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Cancer Type

Document Type

Drug Monographs
Treatment Regimens
Scientific Name:
AZACYTIDINE
Brand Name(s):
Vidaza®

Drug Monograph

Pharmacology

Mechanism of Action

Azacytidine causes hypomethylation of DNA, restoring normal function to genes which are critical for differentiation and proliferation.  Azacytidine causes death of rapidly dividing cells, including cancer cells, but non-proliferating cells are not sensitive to this drug.  Although azacytidine also causes direct cytotoxicity on abnormal hematopoietic cells, this does not appear to be the mechanism of action at clinical doses.

Pharmacokinetics

Absorption:
rapid absorption after SC dosage; 89% bioavailability of SC dose (vs. IV dose)
Distribution:
Peak plasma concentration in 0.5 hr
Vd = 76+/- 26L (IV dose)
Metabolism
No information
Excretion:
Urinary excretion primary route of elimination
t½ : Approx. 4 hours

Side Effects

IMMEDIATE ONSET (hours to days)
   nausea (70%) and vomiting (54%)
   injection site erythema (35%), bruising (14%) and pruritis (7%)
* hypersensitivity (rare) or anaphylactic shock (rare)
   pyrexia (52%), ecchymosis (30%), rigors (25%)
EARLY ONSET  (days to weeks)
* anemia (70%), thrombocytopenia (65%), leukopenia (48%), neutropenia (32%- febrile neutropenia 17%)
   diarrhea (48%), constipation (34%), anorexia (20%), abdominal pain (16%), stomatitis (8%), dyspepsia (7%)
   fatigue (36%), weakness (29%), malaise (11%), lethargy (8%)
   cough (30%), dyspnea (29%), lung sounds (crackles 10%, rales 9%, wheezing 9%)
   arthralgia (22%), headache (22%), back pain (19%), limb pain (20%), myalgia (16%)
   peripheral edema (19%), epistaxis (17%)
   erythema (17%), rash (14%), pruritis (12%), night sweats (9%)
   Cardiovascular symptoms- chest pain (17%), tachycardia (9%), hypotension (7%)
* atrial fibrillation (rare), congestive heart failure (rare)
   Anxiety (13%),  depression (12%), insomnia (11%)
DELAYED/LATE ONSET
* leukemia, other cancers, loss of fertility (all from animal studies)

Therapeutics

Approved Indications

OTHER ONCOLOGY USES (Not Approved in Canada)
• Myelodysplastic syndromes- subtypes: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEBT),  chronic myelomonocytic leukemia (CMMoL)

Routes

Subcutaneous injection

Administration

• Subcutaneous injection daily for 7 days each cycle.
• Resuspend drug immediately before administration by inverting syringe 2-3 times and rolling between palms within 30 seconds of SC injection.

Dosing

Subcutaneous:
• 75 mg/m2 SC daily for 7 days
• Repeat every 4 weeks for at least 4 cycles; if no toxicity after 2 cycles, may increase to 100 mg/m2 SC daily for 7 days

Dose Adjustment Criteria

Myelosuppression:
If nadir counts ANC = 0.5-1.5 x 109/L or platelets = 25-50  x 109/L, reduce dose to 67% next cycle; 
If nadir counts ANC <0.5 x 109/L or platelets <25  x 109/L, reduce dose to 50% next cycle
Renal or Hepatic Dysfunction:
If unexpected elevations in Serum Creatinine or BUN, or decrease in serum bicarbonate, reduce dose to 50% next cycle
(Suggested action)

Antiemetic Risk

HIGH RISK (30-90% of patients)
• Use a serotonin receptor antagonist PLUS dexamethasone pre-chemotherapy and post-chemotherapy

Contraindications

• Advanced malignant hepatic tumours • Hypersensitivity to azacytidine or mannitol

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Complete blood count including differential, platelets and hemoglobin (CBC) and serum uric acid levels before each cycle of treatment and at the nadir (10-14 days after treatment)

SUGGESTED CRITERIA
• Baseline & periodic liver function tests [serum alkaline phosphatase, GGT, ALT, AST & Bilirubin levels] and renal function tests [serum creatinine, electrolytes]

Significant Interactions

No known drug-drug interactions.

Product Information

Commercial Product Description

Brand Name: VidazaTM Vials with 100 mg Azacytidine

Pharmaceutical Considerations

Injection:
Vials with 100 mg lyophilized powder for reconstitution. Store vials at room temperature.  Reconstitute with 4 mL sterile water for injection- Volumes greater than 4 mL should be prepared in 2 syringes.  Doses should be given within 1 hour of preparation,  or refrigerated immediately after preparation for delayed administration within 8 hours.  Allow refrigerated suspension to warm for 30 minutes to room temperature.

Handling Risk Level

Pregnancy C/Carcinogen 2AKNOWN HAZARDOUS DRUG
FDA Pregnancy Risk Factor C
IARC Carcinogen Risk Group 2A (Probable Carcinogen)

  • This drug must be handled using precautions outlined in CCNS Policies for Occupational Safety, Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy

Note

HANDLING RISK LEVEL:
HAZARD RISK LEVEL 1
FDA Pregnancy Risk Factor C
IARC Carcinogen Risk Group 2A (Probable Carcinogen)
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

NOTE:
EMERGING INFORMATION
This drug is under investigation and has not been widely used in oncology practice.  As new information is discovered, portions of this monograph may become outdated.  Refer to primary literature and revisions to official product monograph to ensure that information on this drug is current.

GUIDELINES:
NCDF Coverage Criteria: Azacitidine ss a single agent for the treatment of patients not eligible for hematopoietic stem cell transplantation (SCT) with intermediate -2 and high risk MDS and AML with 20-30% blasts and multi-lineage dysplasia.

Availability & Funding

Administrative Information (Nova Scotia)

• CCNS Provincial Formulary Status- Intermediate Level-NCDF Funding • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs • Pharmacare Formulary Status- Non-Formulary • NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety.

New Cancer Drug Fund Status (Nova Scotia)

New Cancer Drug Fund (NCDF) funding approved for: Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)- As a single agent for the treatment of patients not eligible for hematopoietic stem cell transplantation (SCT) with intermediate -2 and high risk MDS and AML with 20-30% blasts and multi-lineage dysplasia.