecutive cycles: Interrupt dose; after platelets ≥50 Gi/L, then resume at reduced dose of 200 mg; if thrombocytopenia with bleeding continues after dose reduction, reduce treatment duration by 7 days; if thrombocytopenia with bleeding reoccurs after dose and schedule reduction, discontinue treatment

Gastrointestinal toxicity (PO)

  • Grade 3 or 4 nausea, vomiting, or diarrhea
    • Interrupt dose; resume at same dose once toxicity has resolved to Grade ≤1
    • If toxicity reoccurs, interrupt dose until resolved to Grade ≤1, then resume at reduced dose of 200 mg
    • If toxicity continues after dose reduction, reduce treatment duration by 7 days
    • If toxicity continues or reoccurs after dose and schedule reduction, discontinue treatment

Other adverse reactions (PO)

  • Interrupt dose and provide medical support; resume at same dose once toxicity has resolved to Grade ≤1
  • If toxicity reoccurs, interrupt dose until resolved to Grade ≤1, then resume at reduced dose of 200 mg
  • If toxicity continues after dose reduction, reduce treatment duration by 7 days
  • If toxicity continues or reoccurs after dose and schedule reduction, discontinue treatment

Renal impairment

  • Mild-severe (CrCl 15-89 mL/min): No dosage adjustment necessary
  • Monitor patients with severe renal impairment (CrCl 15-29 mL/min) more frequently and modify dosage for adverse reactions

Hepatic impairment

  • Mild (total bilirubin ≤ULN and AST >ULN, or total bilirubin 1-1.5x ULN and any AST): No dosage adjustment necessary
  • Moderate (total bilirubin >1.5-3x ULN): Recommended dose not established
  • Severe (total bilirubin >3x ULN): Not studied

Dosing Considerations

Do not substitute PO for IV/SC azacitidine

Indications and dosing regimen for PO differ from that of IV/SC azacitidine

Monitoring parameters

  • Verify pregnancy status of females of reproductive potential before initiating treatment
  • PO
    • Monitor CBC every other week for first 2 cycles and before start of each cycle thereafter
    • Increase monitoring to every other week for 2 cycles after any dose reduction for myelosuppression
  • IV or SC
    • Obtain CBC, liver chemistries and serum creatinine before first dose

Safety and efficacy not established

Azacitidine and its metabolites undergo substantial renal excretion; renal impairment may increase risk of toxicity

Select dose carefully and monitor renal function in geriatric patients; owing to increased risk of decreased renal function

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Adverse Effects

>10% (SC or IV)

All grades

  • Nausea (48-71%)
  • Anemia (51-70%)
  • Thrombocytopenia (66-70%)
  • Neutropenia (32-66%)
  • Constipation (34-50%)
  • Vomiting (27-54%)
  • Pyrexia (30-52%)
  • Leukopenia (18-48%)
  • Injection site erythema (35-43%)
  • Diarrhea (36%)
  • Ecchymosis (31%)
  • Dyspnea (29%)
  • Injection site reaction (14-29%)
  • Petechiae (24%)
  • Fatigue (24%)
  • Injection site pain (23%)
  • Arthralgia (22%)
  • Headache (22%)
  • Anorexia (21%)
  • Dizziness (19%)
  • Injection site pain (5-19%)
  • Erythema (17%)
  • Febrile neutropenia (14-16%)
  • Chest pain (16%)
  • Myalgia (16%)
  • Nasopharyngitis (15%)
  • Rash (14%)
  • Injection site bruising (5-14%)
  • Abdominal pain (13%)
  • Upper respiratory tract infection (13%)
  • Anxiety (13%)
  • Abdominal tenderness (12%)
  • Malaise (11%)
  • Pneumonia (11%)
  • Insomnia (11%)

Grade 3-4

  • Anemia (44%)
  • Thrombocytopenia (34%)
  • Neutropenia (28%)
  • Pyrexia (18%)
  • Fatigue (12%)
  • Nausea (12%)

>10% (PO)

All grades

  • Nausea (65%)
  • Vomiting (60%)
  • Diarrhea (50%)
  • Fatigue /asthenia (44%)
  • Constipation (39%)
  • Pneumonia (27%)
  • Abdominal pain (22%)
  • Arthralgia (14%)
  • Decreased appetite (13%)
  • Febrile neutropenia (12%)
  • Pain in extremity (11%)
  • Dizziness (11%)

Grade 3-4

  • Neutropenia (49%)
  • Thrombocytopenia (21%)
  • Febrile neutropenia (11%)

1-10% (SC or IV)

All grades

  • Gingival bleeding (10%)
  • Hematoma (6-9%)
  • Hypertension (9%)
  • Lethargy (8%)
  • Stomatitis (8%)
  • Injection site pruritus (7%)
  • Hypotension (7%)
  • Anemia aggravated (6%)
  • Loose stools (6%)
  • Urticaria (6%)
  • Postprocedural hemorrhage (6%)
  • Dyspepsia (6%)
  • Injection site rash (6%)
  • Injection site swelling (5%)
  • Injection site pigmentation changes (5%)
  • Injection site induration (6%)
  • Skin nodule (5%)
  • Injection site granuloma (5%)
  • Chest wall pain (5%)
  • Dry skin (5%)
  • Mouth hemorrhage (5%)
  • <5%
    • Blood and lymphatic system disorders: Agranulocytosis, bone marrow failure, pancytopenia splenomegaly
    • Cardiac disorders: Atrial fibrillation, cardiac failure, cardiac failure congestive, cardiorespiratory arrest, congestive cardiomyopathy
    • Eye disorders: Eye hemorrhage
    • Gastrointestinal disorders: Diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess
    • General disorders and administration site conditions: Catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome
    • Hepatobiliary disorders: cholecystitis. Immune system disorders: anaphylactic shock, hypersensitivity
    • Infections and infestations: Abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis
    • Metabolism and nutrition disorders: Dehydration
    • Musculoskeletal and connective tissue disorders: Bone pain aggravated, muscle weakness, neck pain
    • Neoplasms benign, malignant and unspecified: Leukemia cutis
    • Nervous system disorders: Cerebral hemorrhage, convulsions, intracranial hemorrhage
    • Renal and urinary disorders: Loin pain, renal failure
    • Respiratory, thoracic and mediastinal disorders: Hemoptysis, lung infiltration, pneumonitis, respiratory distress
    • Skin and subcutaneous tissue disorders: Pyoderma gangrenosum, rash pruritic, skin induration. Surgical and medical procedures: cholecystectomy
    • Vascular disorders: Orthostatic hypotension

Grade 3-4

  • Febrile neutropenia (10%)
  • Constipation (8%)
  • Abdominal pain (7%)
  • Vomiting (7%)
  • Dyspnea (5%)
  • Hypertension (4%)
  • Petechiae (4%)
  • Upper respiratory tract infection (4%)
  • Erythema (3%)
  • Pharyngolaryngeal pain (3%)
  • Insomnia (3%)
  • Hypokalemia (3%)
  • Urinary tract infection (3%)
  • Leukopenia (2%)
  • Dyspepsia (2%)
  • Hematuria (2%)
  • Pruritus (2%)
  • Lethargy (2%)
  • Rash (1%)
  • Dyspnea exertional (1%)
  • Rash (1%)
  • Anxiety (1%)
  • Rhinitis (1%)

1-10% (PO)

Grade 3-4

  • Pneumonia (9%)
  • Diarrhea (5%)
  • Fatigue/asthenia (4%)
  • Anemia (4%)
  • Nausea (3%)
  • Vomiting (3%)
  • Abdominal pain (2%)
  • Constipation (1%)
  • Decreased appetite (1%)
  • Arthralgia (1%)

<1% (PO)

Grade 3-4

  • Pain in extremity (<1%)

Frequency Not Defined

IV or SC

  • Nausea
  • Anemia
  • Thrombocytopenia
  • Vomiting
  • Pyrexia
  • Leukopenia
  • Diarrhea
  • Injection site erythema, constipation
  • Neutropenia
  • Ecchymosis
  • Petechiae
  • Rigors
  • Weakness
  • Hypokalemia
  • Postmarketing Reports H3
  • Interstitial lung disease
  • Tumor lysis syndrome
  • Injection site necrosis
  • Sweet’s syndrome (acute febrile neutrophilic dermatosis)
  • Necrotizing fasciitis
  • Differentiation syndrome
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Warnings

Contraindications

IV or SC

  • Advanced malignant hepatic tumors
  • Hypersensitivity to azacitidine or mannitol

PO

  • Hypersensitivity to azacitidine or its components

Cautions

Do not substitute PO azacitidine for IV or SC azacitidine

May anemia, neutropenia and thrombocytopenia; monitor CBC frequently for response and/or toxicity, at a minimum, before each dosing cycle; provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs

Fetal harm may occur when administered to pregnant females

PO azacitidine

  • Safety and effectiveness for MDS have not been established
  • Not recommended for MDS patients outside of controlled trials

IV or SC azacitidine

  • Fatal or serious tumor lysis syndrome may occur despite concomitant use of allopurinol; assess baseline risk and monitor and treat appropriately
  • Hepatic toxicity
    • Exercise caution in patients with liver disease due to the increase risk of hepatotoxicity in patients with severe pre-existing hepatic impairment
    • Safety and effectiveness in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials
  • Renal toxicity
    • Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported
    • Patients with renal impairment may be at increased risk of renal toxicity; closely monitor if treated
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Pregnancy & Lactation

Pregnancy

Based on its mechanism of actions and animal studies, fetal harm may occur when administered to pregnant females

No data available on use in pregnant females to evaluate for drug-associated risks

Verify pregnancy status of females of reproductive potential before initiating treatment

Animal data

  • Teratogenic and caused embryofetal lethality in animals at doses less than the recommended human dose of azacitidine
  • Advise pregnant females of the potential risk to fetus

Contraception

  • IV or SC
    • Females of reproductive potential: Avoid pregnancy during treatment
    • Males with female sexual partners of reproductive potential: Avoid pregnancy and use effective contraception during treatment
  • PO
    • Females of reproductive potential: Use effective contraception during treatment and for at least 6 months after last dose
    • Males with female sexual partners of reproductive potential: Use effective contraception during treatment and for at least 3 months after last dose

Infertility

  • PO
    • Based on animal data, male and female fertility may be impaired

Lactation

There is no information regarding presence of azacitidine in human milk, effects of therapy on breastfed infant, or effects of therapy on milk production

IV or SC: Advise patients not to breastfeed during therapy

PO: Advise patients not to breastfeed during therapy and for 1 week after last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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Pharmacology

Mechanism of Action

Pyrimidine analog of cytidine that inhibits DNA/RNA methyltransferases

Azacitidine is incorporated into RNA and DNA following cellular uptake and enzymatic biotransformation to nucleotide triphosphates

Hypomethylation of DNA and direct cytotoxic effect on abnormal hematopoietic cells in bone marrow

Absorption

Peak plasma concentration: 750 ng/mL (SC)

Peak plasma time

  • SC: 0.5 hr
  • PO: 1 hr

Bioavailability

  • SC: ~89% relative to IV
  • PO: ~11% relative to SC

Effect of food

  • High-fat, high-calorie meal (~800-1000 calories, 50% fat) with PO azacitidine did not affect AUC and decreased peak plasma concentration by 21%

Distribution

Protein bound: ~6-12% (PO)

Blood-to-plasma ratio: ~0.3 (PO)

Vd

  • IV: 76 L
  • PO: 881 L

Metabolism

Undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase

Elimination

Clearance: 167 L/hr (SC)

Half-life

  • PO: ~0.5 hr
  • SC or IV: 4 hr

Excretion

  • PO: <2% unchanged (urine)
  • IV: 85% (urine); <1% (feces)
  • SC: 50% (urine)
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Administration

IV Incompatibilities

Dextrose 5%

IV Compatibilities

Lactated ringer

0.9% NaCl

IV Preparation

Reconstitute each vial with 10 mL sterile water for injection

Vigorously shake or roll vial until all solids are dissolved; resulting concentration is 10 mg/mL; solution should appear clear

Visually inspect parenteral drug product for particulate matter and discoloration before administration, whenever solution and container permit

Withdraw required amount and inject into a 50 -100 mL infusion bag of either 0.9% NaCl or Lactated Ringer

IV Administration

IV administration only when reconstituted with 10 mL of sterile water

Administer total dose over a period of 10 - 40 min; complete administration within 1 hr of reconstitution

SC Preparation

Reconstitute with 4 mL room temperature sterile water for injection for immediate use and refrigerated sterile water (2-8C, 36-46F) for delayed use; inject diluent slowly into vial

Vigorously shake or roll the vial until a uniform suspension is achieved; suspension will be cloudy; resulting concentration is 25 mg/mL

Do not filter suspension after reconstitution; filtering could remove the active substance

For doses requiring >1 vial, divide dose equally between the syringes (eg, dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe) and inject into 2 separate sites

Due to retention in vial and needle, it may not be feasible to withdraw all of the suspension from vial

SC Administration

SC administration only when reconstituted with 4 mL of sterile water

Resuspend the contents of syringe to provide a homogeneous suspension immediately before administration

To resuspend, vigorously roll syringe between the palms until a uniform, cloudy suspension is achieved

Rotate sites for each injection (thigh, abdomen, or upper arm)

Administer new injections at least 1 inch from an old site and never into areas where the site is tender, bruised, red, or hard

Oral Administration

Hazardous drug; follow applicable special handling and disposal procedure

Do not split, crush, or chew tablets

Take a dose about the same time each day

Do not substitute IV or SC azacitidine

Indications and dosing regimen differ from that of IV or SC azacitidine

Premedication

  • Administer an antiemetic 30 min before each dose for the first 2 cycles
  • Omit antiemetics after 2 cycles if no nausea and vomiting has occurred

Missed dose

  • Take dose as soon as possible on the same day, and resume the normal schedule the following day; do not take 2 doses on the same day

Vomited dose

  • If dose is vomited, do not take another dose on the same day
  • Resume normal schedule the following day

Storage

Cytotoxic drug; follow applicable special handling and disposal procedures

Unused vials

Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)

Reconstituted vial or diluted IV infusion bag

  • Store for up to 1 hr at 25ºC (77ºF)

Reconstituted suspension or prepared SC syringes

  • Reconstituted with non-refrigerated water for injection: Store for up to 1 hr at 25ºC (77ºF) or for up to 8 hr between 2-8ºC (36-46ºF)
  • Reconstituted with refrigerated (2-8ºC, 36-46ºF) water for injection: Store for 22 hr at 2-8ºC (36-46ºF)

Tablets

  • Store bottles at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
  • Keep bottle tightly closed
  • Store and dispense in the original bottle (with 2 desiccant canisters)
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Formulary

FormularyPatient Discounts

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The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

Tier Description
1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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Code Definition
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Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.