Class: DNA demethylation agent
- Injection, lyophilized powder 100 mg
Believed to cause hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in bone marrow.
Rapidly absorbed after subcutaneous administration; C max is 750 ng/mL in 0.5 h. Subcutaneous bioavailability is 89% compared with IV administration.
Mean Vd is approximately 76 L.
Mean apparent subcutaneous Cl is 167 L/h and mean half-life is approximately 41 min. After subcutaneous administration, mean urinary excretion is 50%. Mean elimination half-life is 4 h.
Special PopulationsRenal Function Impairment
Effects on pharmacokinetics have not been studied.Hepatic Function Impairment
Effects on pharmacokinetics have not been studied.
Indications and Usage
Treatment of myelodysplastic syndrome 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.
Refractory acute lymphocytic leukemia; refractory acute myelogenous leukemia.
Advanced malignant hepatic tumors; hypersensitivity to mannitol or azacitidine.
Dosage and AdministrationAdults
IV/Subcutaneous Recommended starting dosage is 75 mg/m 2 daily for 7 days, every 4 wk. Premedicate patient for nausea and vomiting. Increase dose to 100 mg/m 2 if no beneficial effect is seen after 2 treatment cycles and if no toxicity other than nausea and vomiting occurs. It is recommended that patients be treated for a minimum of 4 to 6 cycles. Treatment may be continued as long as patient continues to benefit.Dosage Adjustments Based on Hematologic Laboratory Values
IV/Subcutaneous For patients with baseline WBC at least 3 × 10 9 /L, absolute neutrophil count (ANC) at least 1.5 × 10 9 /L, and platelets at least 75 × 10 9 /L at the start of treatment, adjust dose based on nadir counts for any given cycle as follows:
- ANC less than 0.5 × 10 9 /L and platelets less than 25 × 10 9 /L, administer 50% of dose in next course.
- ANC 0.5 to 1.5 × 10 9 /L and platelets 25 to 50 × 10 9 /L, administer 67% of dose in next course.
- ANC more than 1.5 × 10 9 /L and platelets more than 50 × 10 9 /L, administer 100% of dose in next course.
- For patients with baseline WBC less than 3 × 10 9 /L, ANC less than 1.5 × 10 9 /L, or platelets less than 75 × 10 9 /L at the start of treatment, base dose adjustments on nadir counts and bone marrow biopsy cellularity at time of nadir as follows, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of course) at time of next cycle, in which case continue the dose of the current treatment.
- Dosage Adjustments Based on Nadir Counts and Bone Marrow Biopsy Cellularity
- If WBC or platelet nadir percent decrease in counts from baseline is 50% to 75% and bone marrow biopsy cellularity at time of nadir is 30% to 60%, give 100% of dose in next course.
- If WBC or platelet nadir percent decrease in counts from baseline is 50% to 75% and bone marrow biopsy cellularity at time of nadir is 15% to 30%, give 50% of dose in next course.
- If WBC or platelet nadir percent decrease in counts from baseline is 50% to 75% and bone marrow biopsy cellularity at time of nadir is less than 15%, give 33% of dose in next course.
- If WBC or platelet nadir percent decrease in counts from baseline is more than 75% and bone marrow biopsy cellularity at time of nadir is 30% to 60%, give 75% of dose in next course.
- If WBC or platelet nadir percent decrease in counts from baseline is more than 75% and bone marrow biopsy cellularity at time of nadir is 15% to 30%, give 50% of dose in next course.
- If WBC or platelet nadir percent decrease in counts from baseline is more than 75% and bone marrow biopsy cellularity at time of nadir is less than 15%, give 33% of dose in next course.
- If a nadir as previously defined has occurred, give the next course of treatment 28 days after the start of the preceding course provided that both WBC and platelet counts are more than 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, treat the patient with 50% of the scheduled dose.
IV/Subcutaneous If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, reduce dosage by 50% on next course. If unexplained elevations of BUN or serum creatinine occur, delay the next cycle until values return to normal or baseline and reduce dose by 50% on next treatment course.
Azacitidine is a cytotoxic drug. Use caution when handling and preparing azacitidine suspension and solution.
- The solution is for IV administration.
- Azacitidine is compatible with sodium chloride 0.9% or Ringer's lactate.
- Azacitidine is NOT compatible with dextrose 5% solution, HESpan , or solutions containing bicarbonate.
- Discard unused portions of vial. Do not save any unused portions for future use.
Store unreconstituted vials at 59° to 86°F.Suspension
Reconstituted suspension for subcutaneous use may be stored for up to 1 h at 77°F or up to 8 h between 36° and 46°F.Solution
Reconstituted solution for IV administration may be stored at 77°F, but administration must be completed within 1 h of reconstitution.
None well documented.
Laboratory Test Interactions
None well documented.
Hypertension (9%); hypotension (7%); atrial fibrillation, cardiac failure, cardiorespiratory arrest, congestive cardiac failure, congestive cardiomyopathy, orthostatic hypotension (less than 5%).
Fatigue (24%); headache (22%); dizziness (19%); anxiety (13%); insomnia, malaise (11%); lethargy (8%); cerebral hemorrhage, convulsions, intracranial hemorrhage (less than 5%).
Ecchymosis (31%); petechiae (24%); erythema (17%); rash (14%); pruritus (12%); urticaria (6%); dry skin, skin nodule (5%); cellulitis, leukemia cutis, pruritic rash, pyoderma gangrenosum, skin induration (less than 5%).
Nasopharyngitis (15%); pharyngolaryngeal pain, rhinitis (6%); eye hemorrhage, streptococcal pharyngitis (less than 5%).
Nausea (71%); vomiting (54%); constipation (50%); diarrhea (36%); anorexia (21%); abdominal pain (13%); abdominal tenderness (12%); gingival bleeding (10%); stomatitis (8%); dyspepsia, loose stools (6%); mouth hemorrhage (5%); diverticulitis, GI hemorrhage, melena, perirectal abscess (less than 5%).
UTI (9%); hematuria (6%); loin pain, renal failure (less than 5%).
Anemia, thrombocytopenia (70%); neutropenia (66%); leukopenia (48%); febrile neutropenia (16%); hematoma (9%); aggravated anemia, postprocedural hemorrhage (6%); agranulocytosis, bone marrow failure, pancytopenia, splenomegaly (less than 5%).
Cholecystectomy, cholecystitis (less than 5%).
Anaphylactic shock, hypersensitivity (less than 5%).
Injection-site erythema (43%); injection-site reaction (29%); injection-site pain (23%); injection-site bruising (14%); injection-site pruritus (7%); injection-site hematoma, injection-site rash (6%); injection-site granuloma, injection-site induration, injection-site pigmentation changes, injection-site swelling (5%); catheter-site hemorrhage, injection-site infection (less than 5%).
Decreased weight (8%); hypokalemia (6%); dehydration (less than 5%).
Arthralgia (22%); myalgia (16%); aggravated bone pain, muscle weakness, neck pain (less than 5%).
Dyspnea (29%); upper respiratory tract infection (13%); pneumonia (11%); exertional dyspnea (5%); hemoptysis, Klebsiella pneumonia, lung infiltration, pneumonitis, respiratory distress (less than 5%).
Pyrexia (52%); chest pain (16%); chest wall pain (5%); bacterial infection, blastomycosis, cellulitis, general physical health deterioration, Klebsiella sepsis, limb abscess, neutropenic sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, systemic inflammatory response syndrome, toxoplasmosis (less than 5%).
Monitor for hematologic response. Perform CBCs as needed, but at least prior to each cycle, to monitor response and toxicity. Obtain liver function and serum creatinine prior to initiation of therapy.Renal function
Ensure that renal function is evaluated prior to starting therapy and before each cycle. If unexplained elevations in BUN or creatinine occur, delay next cycle until values return to normal or baseline and reduce the dose 50% on the next treatment course.
Category D .
Safety and efficacy not established.
Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.
Monitor for toxicity because azacitidine and its metabolites are primarily excreted by the kidneys.
Use with caution.
Anemia, neutropenia, and thrombocytopenia may occur; monitor CBC.
Elevated serum creatinine, renal failure, and renal tubular acidosis may occur.
Avoid contact with skin and mucous membranes. If accidental skin contact occurs, wash thoroughly with soap and water. If mucous membrane contact occurs, flush thoroughly with water. If eye contact occurs, flush eyes using standard irrigation techniques.
Use in men
Advise men to use effective contraception during treatment.
Bone marrow suppression, diarrhea, nausea, vomiting.
- Advise patient that medication will be prepared and administered by health care provider in a health care setting.
- Review dosing schedule with patient.
- Advise patient to immediately report any of the following to health care provider: difficulty breathing; fever, chills, or other signs of infection; hives; pain, redness, or swelling at injection-site; rash; unusual bleeding or bruising.
- Advise patient to report any of the following to health care provider: persistent nausea, vomiting, or appetite loss; persistent or worsening general body weakness.
- Caution men to use effective contraception during therapy.
- Caution women of childbearing potential to avoid becoming pregnant during therapy.
- Advise patients to inform health care provider about any underlying liver or renal dysfunction.
Copyright © 2009 Wolters Kluwer Health.