-------------------------------CONTRAINDICATIONS------------------------------

HIGHLIGHTS OF PRESCRIBING INFORMATION  Advanced malignant hepatic tumors (4.1).

These highlights do not include all the information needed to use  Hypersensitivity to azacitidine or mannitol (4.2).
VIDAZA safely and effectively. See full prescribing information for
VIDAZA. -----------------------WARNINGS AND PRECAUTIONS------------------------
 Anemia, neutropenia and thrombocytopenia: Monitor complete blood
VIDAZA (azacitidine for injection) for SC or IV use counts frequently (CBC) (5.1).
Initial U.S. Approval: 2004  Hepatotoxicity: Patients with severe preexisting hepatic impairment are
at higher risk for toxicity (5.2).
 Renal impairment: Monitor patients with renal impairment for toxicity
----------------------------INDICATIONS AND USAGE--------------------------- since azacitidine and its metabolites are primarily excreted by the
VIDAZA is a nucleoside metabolic inhibitor indicated for the treatment of kidneys (5.3).
patients with the following FAB myelodysplastic syndrome (MDS) subtypes:  Monitor liver chemistries and serum creatinine prior to initiation of
Refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) therapy and with each cycle (2.1).
(if accompanied by neutropenia or thrombocytopenia or requiring  VIDAZA may cause fetal harm when administered to a pregnant
transfusions), refractory anemia with excess blasts (RAEB), refractory anemia
woman. Women of childbearing potential should be apprised of the
with excess blasts in transformation (RAEB-T), and chronic myelomonocytic
potential hazard to a fetus (5.4, 8.1).
leukemia (CMMoL). (1)
 Men should be advised not to father a child while receiving VIDAZA
(5.5, 13.1).
----------------------DOSAGE AND ADMINISTRATION-----------------------
 The recommended starting dose for the first treatment cycle, for all
patients regardless of baseline hematology values, is VIDAZA 75 mg/m2
------------------------------ADVERSE REACTIONS-------------------------------
daily for 7 days to be administered by subcutaneous (SC) injection or Most common adverse reactions (>30%) by SC route are: nausea, anemia,
intravenous (IV) infusion. Premedicate for nausea and vomiting. (2.1)
thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site
 Repeat cycles every 4 weeks (2.2). After 2 cycles, may increase dose to erythema, constipation, neutropenia and ecchymosis. Most common adverse
100 mg/m2 if no beneficial effect is seen and no toxicity other than reactions by IV route also included petechiae, rigors, weakness and
nausea and vomiting has occurred (2.2). Patients should be treated for a hypokalemia (6.1).
minimum of 4 to 6 cycles. Complete or partial response may require
additional treatment cycles (2.2). To report SUSPECTED ADVERSE REACTIONS, contact Celgene
 Continue treatment as long as the patient continues to benefit (2.2). Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or
 Monitor patients for hematologic response and for renal toxicity; delay www.fda.gov/medwatch.
or reduce dosage as appropriate (2.3, 2.4, 2.5).
------------------------------DRUG INTERACTIONS-------------------------------
 No formal clinical assessments of drug-drug interactions between
---------------------DOSAGE FORMS AND STRENGTHS---------------------- VIDAZA and other agents have been conducted (7).
 Lyophilized powder in 100 mg single-use vials (3).
-----------------------USE IN SPECIFIC POPULATIONS------------------------
 Nursing Mothers: Discontinue drug or nursing taking into consideration
importance of drug to mother (8.3).

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 1/ 2014

FULL PRESCRIBING INFORMATION: CONTENTS* 8.6 Renal Impairment

8.7 Gender
1 INDICATIONS AND USAGE 8.8 Race
1.1 Myelodysplastic Syndromes (MDS)
2 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE
2.1 First Treatment Cycle 11 DESCRIPTION
2.2 Subsequent Treatment Cycles 12 CLINICAL PHARMACOLOGY
2.3 Dosage Adjustment Based on Hematology Laboratory Values 12.1 Mechanism of Action
2.4 Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity 12.3 Pharmacokinetics
2.5 Use in Geriatric Patients 13 NONCLINICAL TOXICOLOGY
2.6 Preparation of VIDAZA 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
2.7 Instructions for Subcutaneous Administration 14 CLINICAL STUDIES
2.8 Instructions for Intravenous Administration 15 REFERENCES
3 DOSAGE FORMS AND STRENGTHS 16 HOW SUPPLIED/STORAGE AND HANDLING
4 CONTRAINDICATIONS 17 PATIENT COUNSELING INFORMATION
4.1 Advanced Malignant Hepatic Tumors *Sections or subsections omitted from the full prescribing information are not
4.2 Hypersensitivity to Azacitidine or Mannitol listed.
5 WARNINGS AND PRECAUTIONS
5.1 Anemia, Neutropenia and Thrombocytopenia
5.2 VIDAZA Toxicity in Patients with Severe Pre-existing Hepatic
Impairment
5.3 Renal Toxicity
5.4 Use in Pregnancy
5.5 Use in Males
6 ADVERSE REACTIONS
6.1 Adverse Reactions in Clinical Trials
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Myelodysplastic Syndromes (MDS)

VIDAZA® 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. It is recommended that patients be treated 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 3.0 x109/L, ANC 1.5 x109/L, and
platelets 75.0 x109/L, adjust the dose as follows, based on nadir counts for any given
cycle:
 Nadir Counts % Dose in the Next
Course
ANC (x109/L) Platelets (x109/L)
<0.5 <25.0 50%
0.5 –1.5 25.0-50.0 67%
>1.5 >50.0 100%

 For patients whose baseline counts are WBC <3.0 x109/L, ANC<1.5 x109/L, or platelets
<75.0 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.

WBC or Platelet Bone Marrow

Nadir Biopsy Cellularity at Time of Nadir
% decrease in (%)
counts
30-60 15-30 <15
from baseline

% Dose in the Next Course

50 - 75 100 50 33
>75 75 50 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 >25% above the nadir and rising. If a >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 <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 VIDAZA

VIDAZA is a cytotoxic drug and, as with other potentially toxic compounds, caution should be
exercised when handling and preparing VIDAZA suspensions [see How Supplied/Storage and
Handling (16)].

If reconstituted VIDAZA 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 VIDAZA vial is single-use 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

VIDAZA 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.

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 VIDAZA is reconstituted using
water for injection that has not been refrigerated, the reconstituted product may be held under
refrigerated conditions (2ºC - 8ºC, 36ºF - 46ºF) for up to 8 hours. When VIDAZA is
reconstituted using refrigerated (2ºC - 8ºC, 36ºF - 46ºF) water for injection, the reconstituted
product may be stored under refrigerated conditions (2ºC - 8ºC, 36ºF - 46ºF) for up to 22 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.
VIDAZA 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: VIDAZA reconstituted with non-refrigerated water for injection for
subcutaneous administration may be stored for up to 1 hour at 25°C (77°F) or for up to 8 hours
between 2°C and 8°C (36°F and 46°F); when reconstituted with refrigerated (2ºC - 8ºC,
36ºF - 46ºF) water for injection, it may be stored for 22 hours between 2°C and 8°C (36°F and
46°F).

2.8 Instructions for Intravenous Administration

Reconstitute the appropriate number of VIDAZA 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 VIDAZA solution to deliver the desired dose and inject into a
50 -100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringer’s
Injection.

Intravenous Solution Incompatibility

VIDAZA is incompatible with 5% Dextrose solutions, Hespan, or solutions that contain

bicarbonate. These solutions have the potential to increase the rate of degradation of VIDAZA
and should therefore be avoided.

Intravenous Administration

VIDAZA solution is administered intravenously. Administer the total dose over a period of
10 - 40 minutes. The administration must be completed within 1 hour of reconstitution of the
VIDAZA vial.

Solution Stability: VIDAZA 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

VIDAZA (azacitidine for injection) is supplied as lyophilized powder in 100 mg single-use vials.

4 CONTRAINDICATIONS

4.1 Advanced Malignant Hepatic Tumors

VIDAZA is contraindicated in patients with advanced malignant hepatic tumors [see Warnings
and Precautions (5.2)].

4.2 Hypersensitivity to Azacitidine or Mannitol

VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.

5 WARNINGS AND PRECAUTIONS

5.1 Anemia, Neutropenia and Thrombocytopenia

VIDAZA 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 VIDAZA 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 <30 g/L.
Azacitidine is contraindicated in patients with advanced malignant hepatic tumors [see
Contraindications (4.1)].

Safety and effectiveness of VIDAZA 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 <20 mEq/L in association with an alkaline urine and hypokalemia
(serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and
etoposide. If unexplained reductions in serum bicarbonate <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 Use in Pregnancy

VIDAZA may cause fetal harm when administered to a pregnant woman. Azacitidine caused
congenital malformations in animals. Women of childbearing potential should be advised to
avoid pregnancy during treatment with VIDAZA. There are no adequate and well-controlled
studies in pregnant women using VIDAZA. If this drug is used during pregnancy or if a patient
becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to
the fetus [see Use in Specific Populations (8.1)].

5.5 Use in Males

Men should be advised to not father a child while receiving treatment with VIDAZA. In animal
studies, pre-conception treatment of male mice and rats resulted in increased embryofetal loss in
mated females [see Nonclinical Toxicology (13)].

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 coma [see Warnings and Precautions (5.2)]
o Elevated serum creatinine, renal failure, and renal tubular acidosis [see Warnings and
Precautions (5.3)]

Most Commonly Occurring Adverse Reactions (SC or IV Route): nausea, anemia,

thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation,
neutropenia, ecchymosis. The most common adverse reactions by IV route also included
petechiae, rigors, weakness and hypokalemia.

Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV

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 VIDAZA in 443 MDS patients from 4 clinical
studies. Study 1 was a supportive-care controlled trial (SC administration), Studies 2 and 3 were
single arm studies (one with SC administration and one with IV administration), and Study 4 was
an international randomized trial (SC administration) [see Clinical Studies (14)].
In Studies 1, 2 and 3, a total of 268 patients were exposed to VIDAZA, including 116 exposed
for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles
(approximately one year). VIDAZA 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 IV 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 VIDAZA. 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 VIDAZA doses
of 75 mg/m2.

Table 1 presents adverse reactions occurring in at least 5% of patients treated with VIDAZA
(SC) in Studies 1 and 2. It is important to note that duration of exposure was longer for the
VIDAZA-treated group than for the observation group: patients received VIDAZA for a mean of
11.4 months while mean time in the observation arm was 6.1 months.

Table 1: Most Frequently Observed Adverse Reactions ( 5.0% in All SC

VIDAZA Treated Patients; Studies 1 and 2)
Number (%) of Patients
b c
System Organ Class All VIDAZA Observation
a
Preferred Term (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)
 Table 1: Most Frequently Observed Adverse Reactions ( 5.0% in All SC
VIDAZA Treated Patients; Studies 1 and 2)
Number (%) of Patients
b c
System Organ Class All VIDAZA Observation
a
Preferred Term (N=220) (N=92)
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)
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 VIDAZA, including patients after crossing over from
observations.
c
Includes adverse reactions from observation period only; excludes any adverse events after crossover to VIDAZA.

Table 2 presents adverse reactions occurring in at least 5% of patients treated with VIDAZA in
Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with
VIDAZA was longer (mean 12.2 months) compared with best supportive care (mean
7.5 months).
 Table 2: Most Frequently Observed Adverse Reactions ( 5.0% in the
VIDAZA Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions;
Study 4)
Number (%) of Patients
Any Grade Grade 3/4
Best Best
Supportive Supportive
System Organ Class VIDAZA Care Only VIDAZA Care Only
a
Preferred Term (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)
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 SC administration of VIDAZA, adverse reactions of neutropenia,
thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site
erythema/reaction tended to increase in incidence with higher doses of VIDAZA. Adverse
reactions that tended to be more pronounced during the first 1 to 2 cycles of SC 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 IV and SC studies. Adverse
reactions that appeared to be specifically associated with the IV 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 SC or IV VIDAZA, the following serious adverse reactions occurring
at a rate of < 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.

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 VIDAZA.
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)

7 DRUG INTERACTIONS

No formal clinical assessments of drug-drug interactions between VIDAZA and other agents
have been conducted [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [see Warning and Precautions (5.4)]

VIDAZA may cause fetal harm when administered to a pregnant woman. Azacitidine was
teratogenic in animals. There are no adequate and well controlled studies with VIDAZA in
pregnant women. Women of childbearing potential should be advised to avoid pregnancy during
treatment with VIDAZA. If this drug is used during pregnancy or if a patient becomes pregnant
while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Female partners of male patients receiving VIDAZA should not become pregnant [see
Nonclinical Toxicology (13.1)].

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 ~3-12 mg/m2 (approximately 4%-16% the recommended
human daily dose on a mg/m2 basis).

In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8
(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 1-3)
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 3-12 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).

8.3 Nursing Mothers

It is not known whether azacitidine or its metabolites are excreted in human milk. Because many
drugs are excreted in human milk and because of the potential for tumorigenicity shown for
azacitidine in animal studies and the potential for serious adverse reactions in nursing infants
from VIDAZA, a decision should be made whether to discontinue nursing or to discontinue the
drug, taking into consideration the importance of the drug to the mother.

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 < 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 < 30 mL/min) has no major effect on the exposure of azacitidine
after multiple SC 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 VIDAZA was reported during clinical trials. A patient experienced
diarrhea, nausea, and vomiting after receiving a single IV 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 VIDAZA overdosage.

11 DESCRIPTION

VIDAZA (azacitidine for injection) contains azacitidine, which is a pyrimidine nucleoside

analog of cytidine. Azacitidine is 4-amino-1--D-ribofuranosyl-s-triazin-2(1H)-one. The
structural formula is as follows:
 NH2

N N

HO N
O
O

OH OH

The empirical formula is C8H12N4O5. The molecular weight is 244. Azacitidine is a white to off-
white solid. 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. Vials of VIDAZA contain 100 mg of azacitidine and 100 mg mannitol as a sterile
lyophilized powder.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

VIDAZA is a pyrimidine nucleoside analog of cytidine. VIDAZA 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 (SC) dose and a single 75 mg/m2 intravenous (IV) dose. Azacitidine is
rapidly absorbed after SC administration; the peak plasma azacitidine concentration of
750 ± 403 ng/ml occurred in 0.5 hour. The bioavailability of SC azacitidine relative to IV
azacitidine is approximately 89%, based on area under the curve. Mean volume of distribution
following IV dosing is 76 ± 26 L. Mean apparent SC clearance is 167 ± 49 L/hour and mean
half-life after SC administration is 41 ± 8 minutes. The AUC and Cmax of SC administration of
azacitidine in 21 patients with cancer 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.

Published studies indicate that urinary excretion is the primary route of elimination of azacitidine
and its metabolites. Following IV administration of radioactive azacitidine to 5 cancer patients,
the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for
<1% of administered radioactivity over 3 days. Mean excretion of radioactivity in urine
following SC administration of 14C-azacitidine was 50%. The mean elimination half-lives of
total radioactivity (azacitidine and its metabolites) were similar after IV and SC administrations,
about 4 hours.

Specific Populations
In patients with cancer the pharmacokinetics of azacitidine in 6 patients with normal renal
function (CLcr > 80 mL/min) and 6 patients with severe renal impairment (CLcr < 30 mL/min)
were compared following daily SC 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 (IV 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
20-80% the recommended human daily dose on a mg/m2 basis) revealed an increased incidence
of testicular tumors compared with controls.

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
15-30 mg/m2 (approximately 20-40%, 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 compared the
safety and efficacy of subcutaneous VIDAZA 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 50.0 x 109/L; required platelet transfusions; or
were neutropenic (ANC <1.0 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 hematopoeitic growth factors was prohibited. Baseline
patient and disease characteristics are summarized in Table 3; the 2 groups were similar.

VIDAZA 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 VIDAZA 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 VIDAZA treatment.
Table 3. Baseline Demographics and Disease Characteristics
VIDAZA Observation
(N=99) (N=92)
Gender (n%)
Male 72 (72.7) 60 (65.2)
Female 27 (27.3) 32 (34.8)
Race (n%)
White 93 (93.9) 85 (92.4)
Black 1 (1.0) 1 (1.1)
Hispanic 3 (3.0) 5 (5.4)
Asian/Oriental 2 (2.0) 1 (1.1)
Age (years)
N 99 91
Mean ± SD 67.3 ± 10.39 68.0 ± 10.23
Range 31 - 92 35 - 88
Adjudicated MDS diagnosis at
study entry (n%)
RA 21 (21.2) 18 (19.6)
RARS 6 (6.1) 5 (5.4)
RAEB 38 (38.4) 39 (42.4)
RAEB-T 16 (16.2) 14 (15.2)
CMMoL 8 (8.1) 7 (7.6)
AML 10 (10.1) 9 (9.8)
Transfusion product used in 3
months before study entry (n%)
Any transfusion product 70 (70.7) 59 (64.1)
Blood cells, packed human 66 (66.7) 55 (59.8)
Platelets, human blood 15 (15.2) 12 (13.0)
Hetastarch 0(0.0) 1(1.1)
Plasma protein fraction 1(1.0) 0(0.0)
Other 2(2.0) 2(2.2)
Table 4. Response Criteria
RA RARS RAEB RAEB-T CMMoL
Complete Marrow <5% blasts
Response
(CR), Normal CBC if abnormal at baseline
Peripheral Absence of blasts in the peripheral circulation
duration
Blood
4 weeks
Partial No marrow requirements ≥50% decrease in blasts
Marrow
Response Improvement of marrow dyspoiesis
(PR), ≥50% restoration in the deficit from normal levels of baseline white
duration Peripheral cells, hemoglobin and platelets if abnormal at baseline
4 weeks Blood
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 VIDAZA-treated patients without AML
(16.2% for all VIDAZA 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 VIDAZA 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.

Table 5. Response Rates

Observation Before
VIDAZA
Crossover
(N=89)
(N=83)
Response n (%) n (%) P value
Overall (CR+PR) 14 (15.7) 0 ( 0.0) (<0.0001)
Complete (CR) 5 ( 5.6) 0 ( 0.0) (0.06)
Partial (PR) 9 (10.1) 0 ( 0.0) --

Patients in the observation group who crossed over to receive VIDAZA 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 VIDAZA 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 VIDAZA 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. VIDAZA 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 VIDAZA-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 38-88 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 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 Azacitidine plus BSC Conventional Care

(n= 179) Regimens
(n= 179)
Number and percent of patients 50/111 (45.0%) 13/114 (11.4%)
who 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 10/68 (14.7%) 28/65 (43.1%)

who were transfusion-independent
at baseline who became
transfusion-dependent 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. Otherwise, the patient was
considered transfusion dependent.

15 REFERENCES

1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health

Care Settings. NIOSH Alert 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational
Exposure to Hazardous Drugs. OSHA, 1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous

drugs. Am J Health-Syst Pharm. (2006) 63:1172-1193.

4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy
guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing
Society.
16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

VIDAZA (azacitidine for injection) is supplied as a lyophilized powder in 100 mg single-use

vials packaged in cartons of 1 vial (NDC 59572-102-01).

Storage

Store unreconstituted vials at 25º C (77º F); excursions permitted to 15º-30º C (59º-86º F) (See
USP Controlled Room Temperature).

Handling and Disposal

Procedures for proper handling and disposal of anticancer drugs should be applied. Several
guidelines on this subject have been published.1-4 There is no general agreement that all of the
procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATION

Instruct patients to inform their physician about any underlying liver or renal disease.

Advise women of childbearing potential to avoid becoming pregnant while receiving treatment
with VIDAZA. For nursing mothers, a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into consideration the importance of the drug to the mother.

Advise men not to father a child while receiving treatment with VIDAZA.

Manufactured for: Celgene Corporation

Summit, NJ 07901

Manufactured by:

Baxter Oncology GmbH

33790 Halle/Westfalen Germany

Or

BSP Pharmaceuticals S.r.l.

04013 Latina Scalo (Lt)
Italy

VIDAZA® is a registered trademark of Celgene Corporation.

©2004-2014 Celgene Corporation, All Rights Reserved.
VIDPI.008 01/14