Azacitidine
Pronouncation: (ay-za-SYE-ti-deen)Class: DNA demethylation agent
Trade Names:
Vidaza
- Powder for injection, lyophilized 100 mg
Pharmacology
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Believed to cause hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in bone marrow.
Pharmacokinetics
Absorption
Rapidly absorbed after subcutaneous administration; C max of 750 ng/mL in 0.5 h. Subcutaneous bioavailability is 89% compared with IV administration.
Distribution
Mean Vd is approximately 76 L.
Elimination
Mean apparent subcutaneous Cl is 167 L/h and mean t ½ is approximately 41 min. After subcutaneous administration, mean urinary excretion is 50%. Mean elimination t ½ is 4 h.
Special Populations
Renal or hepatic function impairment, gender, age, raceEffects 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.
Unlabeled Uses
Refractory acute lymphocytic leukemia, refractory acute myelogenous leukemia.
Contraindications
Advanced malignant hepatic tumors; hypersensitivity to mannitol or azacitidine.
Dosage and Administration
AdultsIV/Subcutaneous Recommended starting dose 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 cycles. Treatment may be continued as long as patient continues to benefit.
Dosage Adjustments Based on Hematologic Laboratory ValuesAdults
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; platelets less than 25 × 10 9 /L, administer 50% of dose in next course.
- ANC 0.5 to 1.5 × 10 9 /L; platelets 25 to 50 × 10 9 /L, administer 67% of dose in next course.
- ANC more than 1.5 × 10 9 /L, 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 more than 25% increase above 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.
Adults
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.
General Advice
Suspension- Reconstitute powder with 4 mL of sterile water for injection. Inject diluent slowly into vial then invert vial 2 to 3 times and gently rotate until a uniform suspension is obtained. Resulting suspension contains 25 mg/mL of azacitidine.
- Draw contents into syringe. Divide doses more than 4 mL equally into 2 syringes.
- Immediately prior to administration resuspend the contents by inverting syringe 2 to 3 times and gently rolling the syringe between the palms for 30 sec.
- Rotate sites for each injection (eg, thigh, abdomen, upper arm). Give new injections at least 1 inch from an old site and never into areas where the site is tender, bruised, red, or hard.
- Reconstitute the appropriate number of azacitidine vials to achieve the desired dose.
- Reconstitute each vial with 10 mL of sterile water for injection. Vigorously shake or roll the vial until all solids are dissolved. The resulting solution will contain azacitidine 10 mg/mL. The solution should be clear.
- Withdraw the required amount of azacitidine solution to deliver the desired dose and inject into a 50 to 100 mL bag of either sodium chloride 0.9% or Ringer's lactate.
- Administer IV solution over a period of 10 to 40 min. Administration must be completed within 1 h of reconstitution.
- The suspension is for subcutaneous administration.
- The solution is for IV administration.
- Azacitidine is incompatible with dextrose 5% solution, Hespan , or solutions containing bicarbonate.
- Discard unused portions of vial. Do not save any unused portions for future use.
- Azacitidine is a cytotoxic drug. Use caution when handling and preparing azacitidine suspension and solution.
Storage/Stability
Store unreconstituted vials at 59° to 86°F.
SuspensionReconstituted 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.
SolutionReconstituted solution for IV administration may be stored at 77°F, but administration must be completed within 1 h of reconstitution.
Drug Interactions
None well documented.
Laboratory Test Interactions
None well documented.
Adverse Reactions
Cardiovascular
Cardiac murmur (10%); tachycardia (9%); hypotension (7%); syncope (6%); atrial fibrillation, cardiac failure, cardio-pulmonary arrest, CHF, congestive cardiomyopathy, orthostatic hypotension (less than 5%).
CNS
Fatigue (36%); headache (22%); dizziness (19%); aggravated fatigue, anxiety, decreased appetite (13%); depression (12%); insomnia, malaise (11%); lethargy (8%); hypoesthesia (5%); confusion, convulsions, intracranial hemorrhage (less than 5%).
Dermatologic
Petechiae (24%); erythema (17%); pallor (16%); skin lesion (15%); rash (14%); pruritus (12%); increased sweating (11%); night sweats (9%); urticaria (6%); dry skin, skin nodule (5%); pruritic rash, pyoderma gangrenosum, skin induration (less than 5%).
EENT
Pharyngitis (20%); epistaxis (16%); nasopharyngitis (15%); rhinorrhea (10%); nasal congestion, postnasal drip (6%); streptococcal pharyngitis (less than 5%).
GI
Nausea (71%); vomiting (54%); diarrhea (36%); constipation (34%); anorexia (21%); abdominal pain (16%); abdominal tenderness (12%); upper abdominal pain (11%); gingival bleeding (10%); oral mucosal petechiae, stomatitis (8%); dyspepsia, hemorrhoids (7%); abdominal distention, loose stools (6%); dysphagia, mouth hemorrhage, tongue ulceration (5%); diverticulitis, GI hemorrhage, melena, perirectal abscess (less than 5%).
Genitourinary
Dysuria, UTI (8%); hematuria, loin pain, renal failure (less than 5%).
Hematologic-Lymphatic
Anemia (70%); thrombocytopenia (66%); leukopenia (48%); neutropenia (32%); febrile neutropenia (16%); lymphadenopathy (10%); hematoma (9%); aggravated anemia, postprocedural hemorrhage (6%); agranulocytosis, bone marrow depression, splenomegaly (less than 5%).
Hepatic
Cholecystectomy, cholecystitis (less than 5%).
Hypersensitivity
Anaphylactic shock, hypersensitivity (less than 5%).
Lab Tests
Hypokalemia (13%).
Local
Injection-site erythema (35%); ecchymosis (31%); injection-site pain (23%); injection-site bruising or reaction (14%); injection-site pruritus (7%); injection-site granuloma, injection-site pigmentation changes, injection-site swelling (5%); catheter-site hemorrhage, injection-site infection (less than 5%).
Metabolic-Nutritional
Decreased weight (16%); dehydration (less than 5%).
Musculoskeletal
Arthralgia (22%); myalgia (16%); muscle cramps (6%); aggravated bone pain, muscle weakness, neck pain (less than 5%).
Respiratory
Cough (30%); dyspnea (29%); exertional dyspnea (14%); upper respiratory tract infection (13%); crackles in lung, pneumonia, productive cough (11%); rales, wheezing (9%); decreased breath sounds (8%); pleural effusion, rhonchi (6%); atelectasis, exacerbated dyspnea, sinusitis (5%); hemoptysis, Klebsiella pneumonia, lung infiltration, pneumonitis, respiratory distress (less than 5%).
Miscellaneous
Pyrexia (52%); weakness (29%); rigors (26%); limb pain (20%); back pain, contusion, peripheral edema (19%); chest pain (16%); pitting edema (15%); pain (11%); herpes simplex (9%); cellulitis (8%); peripheral swelling, transfusion reaction (7%); chest wall pain, postprocedural pain (5%); bacterial infection, blastomycosis, general physical health deterioration, Klebsiella sepsis, leukemia cutis, limb abscess, sepsis, staphylococcal bacteremia, staphylococcal infection, systemic inflammatory response syndrome, toxoplasmosis (less than 5%).
Precautions
MonitorRenal functionEnsure 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. Monitor for hematologic response. |
Pregnancy
Category D .
Lactation
Undetermined.
Children
Safety and efficacy not established.
Elderly
Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.
Renal Function
Monitor for toxicity because azacitidine and its metabolites are primarily excreted by the kidneys.
Hepatic Function
Use with caution.
Hematologic
Neutropenia and thrombocytopenia may occur; monitor CBC.
Renal abnormalities
Elevated serum creatinine, renal failure, and death may occur.
Skin/Mucus membranes
Avoid contact with skin and mucus membranes. If accidental skin contact occurs, wash thoroughly with soap and water. If mucus 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.
Overdosage
Symptoms
Bone marrow suppression, diarrhea, nausea, vomiting.
Patient Information
- 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.
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More Azacitidine resources:
Azacitidine - Includes detailed dosage instructions.
