Generic Name: Azacitidine
Class: Antineoplastic Agents
Chemical Name: 4-Amino-1-β-d-ribofuranosyl-s-triazin-2(1H)-one
Molecular Formula: C8H12N4O5
CAS Number: 320672

Introduction

Antineoplastic agent;1 2 3 4 6 7 a synthetic pyrimidine nucleoside analog of cytidine.1 7

Uses for Vidaza

Myelodysplastic Syndrome (MDS)

Treatment of MDS;1 2 3 4 6 designated an orphan drug by FDA for this use.5

Used in patients with the following French-American-British (FAB) subtypes of MDS:1 2 3 4 6 refractory anemia (RA) or RA with ringed sideroblasts (RARS) if requiring blood transfusions or accompanied by neutropenia or thrombocytopenia, RA with excess blasts (RAEB), RAEB in transformation (RAEB-T) (now reclassified; see Acute Myelogenous Leukemia [AML] under Uses), and chronic myelomonocytic leukemia (CMMoL).1 9 12

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Use in combination with supportive care is superior to supportive care alone in improving hematologic deficits (e.g., transfusion dependence).1 6 12 Improved response rates (complete responses, partial responses, and hematologic improvements), as well as improved survival, when compared with conventional care (best supportive care, low-dose cytarabine, or an anthracycline/cytarabine induction regimen) in high-risk MDS patients.1 10004 10005 10006 10012

Acute Myelogenous Leukemia (AML)

May be considered a reasonable choice (accepted, with possible conditions) for the treatment of AML with multilineage dysplasia (previously classified as RAEB-T, a high-risk subtype of MDS10013 ), including in patients with poor-risk cytogenetics.10001 10002 10003 10004 10005 10011

May be considered a reasonable choice (accepted, with possible conditions) for initial treatment of AML in geriatric patients (>60 years of age) who are not candidates for standard induction therapy (i.e., because of compromised performance status or the presence of a clinically important comorbidity).10002 10007 10008 10009 10011

Use can be recommended (accepted) in geriatric patients with AML with normal to favorable karyotypes; use in geriatric patients with AML with poor-risk or complex cytogenetics is not fully established because of equivocal evidence.10007 10009 10011

Use in geriatric patients with relapsed or refractory AML is not fully established because of equivocal evidence.10007 10008 10011

Vidaza Dosage and Administration

General

  • Consult specialized references for proper handling and disposal of antineoplastics.1

  • Pretreatment for nausea and vomiting is recommended by the manufacturer.1 9

Administration

Administer by sub-Q injection or short IV infusion.1

Has been administered by continuous IV infusion in at least one clinical trial.1 6 10 11

Sub-Q Administration

Administer suspension by sub-Q injection into the thigh, abdomen, or upper arm; rotate injection sites.1

Give new injections ≥2.54 cm (1 inch) from an old site; do not give injections into areas where the skin is tender, bruised, red, or hard.1

If the dose exceeds 4 mL, divide the dose equally into 2 syringes and inject into 2 separate sites.1

Immediately prior to administration, resuspend syringe contents by vigorously rolling the syringe between the palms until a uniform suspension is achieved.1

Handle cautiously; if the reconstituted suspension contacts skin or mucosa, wash the skin immediately and thoroughly with soap and water or flush the mucosa with copious amounts of water.1

Reconstitution

Reconstitute vial containing 100 mg of azacitidine with 4 mL of sterile water for injection to provide a suspension containing 25 mg/mL.1 Suspension will be cloudy.1

Vigorously shake or roll the vial until complete dissolution has occurred.1

Do not administer such concentrated suspensions IV.1 14

Vials are intended for single use only; discard any unused portions of the suspension.1

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Infuse IV solution over 10–40 minutes.1 IV administration must be completed within 1 hour of reconstitution.1

The concentrated suspension intended for sub-Q injection must not be administered IV.1 14

Handle cautiously; if the reconstituted solution contacts skin or mucosa, wash the skin immediately and thoroughly with soap and water or flush the mucosa with copious amounts of water.1

Reconstitution

Reconstitute vial containing 100 mg of azacitidine with 10 mL of sterile water for injection to provide a solution containing 10 mg/mL.1 Solution should be clear.1

Shake vial vigorously or roll until complete dissolution has occurred.1

Reconstituted solution should be further diluted prior to IV administration.1

Dilution

Withdraw the desired dose of reconstituted azacitidine solution from the vial and inject into a 50- to 100-mL infusion bag containing 0.9% sodium chloride injection or lactated Ringer’s injection.1

Vials are intended for single use only; discard any unused portions.1

Rate of Administration

Infuse solution over 10–40 minutes.1

Dosage

Adults

Myelodysplastic Syndrome (MDS)
Sub-Q or IV

Initially, 75 mg/m2 daily for 7 days every 4 weeks.1 2 6 9

Daily dosage may be increased to 100 mg/m2 if no beneficial effect is observed after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred.1 9

The manufacturer recommends that patients receive at least 4–6 treatment cycles, although additional treatment cycles may be needed to achieve complete or partial response.1

Continue azacitidine as long as the patient is deriving benefit from therapy.1 9

Monitor for hematologic and renal toxicities (see Hematologic Effects and also Renal Toxicity, under Cautions); delay treatment or reduce dosage accordingly.1 9

Acute Myelogenous Leukemia (AML)
Sub-Q or IV

Dosage of 75 mg/m2 daily for 7 days every 28 days has been used.10001 10002 10005 10007 10009 In several clinical trials, patients who achieved complete response received 3 additional cycles of the drug; those exhibiting partial response or improvement received the drug until complete response or relapse occurred.10001

Dosage Modification for Hematologic Toxicity in Patients with Baseline (start of treatment) WBC of ≥3000/mm3, ANC of ≥1500/mm3, and Platelet Count of ≥75,000/mm3
Sub-Q or IV

Adjust the azacitidine dosage in the next treatment cycle based on nadir ANC and platelet counts observed in the current cycle.1 (See Table 1.)

Table 1. Dosage Modification for Hematologic Toxicity if Baseline WBC is ≥3000/mm3, ANC is ≥1500/mm3, and Platelet Count is ≥75,000/mm31

Nadir ANC (per mm3)

Nadir Platelets (per mm3)

Dosage in Next Cycle (expressed as % of dose in current cycle)

<500

<25,000

50%

500–1500

25,000–50,000

67%

>1500

>50,000

100%

Dosage Modification for Hematologic Toxicity in Patients with Baseline (start of treatment) WBC of <3000/mm3, ANC of <1500/mm3, or Platelet Count of <75,000/mm3
Sub-Q or IV

Base dosage adjustments on nadir blood cell counts and bone marrow biopsy cellularity at the time of the nadir count (see Table 2), unless clear improvement in differentiation (increased percentage of mature granulocytes and higher ANC) is observed at the time of initiation of the subsequent cycle relative to the time of initiation of the previous cycle.1 If such improvement in differentiation is observed, continue the current dosage.1

The next 7-day course of azacitidine should be given 28 days after initiation of the previous course, provided that both the WBC and platelet counts at day 28 exceed the nadir counts by ≥25% and are increasing.1 If an increase in WBC and platelet counts of ≥25% has not occurred by day 28, reassess these blood cell counts every 7 days;1 if increases of ≥25% do not occur by day 42, patients should receive 50% of the scheduled dosage.1

Table 2. Dosage Modification for Hematologic Toxicity if Baseline WBC is <3000/mm3, ANC is <1500/mm3, or Platelet Count is <75,000/mm31

Nadir WBC or Platelet Count (expressed as % decrease from baseline count)

Bone Marrow Biopsy Cellularity (%) at Time of Nadir Count

Dosage in Next Cycle (expressed as % of dose in previous cycle)

50–75

30–60

100

15–30

50

<15

33

>75

30–60

75

15–30

50

<15

33

Dosage Modification for Renal Impairment
Sub-Q or IV

If unexplained elevations of BUN or Scr occur, delay the next cycle until such values return to normal or baseline levels and reduce the dosage of azacitidine in the next treatment cycle by 50%.1

Dosage Modification for Serum Electrolyte Disturbances
Sub-Q or IV

If unexplained decreases in serum bicarbonate concentrations (to <20 mEq/L) occur, reduce the dosage of azacitidine in the next treatment cycle by 50%.1

Special Populations

No special population dosage recommendations at this time.1 9

Cautions for Vidaza

Contraindications

  • Known hypersensitivity to azacitidine or mannitol.1

  • Advanced malignant hepatic tumors.1

Warnings/Precautions

Hematologic Effects.

Possible neutropenia, thrombocytopenia, or anemia.1

Perform CBC and platelet counts prior to each treatment cycle and periodically thereafter as needed.1

After administration of the recommended dosage for the first cycle, reduce or delay dosage for subsequent cycles based on nadir blood cell counts and hematologic response.1 (See Dosage under Dosage and Administration.)

Hepatotoxicity

Progressive hepatic coma and death reported rarely in patients with extensive tumor burden secondary to metastatic disease, particularly in those with baseline serum albumin concentrations of <3 g/dL.1

Contraindicated in patients with advanced malignant hepatic tumors.1

Perform liver function tests prior to initiation of therapy.1

Renal Toxicity

Renal abnormalities (e.g., elevated Scr, renal tubular acidosis), renal failure, and death reported rarely in patients treated with IV azacitidine in combination with other antineoplastic agents (e.g., etoposide) for conditions other than MDS (e.g., chronic myelogenous leukemia).1

Determine Scr prior to initiation of therapy.1

If unexplained reductions in serum bicarbonate concentrations to <20 mEq/L or elevations of BUN or Scr occur, reduce the dosage or withhold therapy with the drug.1 (See Dosage under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Advise male patients to not father a child while receiving azacitidine.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether azacitidine or its metabolites are distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <16 years of age.13

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1

Assess renal function periodically, since azacitidine and its metabolites are substantially eliminated by the kidneys and geriatric patients are more likely to have decreased renal function.1

Hepatic Impairment

Potentially hepatotoxic in patients with severe preexisting hepatic impairment; use with caution in patients with liver disease.1 (See Hepatotoxicity under Cautions.)

Safety and efficacy not established in patients with MDS and hepatic impairment.1

Renal Impairment

Close monitoring for toxicity is recommended.1 Azacitidine and its metabolites are substantially eliminated by the kidneys.1

Safety and efficacy not established in patients with MDS and renal impairment.1

Common Adverse Effects

Sub-Q or IV administration: Nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, fatigue, injection site erythema, constipation, neutropenia, ecchymosis.1 With IV administration, petechiae, rigors, weakness, and hypokalemia also occur commonly.1

Interactions for Vidaza

Not known whether metabolism of azacitidine is affected by known inhibitors or inducers of hepatic microsomal enzymes.1

Not known whether azacitidine inhibits CYP isoenzymes.1 Azacitidine does not induce CYP isoenzyme 1A2, 2C19, 3A4, or 3A5 in vitro.1

No formal drug interaction studies to date.1

Vidaza Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed after sub-Q administration, with peak plasma concentration attained in about 0.5 hour.1 Bioavailability is 89% relative to an IV dose.1

Elimination

Metabolism

In vitro study suggests that azacitidine may be metabolized in the liver.1

Elimination Route

Azacitidine and its metabolites are eliminated principally in urine.1

Half-life

Elimination half-life is about 4 hours.1

Stability

Storage

Parenteral

Powder for Injection

Powder: 25°C (may be exposed to 15–30°C).1

Reconstituted suspension for sub-Q injection (in vial or syringe): 25°C for up to 1 hour or 2–8°C for up to 8 hours.1 Refrigerated suspensions may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration.1

Reconstituted solution for IV infusion: 25°C; complete IV administration within 1 hour of reconstitution.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1

Compatible

Ringer’s injection, lactated

Sodium chloride 0.9%

Incompatible

Dextrose in water

Hetastarch

Drug Compatibility

Incompatible with solutions containing sodium bicarbonate.1

Actions

  • Exerts antineoplastic effect by inhibiting DNA methyltransferase, thereby causing hypomethylation of DNA,6 7 and by direct cytotoxic effect on abnormal hematopoietic cells in the bone marrow.1 9

Advice to Patients

  • Importance of women informing clinicians immediately if they are or plan to become pregnant.1 Advise women to avoid pregnancy and advise men not to father a child during therapy.1

  • Importance of women informing clinicians if they plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., underlying hepatic or renal disease).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Azacitidine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV or subcutaneous use

100 mg

Vidaza

Celgene

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 23, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Celgene Corporation. Vidaza (azacitidine for injection) prescribing information. Summit, NJ; 2008 Aug.

2. Gryn J, Zeigler ZR, Shadduck RK et al. Treatment of myelodysplastic syndromes with 5-azacytidine. Leuk Res. 2002; 26:893-7. [IDIS 518520] [PubMed 12163049]

3. Suwanawiboon B, Sumida KN. 5-Azacitidine: an alternative treatment of myelodysplastic syndromes in patients with refractory response to hematopoietic growth factor; a case report and review of literature. Hawaii Med J. 2004; 63:14-6, 25. [PubMed 15011897]

4. Leone G, Voso MT, Teofili L et al. Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. Clin Immunol. 2003; 109:89-102. [PubMed 14585280]

5. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD; From FDA website.

6. Silverman LR, Demakos EP, Bercedis L et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002; 20:2429-40. [IDIS 486284] [PubMed 12011120]

7. Silverman LR. Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes (MDS). Oncologist. 2001; 6(Suppl 5):8-14. [PubMed 11700387]

8. Kantarjian HM. Treatment of myelodysplastic syndrome: questions raised by the azacitidine experience. J Clin Oncol. 2002; 20:2415-6. [IDIS 486283] [PubMed 12011118]

9. Pharmion. AHFS Product information form on Vidaza (azacitidine) for injectable suspension. Boulder, CO; undated.

10. Silverman LR, Holland JF, Davis RB et al. Azacitidine (Aza C) in myelodysplastic syndromes (MDS). Ann Hematol. 1994; 68:A12.

11. Silverman LR, Holland JF, Weinberg RS et al. Effect of treatment with 5-azacitidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes. Leukemia. 1993; 7(Suppl):21-9. [PubMed 7683352]

12. US Food and Drug Administration Center for Drug Evaluation and Research. Azacitidine medical officer’s review. 2004 May 19. From FDA website.

13. Pharmion, Boulder, CO; Personal communication.

14. Pharmion. Vidaza (azacitidine for injectable suspension) prescribing information. Boulder, CO; 2004 Aug 31.

10001. Silverman L, McKenzie D, Peterson B et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006; 24: 3895-3903. [PubMed 16921040]

10002. Sudan N, Rossetti J, Shadduck R et al. Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer. 2006; 107:1839-43. [PubMed 16967444]

10003. Kaminskas E, Farrell A, Abraham S et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res. 2005; 11: 3604-3608. [PubMed 15897554]

10004. Fenaux P, Mutfi G, Santini V et al. Azacitidine treatment prolongs overall survival in higher-risk MDS patients compared with conventional care regimens: Results of the AZA-001 Phase III study. Blood. 2007; 110: Abstract No. 817.

10005. List AF, Fenaux P, Mutfi GJ et al. Effect of azacitidine (AZA) on overall survival in higher-risk myelodysplastic syndromes (MDS) without complete remission. J Clin Oncol. 2008; 26: Abstract No. 7006.

10006. Mufti GJ, Fenaux P, Hellstrom-Lindberg E. et al. Treatment of high-risk MDS patients (pts) with -7/del(7q) with azacitidine (AZA) versus conventional care regimens (CCR): effects on overall survival. J Clin Oncol. 2008; 26: Abstract No. 7033.

10007. Fabre C, Gardin G, Mbida R et al. Treatment of AML with Azacytidine (AZA): Current results of the French ATU program. Blood. 2007; 110 (11): Abstract No. 1849.

10008. Al-Ali H, Schwind S, Becket C et al. 5-Azacitidine induces hematologic responses in a high proportion of patients with acute myeloid leukemia refractory to or not eligible for intensive chemotherapy. Blood. 2006; 108: Abstract No. 1953

10009. Goldberg S, Hsu J, Orr A et al. 5-Azacitidine therapy in elderly patients with acute myelogenous leukemia yields similar survival compared to 3+ 7 induction chemotherapy with less transfusional support, bacteremias and hospital days. Blood. 2006; 108: Abstract No. 4569.

10010. Jain N, Mattiuzzi G, Cortes J et al. Benefit of anti-infectious prophylaxis in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome receiving frontline targeted therapy. Blood. 2007; 110: Abstract No. 2858.

10011. AHFS drug information off-label use determinations. McEvoy GK, ed. Azacitidine. Bethesda, MD: American Society of Health-System Pharmacists; 2008 Apr. From AHFS drug information website.

10012. Silverman LR, Demakos EP, Peterson BL et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002; 20:2429-40. [IDIS 486284] [PubMed 12011120]

10013. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002; 100:2292-302. [PubMed 12239137]

Hide
(web4)