Azacitidine

Pronunciation: ay-za-SYE-ti-deen
Class: DNA demethylation agent

Trade Names

Vidaza
- Injection, lyophilized powder 100 mg

Pharmacology

Believed to cause hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in bone marrow.

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Pharmacokinetics

Absorption

Rapidly absorbed after subcutaneous administration; C max is 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 half-life is approximately 41 min. After subcutaneous administration, mean urinary excretion is 50%. Mean elimination half-life is 4 h.

Special Populations

Renal 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.

Unlabeled Uses

Refractory acute lymphocytic leukemia; refractory acute myelogenous leukemia.

Contraindications

Advanced malignant hepatic tumors; hypersensitivity to mannitol or azacitidine.

Dosage and Administration

Adults

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
Adults

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.
Dosage Adjustments Based on Renal Function and Serum Electrolytes
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

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.

Storage/Stability

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.

Drug Interactions

None well documented.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension (9%); hypotension (7%); atrial fibrillation, cardiac failure, cardiorespiratory arrest, congestive cardiac failure, congestive cardiomyopathy, orthostatic hypotension (less than 5%).

CNS

Fatigue (24%); headache (22%); dizziness (19%); anxiety (13%); insomnia, malaise (11%); lethargy (8%); cerebral hemorrhage, convulsions, intracranial hemorrhage (less than 5%).

Dermatologic

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%).

EENT

Nasopharyngitis (15%); pharyngolaryngeal pain, rhinitis (6%); eye hemorrhage, streptococcal pharyngitis (less than 5%).

GI

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%).

Genitourinary

UTI (9%); hematuria (6%); loin pain, renal failure (less than 5%).

Hematologic-Lymphatic

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%).

Hepatic

Cholecystectomy, cholecystitis (less than 5%).

Hypersensitivity

Anaphylactic shock, hypersensitivity (less than 5%).

Local

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%).

Metabolic-Nutritional

Decreased weight (8%); hypokalemia (6%); dehydration (less than 5%).

Musculoskeletal

Arthralgia (22%); myalgia (16%); aggravated bone pain, muscle weakness, neck pain (less than 5%).

Respiratory

Dyspnea (29%); upper respiratory tract infection (13%); pneumonia (11%); exertional dyspnea (5%); hemoptysis, Klebsiella pneumonia, lung infiltration, pneumonitis, respiratory distress (less than 5%).

Miscellaneous

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%).

Precautions

Monitor

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.


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

Anemia, neutropenia, and thrombocytopenia may occur; monitor CBC.

Renal abnormalities

Elevated serum creatinine, renal failure, and renal tubular acidosis may occur.

Skin/Mucus membranes

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.

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.
  • Advise patients to inform health care provider about any underlying liver or renal dysfunction.

Copyright © 2009 Wolters Kluwer Health.

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