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AZCT

Cancer Type: Hematologic, Leukemia - Acute Myeloid (AML), Myelodysplastic Syndrome (MDS), Myeloproliferative Neoplasms (MPNs)  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Azacitidine - Intermediate-2 and high-risk myelodysplastic syndrome (MDS)
New Drug Funding Program
    Azacitidine - Acute Myeloid Leukemia (AML)
A - Regimen Name

AZCT Regimen
Azacitidine


Disease Site
Hematologic - Leukemia - Acute Myeloid (AML)
Hematologic - Myelodysplastic Syndrome (MDS)
Hematologic - Myeloproliferative Neoplasms (MPNs)

(CMML)


Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses
  • Treatment of adult patients with intermediate-2 and high-risk MDS according to the International Prognostic Scoring System (IPSS), and who are not eligible for hematopoietic stem cell transplantation
  • Adults with Acute Myeloid Leukemia (AML), with 20-30% blasts and multi-lineage dysplasia, according to the WHO classification who are not eligible for stem cell transplant

Supplementary Public Funding

azaCITIDine
New Drug Funding Program (Azacitidine - Intermediate-2 and high-risk myelodysplastic syndrome (MDS))

azaCITIDine
New Drug Funding Program (Azacitidine - Acute Myeloid Leukemia (AML))


Additional Information

The information provided in this document is intended for use only in the management of adults with leukemia/ MDS /MPN, and for cancer centres with expertise in treating acute leukemia/ MDS/ MPN.

 
B - Drug Regimen

azaCITIDine
75 mg /m² Subcut Daily; Days 1 to 7

 

Alternative Schedule:

azaCITIDine
75 mg /m² Subcut Daily on days 1-5 and 8-9 (5-2-2 regimen)

 

Alternative Schedule:

azaCITIDine
75 mg /m² Subcut Daily; Days 1 to 6
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C - Cycle Frequency

REPEAT EVERY 28 DAYS for a minimum of 6 cycles if tolerated, in the absence of disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate

Other Supportive Care:

Consider the use of supportive measures such as prophylactic antibiotics, transfusion and/or growth factors, according to local practice.
 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.

Dosage with toxicity

Non-hematologic

Toxicity Action
Necrotising fasciitis Discontinue
Renal tubular acidosis (low serum bicarbonate, increasing creatinine) Reduce or delay next dose
Other severe drug related toxicity Consider dose reduction or discontinuation

Hematologic

Normal baseline counts (X 109/L; WBC ≥ 3 and ANC 1.5 and platelets 75):

Table 1:

Nadir Counts

% Dose in the next cycle

 

ANC (X 109/L)

 

Platelets (X 109/L)

1

and/or

50

Delay until recovery* then 50% if recovery requires > 14 days

> 1

and/or

> 50

Delay until recovery* then 100%

* Recovery = Counts Nadir count + (0.5 x {Baseline count – Nadir count} )

 

 

Low baseline counts (X 109/L; WBC < 3 or ANC < 1.5 or platelets < 75):

 

Table 2:             

ANC or WBC or platelets from baseline

 

Improvement in any cell line differentiation?

Action

Recovery* within 14 days?

Action

< 50%

 

 

Treat on time

with no ↓ in dose

N/A

N/A

> 50%

And

Yes

Treat on time

with no ↓ in dose

N/A

N/A

> 50%

And

No

Hold until recovery*

Yes

No ↓ in dose

> 50%

And

No

Hold until recovery*

No

Check marrow cellularity

(Table 3)

* Recovery = Counts Nadir count + (0.5 x {Baseline count – Nadir count} )

 

 

 

Table 3:

Bone marrow cellularity

(Refer to Table 2)           

Action and % Dose in next cycle

if recovery* is not achieved within 14 days

Recovery 21 days

Recovery > 21 days

> 50%

No dose adjustment needed

15 – 50%

Hold until recovery*; 100%

Hold until recovery*; 50%

< 15%

Hold until recovery*; 100%

Hold until recovery*; 33%

* Recovery = Counts Nadir count + (0.5 x {Baseline count – Nadir count] }



Hepatic Impairment

Treat with caution. Azacitidine is contraindicated in patients with advanced malignant hepatic tumours and has not been studied in patients with hepatic impairment.


Renal Impairment

Monitor patients with renal impairment closely as azacitidine and its metabolites are primarily excreted renally. Azacitidine can be administered to patients with renal impairment without initial dose adjustment. Subsequent dosage modifications should be made if reductions in serum bicarbonate levels and/or elevations in serum creatinine or BUN occur. The following are suggested modifications.

Creatinine / BUN

 

Serum bicarbonate (mmol/L)

Action and Dose (% previous dose)

≥ 2x ULN

 and/or

 < 20

There are no specific recommendations for dose reductions if present prior to starting azacitidine.

< 2 x ULN
 and
< 20
50% on next cycle

≥ 2 X above baseline

 and
 any

Delay until normal or to baseline; 50% on next cycle


Dosage in the Elderly

No overall differences in safety or effectiveness were observed between younger patients and patients ≥ 65 years. Monitor closely as elderly patients are more likely to have deceased renal function or possibly greater sensitivity to the drug. 

 


 
F - Adverse Effects

Refer to azacitidine drug monograph(s) for additional details of adverse effects


Most Common Side Effects 

Less Common Side Effects, but may be
Severe or Life-Threatening

  • Myelosuppression ± infection, bleeding (may be severe)
  • Nausea, vomiting
  • Constipation
  • Injection site reaction (may be severe)
  • Diarrhea
  • Fatigue
  • Musculoskeletal pain
  • Headache
  • Anorexia, weight Loss
  • Dizziness
  • Rash (may be severe)
  • Arrhythmia
  • GI perforation
  • Cardiotoxicity
  • ↑ LFTs
  • Hypersensitivity
  • Pneumonitis
  • Pancreatitis
  • Nephrotoxicity and renal tubular acidosis
  • Seizure
  • Venous thromboembolism
  • Leucocytoclastic vasculitis 
  • Tumour lysis syndrome
  • Necrotizing fasciitis
 
G - Interactions
  • No formal clinical drug interactions have been studied with azacitidine.
  • Azacitidine does not appear to induce or inhibit CYP 450.
  • Use with caution in patients taking other medications known to prolong QTc. 

Refer to azacitidine drug monograph(s) for additional details

 
H - Drug Administration and Special Precautions

Refer to azaCITIDine drug monograph(s) for additional details


Drug Administration

  • For subcutaneous use only. The manufacturer recommends using a fresh 25-gauge subcutaneous needle for injection. 
  • Follow local guidelines on maximum volumes for SC injections. The manufacturer recommends that each syringe can contain up to 100 mg (4 mL) of azacitidine; doses greater than 4 mL should be injected into at least 2 separate sites. 
  • Discard if the drug contains large particles or agglomerates. 
  • Do not filter the suspension after reconstitution.
  • Before injection, ensure contents of syringe are at room temperature. Contents of the syringe must be re-suspended immediately prior to administration, by vigorously rolling the syringe between the palms until a uniform cloudy suspension is achieved. 
  • Rotate injection sites; possible sites include the upper arm, thigh or abdommen. 
  • Do not inject into sites which are red, bruised, tender, or hardened. 
  • New injections should be given at least 2.5 cm from the previous site.
  • If a dose is missed, it should not be given at the same time as the next dose, but should be added to the end of the current dosing cycle.

Contraindications

  • Patients who are hypersensitive to the drug or its excipients
  • Patients with advanced, malignant hepatic tumours

Warnings/precautions

  • Patients with poor performance status, extensive disease or significant cardiac or lung disease
  • Safety and efficacy have not been established in patients with severe CHF, clinically unstable heart or lung disease.
  • Azacitidine should not be used in pregnancy. Females of childbearing potential must use effective contraception during treatment and up to 3 months after the last dose. Males are advised not to father a child during therapy and for 6 months after treatment cessation. 

Refer to azacitidine drug monograph(s) for additional details

 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph. 

Recommended Clinical Monitoring

  • CBC; baseline and before each cycle and as needed to monitor response and toxicity
  • Electrolytes and bicarbonate levels; baseline and before each cycle
  • Liver function tests; baseline and before each cycle
  • Renal function tests; baseline and before each cycle
  • Clinical toxicity assessment for bleeding, infection, cardiac, skin/local, neurological, venous thromboembolism, GI and tumour lysis effects; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Approximate Patient Visit
0.5 hour
Pharmacy Workload (average time per visit)
11.879 minutes
Nursing Workload (average time per visit)
27.5 minutes
 
K - References

Azacitidine drug monograph, Cancer Care Ontario

Fenaux P, Gattermann N, Seymour JF et al. Prolonged survival with improved tolerability in higher-risk myelodysplastic syndromes: azacitidine compared with low dose ara-C. Br J Haematol 2010; 149: 244–9.

Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. Lancet Oncol 2009; 10: 223-32.

Lyons RM, Cosgriff TM, Modi SS, et al.  Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol 2009;27(11):1850-6. 

Sudan N, Rossetti JM, Shadduck RK, et al.  Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer. 2006 Oct 15;107(8):1839-43.  


August 2018 Added PEBC guideline link


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.