HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AZACITIDINE FOR INJECTION safely and effectively. See full
prescribing information for AZACITIDINE FOR INJECTION.
AZACITIDINE for injection, for subcutaneous or intravenous use
Initial U.S. Approval: 2004
----------------------------INDICATIONS AND USAGE-------------------------Azacitidine for Injection is a nucleoside metabolic inhibitor indicated for the
treatment of patients with the following FAB myelodysplastic syndrome
(MDS) subtypes: Refractory anemia (RA) or refractory anemia with ringed
sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or
requiring transfusions), refractory anemia with excess blasts (RAEB),
refractory anemia with excess blasts in transformation (RAEB-T), and chronic
myelomonocytic leukemia (CMMoL) (1).
----------------------DOSAGE AND ADMINISTRATION---------------------­
• 
The recommended starting dose for the first treatment cycle, for all
patients regardless of baseline hematology values, is Azacitidine for
Injection 75 mg/m2 daily for 7 days to be administered by subcutaneous
injection or intravenous infusion. Premedicate for nausea and vomiting
(2.1).
• 
Repeat cycles every 4 weeks (2.2). After 2 cycles, may increase dose to
100 mg/m2 if no beneficial effect is seen and no toxicity other than
nausea and vomiting has occurred (2.2). Patients should be treated for a
minimum of 4 to 6 cycles. Complete or partial response may require
additional treatment cycles (2.2).
• 
Continue treatment as long as the patient continues to benefit (2.2).
• 
Monitor patients for hematologic response and for renal toxicity; delay
or reduce dosage as appropriate (2.3, 2.4, 2.5).

-----------------------WARNINGS AND PRECAUTIONS----------------------­
• 
Anemia, neutropenia and thrombocytopenia: Monitor complete blood
counts frequently (CBC) (5.1).
• 
Hepatic toxicity: Patients with severe preexisting hepatic impairment are
at higher risk for toxicity (5.2).
• 
Renal impairment: Monitor patients with renal impairment for toxicity
since azacitidine and its metabolites are primarily excreted by the
kidneys (5.3).
• 
Embryo-Fetal toxicity: Can cause fetal harm when administered to a
pregnant woman. Advise females and males of reproductive potential of
the potential risk to a fetus and to avoid pregnancy (5.4, 8.1, 8.3).
------------------------------ADVERSE REACTIONS-----------------------------­
Most common adverse reactions (greater than 30%) by subcutaneous route
are: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia,
diarrhea, injection site erythema, constipation, neutropenia and ecchymosis.
Most common adverse reactions by intravenous route also included petechiae,
rigors, weakness and hypokalemia (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Actavis at
1-800-432-8534 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-----------------------USE IN SPECIFIC POPULATIONS----------------------­
Lactation: Advise not to breastfeed (8.2).
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 04/2016

---------------------DOSAGE FORMS AND STRENGTHS--------------------­
• 
For Injection; 100 mg, lyophilized powder in single-dose vial for
reconstitution (3).
-------------------------------CONTRAINDICATIONS----------------------------­
• 
Advanced malignant hepatic tumors (4.1).
• 
Hypersensitivity to azacitidine (4.2).
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Myelodysplastic Syndromes (MDS)
2 DOSAGE AND ADMINISTRATION
2.1 First Treatment Cycle
2.2 Subsequent Treatment Cycles
2.3 Dosage Adjustment Based on Hematology Laboratory Values
2.4 Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity
2.5 Use in Geriatric Patients
2.6 Preparation of Azacitidine for Injection
2.7 Instructions for Subcutaneous Administration
2.8 Instructions for Intravenous Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
4.1 Advanced Malignant Hepatic Tumors
4.2 Hypersensitivity to Azacitidine
5 WARNINGS AND PRECAUTIONS
5.1 Anemia, Neutropenia and Thrombocytopenia
5.2 Hepatic Toxicity in Patients with Severe Pre-existing Hepatic
Impairment
5.3 Renal Toxicity
5.4 Embryo-Fetal Toxicity

Reference ID: 3924281

6

ADVERSE REACTIONS
6.1 Adverse Reactions in Clinical Trials
6.2 Postmarketing Experience
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Gender
8.8 Race
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.

 FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Myelodysplastic Syndromes (MDS)
Azacitidine for Injection is indicated for treatment of patients with the following French-American-British
(FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed
sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia
with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic
myelomonocytic leukemia (CMMoL).
2 DOSAGE AND ADMINISTRATION
2.1 First Treatment Cycle
The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology
laboratory values, is 75 mg/m2 subcutaneously or intravenously, daily for 7 days. Patients should be
premedicated for nausea and vomiting.
Complete blood counts, liver chemistries and serum creatinine should be obtained prior to first dose.
2.2 Subsequent Treatment Cycles
Cycles should be repeated every 4 weeks. The dose may be increased to 100 mg/m2 if no beneficial effect is
seen after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred. Treat patients for a
minimum of 4 to 6 cycles. However, complete or partial response may require additional treatment cycles.
Treatment may be continued as long as the patient continues to benefit.
Patients should be monitored for hematologic response and renal toxicities [see Warnings and Precautions
(5.3)], and dosage delay or reduction as described below may be necessary.
2.3 Dosage Adjustment Based on Hematology Laboratory Values
•  For patients with baseline (start of treatment) WBC greater than or equal to 3 x109/L, ANC greater than
or equal to 1.5 x109/L, and platelets greater than or equal to 75 x109/L, adjust the dose as follows, based
on nadir counts for any given cycle:
Nadir Counts
ANC (x109/L)
<0.5
0.5 to 1.5
>1.5

Platelets (x109/L)
<25
25 to 50
>50

% Dose in the Next
Course
50%
67%
100%

•  For patients whose baseline counts are WBC less than 3 x109/L, ANC less than 1.5 x109/L, or platelets
less than 75 x109/L, dose adjustments should be based on nadir counts and bone marrow biopsy
cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation
(percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time
of the next cycle, in which case the dose of the current treatment should be continued.

Reference ID: 3924281

 WBC or Platelet
Nadir
% decrease in
counts from baseline

50 to 75
>75

Bone Marrow
Biopsy Cellularity at Time of Nadir
(%)
30 to 60
15 to 30
<15

100
75

% Dose in the Next Course
50
50

33
33

If a nadir as defined in the table above has occurred, the next course of treatment should be given 28 days after
the start of the preceding course, provided that both the WBC and the platelet counts are greater than 25%
above the nadir and rising. If a greater than 25% increase above the nadir is not seen by day 28, counts should
be reassessed every 7 days. If a 25% increase is not seen by day 42, then the patient should be treated with 50%
of the scheduled dose.
2.4 Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity
If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, the dosage should be
reduced by 50% on the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, the
next cycle should be delayed until values return to normal or baseline and the dose should be reduced by 50%
on the next treatment course [see Warnings and Precautions (5.3)].
2.5 Use in Geriatric Patients
Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more
likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor
renal function [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5)].
2.6 Preparation of Azacitidine for Injection
Azacitidine for Injection is a cytotoxic drug and, as with other potentially toxic compounds, caution should be
exercised when handling and preparing Azacitidine for Injection suspensions [see How Supplied/Storage and
Handling (16)].
If reconstituted Azacitidine for Injection comes into contact with the skin, immediately and thoroughly wash
with soap and water. If it comes into contact with mucous membranes, flush thoroughly with water.
The Azacitidine for Injection vial is single-dose and does not contain any preservatives. Unused portions of
each vial should be discarded properly [see How Supplied/Storage and Handling (16)]. Do not save any unused
portions for later administration.
2.7 Instructions for Subcutaneous Administration
Azacitidine for Injection should be reconstituted aseptically with 4 mL sterile water for injection. The diluent
should be injected slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved.
The suspension will be cloudy. The resulting suspension will contain azacitidine 25 mg/mL. Do not filter the
suspension after reconstitution. Doing so could remove the active substance.
Preparation for Immediate Subcutaneous Administration: Doses greater than 4 mL should be divided
equally into 2 syringes. The product may be held at room temperature for up to 1 hour, but must be
administered within 1 hour after reconstitution.
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 Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or
drawn into a syringe. Doses greater than 4 mL should be divided equally into 2 syringes. The product must be
refrigerated immediately. When Azacitidine for Injection is reconstituted using water for injection that has not
been refrigerated, the reconstituted product may be held under refrigerated conditions (2°C to 8°C, 36°F to
46°F) for up to 12 hours. When Azacitidine for Injection is reconstituted using refrigerated (2°C to 8°C, 36°F
to 46°F) water for injection, the reconstituted product may be stored under refrigerated conditions (2°C to 8°C,
36°F to 46°F) for up to 30 hours. After removal from refrigerated conditions, the suspension may be allowed to
equilibrate to room temperature for up to 30 minutes prior to administration.
Subcutaneous Administration
To provide a homogeneous suspension, the contents of the dosing syringe must be re-suspended immediately
prior to administration. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy
suspension is achieved.
Azacitidine for Injection suspension is administered subcutaneously. Doses greater than 4 mL should be
divided equally into 2 syringes and injected into 2 separate sites. Rotate sites for each injection (thigh,
abdomen, or upper arm). New injections should be given at least one inch from an old site and never into areas
where the site is tender, bruised, red, or hard.
Suspension Stability: Azacitidine for Injection reconstituted with non-refrigerated water for injection for
subcutaneous administration may be stored for up to 2 hours at 25°C (77°F) or for up to 12 hours between 2°C
and 8°C (36°F and 46°F); when reconstituted with refrigerated (2°C to 8°C, 36°F to 46°F) water for injection, it
may be stored for 30 hours between 2°C and 8°C (36°F and 46°F).
2.8 Instructions for Intravenous Administration
Reconstitute the appropriate number of Azacitidine for Injection vials to achieve the desired dose. Reconstitute
each vial with 10 mL 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. Parenteral drug
product should be inspected visually for particulate matter and discoloration prior to administration, whenever
solution and container permit.
Withdraw the required amount of Azacitidine for Injection solution to deliver the desired dose and inject into a
50 to 100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringer’s Injection.
Intravenous Solution Incompatibility
Azacitidine for Injection is incompatible with 5% Dextrose solutions, Hespan, or solutions that contain
bicarbonate. These solutions have the potential to increase the rate of degradation of Azacitidine for Injection
and should therefore be avoided.
Intravenous Administration
Azacitidine for Injection solution is administered intravenously. Administer the total dose over a period of 10
to 40 minutes. The administration must be completed within 1 hour of reconstitution of the Azacitidine for
Injection vial.
Solution Stability: Azacitidine for Injection reconstituted for intravenous administration may be stored at 25°C
(77°F), but administration must be completed within 1 hour of reconstitution.
3 DOSAGE FORMS AND STRENGTHS
Azacitidine for Injection is supplied as lyophilized powder in 100 mg single-dose vials.
Reference ID: 3924281

 4 CONTRAINDICATIONS
4.1 Advanced Malignant Hepatic Tumors
Azacitidine for Injection is contraindicated in patients with advanced malignant hepatic tumors [see Warnings
and Precautions (5.2)].
4.2 Hypersensitivity to Azacitidine
Azacitidine for Injection is contraindicated in patients with a known hypersensitivity to azacitidine.
5 WARNINGS AND PRECAUTIONS
5.1 Anemia, Neutropenia and Thrombocytopenia
Azacitidine for Injection causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts
frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. After administration of the
recommended dosage for the first cycle, adjust dosage for subsequent cycles based on nadir counts and
hematologic response [see Dosage and Administration (2.3)].
5.2 Hepatic Toxicity in Patients with Severe Pre-existing Hepatic Impairment
Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is
needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been
reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such
patients with baseline albumin less than 30 g/L. Azacitidine is contraindicated in patients with advanced
malignant hepatic tumors [see Contraindications (4.1)].
Safety and effectiveness of Azacitidine for Injection in patients with MDS and hepatic impairment have not
been studied as these patients were excluded from the clinical trials.
5.3 Renal Toxicity
Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported in patients
treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS
conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to less than 20 mEq/L in
association with an alkaline urine and hypokalemia (serum potassium less than 3 mEq/L) developed in 5
patients with CML (an unapproved use) treated with azacitidine and etoposide. If unexplained reductions in
serum bicarbonate less than 20 mEq/L or elevations of BUN or serum creatinine occur, the dosage should be
reduced or held [see Dosage and Administration (2.4)].
Patients with renal impairment may be at increased risk for renal toxicity. Also, azacitidine and its metabolites
are primarily excreted by the kidney. Therefore, these patients should be closely monitored for toxicity [see
Dosage and Administration (2.4, 2.5)]. Patients with MDS and renal impairment were excluded from the
clinical studies.
5.4 Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, Azacitidine for Injection can cause fetal
harm when administered to a pregnant woman. In animal studies, azacitidine caused adverse developmental
effects when administered to mice and rats at doses of 3 to 12 mg/m2 and 6 mg/m2 (approximately 4% to 16%
and 8%) of the recommended human daily dose of 75 mg/m2, respectively. Advise pregnant women of the
potential risk to the fetus.
Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for
Injection and for 1 week following the final dose. Advise males with female partners of reproductive potential

Reference ID: 3924281

 to use effective contraception during treatment with Azacitidine for Injection and for 3 months following the
final dose [see Use in Specific Populations (8.1 and 8.3) and Clinical Pharmacology (12.3)].
6 ADVERSE REACTIONS
The following adverse reactions are described in other labeling sections:
o Anemia, neutropenia and thrombocytopenia [see Warnings and Precautions (5.1)]
o Hepatic Toxicity in Patients with Severe Pre-existing Hepatic Impairment
[see Warnings and Precautions (5.2)]
o Renal Toxicity [see Warnings and Precautions (5.3)]
Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route): nausea, anemia,
thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia,
ecchymosis. The most common adverse reactions by intravenous route also included petechiae, rigors,
weakness and hypokalemia.
Adverse Reactions Most Frequently (Greater Than 2%) Resulting in Clinical Intervention (Subcutaneous
or Intravenous Route):
Discontinuation: leukopenia, thrombocytopenia, neutropenia. 

Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia. 

Dose Reduced: leukopenia, neutropenia, thrombocytopenia. 

6.1 Adverse Reactions in Clinical Trials
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
The data described below reflect exposure to Azacitidine for Injection in 443 MDS patients from 4 clinical
studies. Study 1 was a supportive-care controlled trial (subcutaneous administration), Studies 2 and 3 were
single arm studies (one with subcutaneous administration and one with intravenous administration), and Study 4
was an international randomized trial (subcutaneous administration) [see Clinical Studies (14)].
In Studies 1, 2 and 3, a total of 268 patients were exposed to Azacitidine for Injection, including 116 exposed
for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one
year). Azacitidine for Injection was studied primarily in supportive-care controlled and uncontrolled trials
(n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old
(mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the intravenous study
(n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average
daily doses between 50 and 100 mg/m2.
In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed
to Azacitidine for Injection. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12
cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and
99% were white. Most patients received daily Azacitidine for Injection doses of 75 mg/m2.
Table 1 presents adverse reactions occurring in at least 5% of patients treated with Azacitidine for Injection
(subcutaneous) in Studies 1 and 2. It is important to note that duration of exposure was longer for the
Azacitidine for Injection-treated group than for the observation group: patients received Azacitidine for
Injection for a mean of 11.4 months while mean time in the observation arm was 6.1 months.
Reference ID: 3924281

 Table 1: Most Frequently Observed Adverse Reactions (Greater Than or Equal To 5.0% in All 

Subcutaneous Azacitidine for Injection-Treated Patients; Studies 1 and 2)

Number (%) of Patients
Body System
All Azacitidine for
Injection b
Observationc
a
Adverse Reaction
(N=220)
(N=92)
Blood and lymphatic system disorders
Anemia
153 (69.5)
59 (64.1)
Anemia aggravated
12 (5.5)
5 (5.4)
Febrile neutropenia
36 (16.4)
4 (4.3)
Leukopenia
106 (48.2)
27 (29.3)
Neutropenia
71 (32.3)
10 (10.9)
Thrombocytopenia
144 (65.5)
42 (45.7)
Gastrointestinal disorders
Abdominal tenderness
26 (11.8)
1 (1.1)
Constipation
74 (33.6)
6 (6.5)
Diarrhea
80 (36.4)
13 (14.1)
Gingival bleeding
21 (9.5)
4 (4.3)
Loose stools
12 (5.5)
0
Mouth hemorrhage
11 (5.0)
1 (1.1)
Nausea
155 (70.5)
16 (17.4)
Stomatitis
17 (7.7)
0
Vomiting
119 (54.1)
5 (5.4)
General disorders and administration site conditions
Chest pain
36 (16.4)
5 (5.4)
Injection site bruising
31 (14.1)
0
Injection site erythema
77 (35.0)
0
Injection site granuloma
11 (5.0)
0
Injection site pain
50 (22.7)
0
Injection site pigmentation changes
11 (5.0)
0
Injection site pruritus
15 (6.8)
0
Injection site reaction
30 (13.6)
0
Injection site swelling
11 (5.0)
0
Lethargy
17 (7.7)
2 (2.2)
Malaise
24 (10.9)
1 (1.1)
Pyrexia
114 (51.8)
28 (30.4)
Infections and infestations
Nasopharyngitis
32 (14.5)
3 (3.3)
Pneumonia
24 (10.9)
5 (5.4)
Upper respiratory tract infection
28 (12.7)
4 (4.3)
Injury, poisoning, and procedural complications
Post procedural hemorrhage
13 (5.9)
1 (1.1)
Metabolism and nutrition disorders
Anorexia
45 (20.5)
6 (6.5)
Musculoskeletal and connective tissue disorders
Arthralgia
49 (22.3)
3 (3.3)
Chest wall pain
11 (5.0)
0
Myalgia
35 (15.9)
2 (2.2)
Nervous system disorders
Dizziness
41 (18.6)
5 (5.4)
Headache
48 (21.8)
10 (10.9)
Psychiatric disorders
Anxiety
29 (13.2)
3 (3.3)
Insomnia
24 (10.9)
4 (4.3)
Respiratory, thoracic and mediastinal disorders
Dyspnea
64 (29.1)
11 (12.0)

Reference ID: 3924281

 Skin and subcutaneous tissue disorders
Dry skin
11 (5.0)
1 (1.1)
Ecchymosis
67 (30.5)
14 (15.2)
Erythema
37 (16.8)
4 (4.3)
Rash
31 (14.1)
9 (9.8)
Skin nodule
11 (5.0)
1 (1.1)
Urticaria
13 (5.9)
1 (1.1)
Vascular disorders
Hematoma
19 (8.6)
0
Hypotension
15 (6.8)
2 (2.2)
Petechiae
52 (23.6)
8 (8.7)
a
Multiple terms of the same preferred terms for a patient are only counted once within each
treatment group.
b
Includes adverse reactions from all patients exposed to Azacitidine for Injection, including
patients after crossing over from observations.
c
Includes adverse reactions from observation period only; excludes any adverse events after
crossover to Azacitidine for Injection.

Table 2 presents adverse reactions occurring in at least 5% of patients treated with Azacitidine for Injection in
Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with Azacitidine for
Injection was longer (mean 12.2 months) compared with best supportive care (mean
7.5 months).
Table 2: Most Frequently Observed Adverse Reactions (Greater Than or Equal To 5.0% in the

Azacitidine for Injection-Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions;

Study 4)

Number (%) of Patients
Any Grade
Grade 3/4
Best
Best
Azacitidine
Supportive
Azacitidine
Supportive
Body System
for Injection
Care Only
for Injection
Care Only
Adverse Reactionsa
(N=175)
(N=102)
(N=175)
(N=102)
Blood and lymphatic system disorders
Anemia
90 (51.4)
45 (44.1)
24 (13.7)
9 (8.8)
Febrile neutropenia
24 (13.7)
10 (9.8)
22 (12.6)
7 (6.9)
Leukopenia
32 (18.3)
2 (2.0)
26 (14.9)
1 (1.0)
Neutropenia
115 (65.7)
29 (28.4)
107 (61.1)
22 (21.6)
Thrombocytopenia
122 (69.7)
35 (34.3)
102 (58.3)
29 (28.4)
Gastrointestinal disorders
Abdominal pain
22 (12.6)
7 (6.9)
7 (4.0)
0
Constipation
88 (50.3)
8 (7.8)
2 (1.1)
0
Dyspepsia
10 (5.7)
2 (2.0)
0
0
Nausea
84 (48.0)
12 (11.8)
3 (1.7)
0
Vomiting
47 (26.9)
7 (6.9)
0
0
General disorders and administration
site conditions
Fatigue
42 (24.0)
12 (11.8)
6 (3.4)
2 (2.0)
Injection site bruising
9 (5.1)
0
0
0
Injection site erythema
75 (42.9)
0
0
0
Injection site hematoma
11 (6.3)
0
0
0
Injection site induration
9 (5.1)
0
0
0
Injection site pain
33 (18.9)
0
0
0
Injection site rash
10 (5.7)
0
0
0
Injection site reaction
51 (29.1)
0
1 (0.6)
0
Pyrexia
53 (30.3)
18 (17.6)
8 (4.6)
1 (1.0)

Reference ID: 3924281

 Infections and infestations
Rhinitis
10 (5.7)
1 (1.0)
0
0
Upper respiratory tract infection
16 (9.1)
4 (3.9)
3 (1.7)
0
Urinary tract infection
15 (8.6)
3 (2.9)
3 (1.7)
0
Investigations
Weight decreased
14 (8.0)
0
1 (0.6)
0
Metabolism and nutrition disorders
Hypokalemia
11 (6.3)
3 (2.9)
3 (1.7)
3 (2.9)
Nervous system disorders
Lethargy
13 (7.4)
2 (2.0)
0
1 (1.0)
Psychiatric disorders
Anxiety
9 (5.1)
1 (1.0)
0
0
Insomnia
15 (8.6)
3 (2.9)
0
0
Renal and urinary disorders
Hematuria
11 (6.3)
2 (2.0)
4 (2.3)
1 (1.0)
Respiratory, thoracic and mediastinal
disorders
Dyspnea
26 (14.9)
5 (4.9)
6 (3.4)
2 (2.0)
Dyspnea exertional
9 (5.1)
1 (1.0)
0
0
Pharyngolaryngeal pain
11 (6.3)
3 (2.9)
0
0
Skin and subcutaneous tissue disorders
Erythema
13 (7.4)
3 (2.9)
0
0
Petechiae
20 (11.4)
4 (3.9)
2 (1.1)
0
Pruritus
21 (12.0)
2 (2.0)
0
0
Rash
18 (10.3)
1 (1.0)
0
0
Vascular disorders
Hypertension
15 (8.6)
4 (3.9)
2 (1.1)
2 (2.0)
a
Multiple reports of the same preferred term from a patient were only counted once within each treatment.

In Studies 1, 2 and 4 with subcutaneous administration of Azacitidine for Injection, adverse reactions of

neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site

erythema/reaction tended to increase in incidence with higher doses of Azacitidine for Injection. Adverse 

reactions that tended to be more pronounced during the first 1 to 2 cycles of subcutaneous treatment compared

with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site

erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There 

did not appear to be any adverse reactions that increased in frequency over the course of treatment.

Overall, adverse reactions were qualitatively similar between the intravenous and subcutaneous studies.

Adverse reactions that appeared to be specifically associated with the intravenous route of administration 

included infusion site reactions (e.g. erythema or pain) and catheter site reactions (e.g. infection, erythema, or

hemorrhage). 

In clinical studies of either subcutaneous or intravenous Azacitidine for Injection, the following serious adverse

reactions occurring at a rate of less than 5% (and not described in Tables 1 or 2) were reported:

Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia, splenomegaly. 

Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardio-respiratory arrest,

congestive cardiomyopathy. 

Eye disorders: eye hemorrhage 

Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess. 

Reference ID: 3924281

 General disorders and administration site conditions: catheter site hemorrhage, general physical health

deterioration, systemic inflammatory response syndrome.

Hepatobiliary disorders: cholecystitis.

Immune system disorders: anaphylactic shock, hypersensitivity.

Infections and infestations: abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection,

Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, 

Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis.

Metabolism and nutrition disorders: dehydration. 

Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain. 

Neoplasms benign, malignant and unspecified: leukemia cutis.

Nervous system disorders: cerebral hemorrhage, convulsions, intracranial hemorrhage. 

Renal and urinary disorders: loin pain, renal failure. 

Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory

distress.

Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration. 

Surgical and medical procedures: cholecystectomy. 

Vascular disorders: orthostatic hypotension. 

6.2 Postmarketing Experience
The following adverse reactions have been identified during postmarketing use of Azacitidine for Injection.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
−
−
−
−
−

Interstitial lung disease

Tumor lysis syndrome

Injection site necrosis

Sweet’s syndrome (acute febrile neutrophilic dermatosis)

Necrotizing fasciitis (including fatal cases)


8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Azacitidine for Injection, a nucleoside metabolic inhibitor, can cause fetal harm based on findings from animal
studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. There are no available data on
Azacitidine for Injection use in pregnant women. Azacitidine caused adverse developmental effects, including
CNS anomalies (exencephaly), limb and skeletal anomalies (missing ribs, oligodactily, and club foot), and other
Reference ID: 3924281

 fetal abnormality (cleft palate, cardiomyopathy, and hind paw hematoma) when administered during

organogenesis in mice and rats at doses of 4% to 16% and 8% the recommended human daily dose of

75 mg/m2, respectively [see Data]. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage in the indicated population

is unknown. In the U.S. general population, the estimated background risk of major birth defects and

miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data
Animal Data
Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased
resorption) after a single IP (intraperitoneal) injection of 6 mg/m2 (approximately 8% of the recommended
human daily dose on a mg/m2 basis) azacitidine on gestation day 10. Developmental abnormalities in the brain
have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3 to 12 mg/m2
(approximately 4% to 16% the recommended human daily dose on a mg/m2 basis).
In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4 to 8 (postimplantation) at a dose
of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis), although treatment in
the preimplantation period (on gestation days 1 to 3) had no adverse effect on the embryos. Azacitidine caused
multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m2 (approximately 8% the recommended
human daily dose on a mg/m2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused
fetal death when administered at 3 to 12 mg/m2 on gestation days 9 and 10; average live animals per litter was
reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies
(exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others
(micrognathia, gastroschisis, edema, and rib abnormalities).
8.2 Lactation
There is no information on the presence of Azacitidine for Injection or its metabolites in human milk, the effects
on the breast-fed infant, or the effects on milk production. Because of the potential for serious adverse reactions
in breastfed infants from Azacitidine for Injection, advise women not to breastfeed during treatment and for 24
hours after the final dose.
8.3 Females and Males of Reproductive Potential
Contraception
Females
Azacitidine for Injection can cause fetal harm. Advise females of reproductive potential to use effective
contraception during treatment with Azacitidine for Injection and for 1 week after the final dose [see Use in
Specific Populations (8.1) and Clinical Pharmacology (12.3)].
Males
Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective
contraception during treatment with Azacitidine for Injection and for 3 months after the final dose [see
Nonclinical Toxicology (13.1)].
Infertility
Males

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 Based on animal data, advise males that Azacitidine for Injection may impair fertility [see Nonclinical
Toxicology (13.1)].
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Of the total number of patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and
older. No overall differences in effectiveness were observed between these patients and younger patients. In
addition there were no relevant differences in the frequency of adverse reactions observed in patients 65 years
and older compared to younger patients.
Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years
and older. Survival data for patients 65 years and older were consistent with overall survival results. The
majority of adverse reactions occurred at similar frequencies in patients less than 65 years of age and patients 65
years of age and older.
Elderly patients are more likely to have decreased renal function. Monitor renal function in these patients [see
Dosage and Administration (2.5) and Warnings and Precautions (5.3)].
8.6 Renal Impairment
Severe renal impairment (CLcr less than 30 mL/min) has no major effect on the exposure of azacitidine after
multiple subcutaneous administrations. Therefore, azacitidine can be administered to patients with renal
impairment without Cycle 1 dose adjustment [see Clinical Pharmacology (12.3)].
8.7 Gender
There were no clinically relevant differences in safety and efficacy based on gender.
8.8 Race
Greater than 90% of all patients in all trials were Caucasian. Therefore, no comparisons between Caucasians
and non-Caucasians were possible.
10 OVERDOSAGE
One case of overdose with Azacitidine for Injection was reported during clinical trials. A patient experienced
diarrhea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m2, almost 4
times the recommended starting dose. The events resolved without sequelae, and the correct dose was resumed
the following day. In the event of overdosage, the patient should be monitored with appropriate blood counts
and should receive supportive treatment, as necessary. There is no known specific antidote for Azacitidine for
Injection overdosage.
11 DESCRIPTION
Azacitidine for Injection contains azacitidine, which is a pyrimidine nucleoside analog of cytidine. Azacitidine
is 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The structural formula is as follows:

Reference ID: 3924281

 The molecular formula is C8H12N4O5. The molecular weight is 244. Azacitidine is a white to almost white
powder. Azacitidine was found to be insoluble in acetone, ethanol, and methyl ethyl ketone; slightly soluble in
ethanol/water (50/50), propylene glycol, and polyethylene glycol; sparingly soluble in water, water saturated
octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 in water; and soluble
in dimethylsulfoxide (DMSO).
The finished product is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or
reconstitution as a solution with further dilution for intravenous infusion. Each vial of Azacitidine for Injection
contains 100 mg of azacitidine, 170 mg sucrose, monosodium phosphate monohydrate and disodium hydrogen
phosphate, dihydrate as a sterile lyophilized powder.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Azacitidine for Injection is a pyrimidine nucleoside analog of cytidine. Azacitidine for Injection is believed to
exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal
hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of
DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore
normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of
azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to
normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.
12.3 Pharmacokinetics
The pharmacokinetics of azacitidine were studied in 6 MDS patients following a single 75 mg/m2 subcutaneous
dose and a single 75 mg/m2 intravenous dose.
Absorption
Azacitidine is rapidly absorbed after subcutaneous administration; the peak plasma azacitidine concentration of
750 ± 403 ng/ml occurred in 0.5 hour. The bioavailability of subcutaneous azacitidine relative to intravenous
azacitidine is approximately 89%, based on area under the curve.
Distribution

Mean volume of distribution following intravenous dosing is 76 ± 26 L.

Metabolism
Mean apparent subcutaneous clearance is 167 ± 49 L/hour and mean half-life after subcutaneous administration
is 41 ± 8 minutes. The AUC and Cmax of subcutaneous administration of azacitidine in 21 patients with cancer
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 were approximately dose proportional within the 25 to 100 mg/m2 dose range. Multiple dosing at the

recommended dose-regimen does not result in drug accumulation.

Excretion
Published studies indicate that urinary excretion is the primary route of elimination of azacitidine and its
metabolites. Following intravenous administration of radioactive azacitidine to 5 cancer patients, the
cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for less than 1% of
administered radioactivity over 3 days. Mean excretion of radioactivity in urine following subcutaneous
administration of 14C-azacitidine was 50%. The mean elimination half-lives of total radioactivity (azacitidine
and its metabolites) were similar after intravenous and subcutaneous administrations, about 4 hours.
Specific Populations
In patients with cancer the pharmacokinetics of azacitidine in 6 patients with normal renal function (CLcr
greater than 80 mL/min) and 6 patients with severe renal impairment (CLcr less than 30 mL/min) were
compared following daily subcutaneous dosing (Days 1 through 5) at 75 mg/m2/day. Severe renal impairment
increased azacitidine exposure by approximately 70% after single and 41% after multiple subcutaneous
administrations. This increase in exposure was not correlated with an increase in adverse events. The exposure
was similar to exposure in patients with normal renal function receiving 100 mg/m2. Therefore, a Cycle 1 dose
modification is not recommended.
The effects of hepatic impairment, gender, age, or race on the pharmacokinetics of azacitidine have not been
studied.
Drug-Drug Interactions

No formal clinical drug interaction studies with azacitidine have been conducted. 

An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be
metabolized by the liver. Whether azacitidine metabolism may be affected by known microsomal enzyme
inhibitors or inducers has not been studied.
An in vitro study with cultured human hepatocytes indicated that azacitidine at concentrations up to 100 µM
(intravenous Cmax = 10.6 µM) does not cause any inhibition of CYP2B6 and CYP2C8. The potential of
azacitidine to inhibit other cytochrome P450 (CYP) enzymes is not known.
In vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations of 1.0 µM to 100
µM does not induce CYP 1A2, 2C19, or 3A4/5.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the
hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 8% the recommended human
daily dose on a mg/m2 basis) administered IP three times per week for 52 weeks. An increased incidence of
tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine
IP at 2.0 mg/kg (6.0 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) once a
week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 20 to
80% the recommended human daily dose on a mg/m2 basis) revealed an increased incidence of testicular tumors
compared with controls.

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 The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella
typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P,
WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human
lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster
embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of
azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo
cells.
Administration of azacitidine to male mice at 9.9 mg/m2 (approximately 9% the recommended human daily
dose on a mg/m2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased
fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats
3 times per week for 11 or 16 weeks at doses of 15 to 30 mg/m2 (approximately 20 to 40%, the recommended
human daily dose on a mg/m2 basis) resulted in decreased weight of the testes and epididymides, and decreased
sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a
related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated
females when examined on day 2 of gestation.
14 CLINICAL STUDIES
Myelodysplastic Syndromes (MDS)
Study 1 was a randomized, open-label, controlled trial carried out in 53 U.S. sites that compared the safety and
efficacy of subcutaneous Azacitidine for Injection plus supportive care with supportive care alone
(“observation”) in patients with any of the five FAB subtypes of myelodysplastic syndromes (MDS): refractory
anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation
(RAEB-T), and chronic myelomonocytic leukemia (CMMoL). RA and RARS patients were included if they
met one or more of the following criteria: required packed RBC transfusions; had platelet counts less than or
equal to 50 x 109/L; required platelet transfusions; or were neutropenic (ANC less than 1 x 109/L) with
infections requiring treatment with antibiotics. Patients with acute myelogenous leukemia (AML) were not
intended to be included. Supportive care allowed in this study included blood transfusion products, antibiotics,
antiemetics, analgesics and antipyretics. The use of hematopoietic growth factors was prohibited. Baseline
patient and disease characteristics are summarized in Table 3; the 2 groups were similar.
Azacitidine for Injection was administered at a subcutaneous dose of 75 mg/m2 daily for 7 days every 4 weeks.
The dose was increased to 100 mg/m2 if no beneficial effect was seen after 2 treatment cycles. The dose was
decreased and/or delayed based on hematologic response or evidence of renal toxicity. Patients in the
observation arm were allowed by protocol to cross over to Azacitidine for Injection if they had increases in
bone marrow blasts, decreases in hemoglobin, increases in red cell transfusion requirements, or decreases in
platelets, or if they required a platelet transfusion or developed a clinical infection requiring treatment with
antibiotics. For purposes of assessing efficacy, the primary endpoint was response rate (as defined in Table 4).
Of the 191 patients included in the study, independent review (adjudicated diagnosis) found that 19 had the
diagnosis of AML at baseline. These patients were excluded from the primary analysis of response rate,
although they were included in an intent-to-treat (ITT) analysis of all patients randomized. Approximately 55%
of the patients randomized to observation crossed over to receive Azacitidine for Injection treatment.
Table 3. Baseline Demographics and Disease Characteristics
Azacitidine for
Injection
Observation
(N=99)
(N=92)
Gender (n%)
Male

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72 (72.7)

60 (65.2)

 Female
Race (n%)
White
Black
Hispanic
Asian/Oriental
Age (years)
N
Mean ± SD
Range
Adjudicated MDS diagnosis at study
entry (n%)
RA
RARS
RAEB
RAEB-T
CMMoL
AML
Transfusion product used in 3
months before study entry (n%)
Any transfusion product
Blood cells, packed human
Platelets, human blood
Hetastarch
Plasma protein fraction
Other

Complete
Response
(CR), duration
≥4 weeks
Partial
Response
(PR), duration
≥4 weeks

Marrow
Peripheral
Blood
Marrow
Peripheral
Blood

27 (27.3)

32 (34.8)

93 (93.9)
1 (1.0)
3 (3.0)
2 (2.0)

85 (92.4)
1 (1.1)
5 (5.4)
1 (1.1)

99
67.3 ± 10.39
31 to 92

91
68.0 ± 10.23
35 to 88

21 (21.2)
6 (6.1)
38 (38.4)
16 (16.2)
8 (8.1)
10 (10.1)

18 (19.6)
5 (5.4)
39 (42.4)
14 (15.2)
7 (7.6)
9 (9.8)

70 (70.7)
66 (66.7)
15 (15.2)
0(0.0)
1(1.0)
2(2.0)

59 (64.1)
55 (59.8)
12 (13.0)
1(1.1)
0(0.0)
2(2.2)

Table 4. Response Criteria
RA
RARS
RAEB
<5% blasts
Normal CBC if abnormal at baseline
Absence of blasts in the peripheral circulation

RAEB-T

CMMoL

≥50% decrease in blasts
Improvement of marrow dyspoiesis
≥50% restoration in the deficit from normal levels of baseline white cells,
hemoglobin and platelets if abnormal at baseline
No marrow requirements

No blasts in the peripheral circulation
For CMMoL, if WBC is elevated at baseline, a ≥75% reduction in the excess
count over the upper limit of normal

The overall response rate (CR + PR) of 15.7% in Azacitidine for Injection-treated patients without AML (16.2%
for all Azacitidine for Injection randomized patients including AML) was statistically significantly higher than
the response rate of 0% in the observation group (p<0.0001) (Table 5). The majority of patients who achieved
either CR or PR had either 2 or 3 cell line abnormalities at baseline (79%; 11/14) and had elevated bone marrow
blasts or were transfusion dependent at baseline. Patients responding to Azacitidine for Injection had a decrease
in bone marrow blasts percentage, or an increase in platelets, hemoglobin or WBC. Greater than 90% of the
responders initially demonstrated these changes by the 5th treatment cycle. All patients who had been
transfusion dependent became transfusion independent during PR or CR. The mean and median duration of
clinical response of PR or better was estimated as 512 and 330 days, respectively; 75% of the responding
patients were still in PR or better at completion of treatment. Response occurred in all MDS subtypes as well as
in patients with adjudicated baseline diagnosis of AML.
Reference ID: 3924281

 Response
Overall (CR+PR)
Complete (CR)
Partial (PR)

Table 5. Response Rates
Azacitidine for
Observation Before
Injection
Crossover
(N=89)
(N=83)
n (%)
n (%)
14 (15.7)
0 ( 0.0)
5 ( 5.6)
0 ( 0.0)
9 (10.1)
0 ( 0.0)

P value
(<0.0001)
(0.06)
-­

Patients in the observation group who crossed over to receive Azacitidine for Injection treatment (47 patients)
had a response rate of 12.8%.
Study 2, a multi-center, open-label, single-arm study of 72 patients with RAEB, RAEB-T, CMMoL, or AML
was also carried out. Treatment with subcutaneous Azacitidine for Injection resulted in a response rate (CR +
PR) of 13.9%, using criteria similar to those described above. The mean and median duration of clinical
response of PR or better was estimated as 810 and 430 days, respectively; 80% of the responding patients were
still in PR or better at the time of completion of study involvement. In Study 3, another open-label, single-arm
study of 48 patients with RAEB, RAEB-T, or AML, treatment with intravenous Azacitidine for Injection
resulted in a response rate of 18.8%, again using criteria similar to those described above. The mean and
median duration of clinical response of PR or better was estimated as 389 and 281 days, respectively; 67% of
the responding patients were still in PR or better at the time of completion of treatment. Response occurred in
all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML in both of these studies.
Azacitidine for Injection dosage regimens in these 2 studies were similar to the regimen used in the controlled
study.
Benefit was seen in patients who did not meet the criteria for PR or better, but were considered “improved.”
About 24% of Azacitidine for Injection-treated patients were considered improved, and about 2/3 of those lost
transfusion dependence. In the observation group, only 5/83 patients met criteria for improvement; none lost
transfusion dependence. In all 3 studies, about 19% of patients met criteria for improvement with a median
duration of 195 days.
Study 4 was an international, multicenter, open-label, randomized trial in MDS patients with RAEB, RAEB-T
or modified CMMoL according to FAB classification and Intermediate-2 and High risk according to IPSS
classification. Of the 358 patients enrolled in the study, 179 were randomized to receive azacitidine plus best
supportive care (BSC) and 179 were randomized to receive conventional care regimens (CCR) plus BSC (105
to BSC alone, 49 to low dose cytarabine and 25 to chemotherapy with cytarabine and anthracycline). The
primary efficacy endpoint was overall survival.
The azacitidine and CCR groups were comparable for baseline parameters. The median age of patients was 69
years (range was 38 to 88 years), 98% were Caucasian, and 70% were male. At baseline, 95% of the patients
were higher risk by FAB classification: RAEB (58%), RAEB-T (34%), and CMMoL (3%). By IPSS
classification, 87% were higher risk: Int-2 (41%), High (47%). At baseline, 32% of patients met WHO criteria
for AML.
Azacitidine was administered subcutaneously at a dose of 75 mg/m2 daily for 7 consecutive days every 28 days
(which constituted one cycle of therapy). Patients continued treatment until disease progression, relapse after
response, or unacceptable toxicity. Azacitidine patients were treated for a median of 9 cycles (range 1 to 39),
BSC only patients for a median of 7 cycles (range 1 to 26), low dose cytarabine patients for a median of 4.5
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 cycles (range 1 to 15), and chemotherapy with cytarabine and anthracycline patients for a median of 1 cycle
(range 1 to 3, i.e. induction plus 1 or 2 consolidation cycles).
In the Intent-to-Treat analysis, patients treated with azacitidine demonstrated a statistically significant
difference in overall survival as compared to patients treated with CCR (median survival of 24.5 months vs.
15.0 months; stratified log-rank p=0.0001). The hazard ratio describing this treatment effect was 0.58 (95% CI:
0.43, 0.77).
Kaplan-Meier Curve of Time to Death from Any Cause: (Intent-to-Treat Population)

Key: AZA = azacitidine; CCR = conventional care regimens; CI = confidence interval; HR = Hazard Ratio
Azacitidine treatment led to a reduced need for red blood cell transfusions (see Table 6). In patients treated
with azacitidine who were RBC transfusion dependent at baseline and became transfusion independent, the
median duration of RBC transfusion independence was 13.0 months.
Table 6. Effect of Azacitidine on RBC Transfusions in MDS Patients
Efficacy Parameter
Conventional Care
Azacitidine plus BSC
Regimens
(n= 179)
(n= 179)
Number and percent of patients who
50/111 (45.0%)
13/114 (11.4%)
were transfusion dependent at
baseline who became transfusion
independent on treatment1
(95% CI: 35.6%, 54.8%)

(95% CI: 6.2%, 18.7%)

Number and percent of patients who
10/68 (14.7%)
28/65 (43.1%)
were transfusion-independent at
baseline who became transfusiondependent on treatment
(95% CI: 7.3%, 25.4%)
(95% CI: 30.9%, 56.0%)
1
A patient was considered RBC transfusion independent during the treatment period if the patient
had no RBC transfusions during any 56 consecutive days or more during the treatment period.
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 Otherwise, the patient was considered transfusion dependent.
15 REFERENCES
1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
16 HOW SUPPLIED/STORAGE AND HANDLING
Azacitidine for Injection is supplied as a lyophilized powder in 100 mg single-dose vials packaged in cartons of
1 vial (NDC 0591-2897-49).
Storage
Store unreconstituted vials at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP 

Controlled Room Temperature]. 

Discard unused portion.
Handling and Disposal
Azacitidine for Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
Sterile, Nonpyrogenic, Preservative-free.

This vial stopper is not made with natural rubber latex.

17 PATIENT COUNSELING INFORMATION
Instruct patients to inform their physician about any underlying liver or renal disease.
Embryo-Fetal Toxicity
Advise pregnant women and females of reproductive potential of the potential risk to a fetus [see Warnings and
Precautions (5.4) and Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for
Injection and for one week after the final dose [see Use in Specific Populations (8.3)].
Advise male patients with female partners of reproductive potential to use effective contraception during treatment
with Azacitidine for Injection and for 3 months after the final dose [see Use in Specific Populations (8.3)].
Lactation
Advise women not to breastfeed during treatment with Azacitidine for Injection and for 24 hours after the final
dose [see Use in Specific Populations (8.2)].
Infertility
Advise males of the potential for reduced fertility from Azacitidine for Injection [see Use in Specific Populations
(8.3) and Nonclinical Toxicology (13.1)].

Manufactured by:

Sindan Pharma SRL

11 Ion Mihalache Blvd.

Bucharest 1, Romania 011171

Distributed by: 

Actavis Pharma, Inc.

Reference ID: 3924281

 Parsippany, NJ 07054 USA

M. Actavis
Revised April 2016

Reference ID: 3924281