Azacitidine Injection
Dosage Form: injection,
powder, lyophilized, for solution
INDICATIONS AND USAGE
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).
DOSAGE AND ADMINISTRATION
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.
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.
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
|
% Dose in the
Next
|
|
|
Course
|
|
ANC (x109/L)
|
Platelets (x109/L)
|
|
|
<0.5
|
<25
|
50%
|
|
0.5 to 1.5
|
25.0 to 50
|
67%
|
|
>1.5
|
>50
|
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.
|
WBC or Platelet
|
Bone Marrow
|
|
Nadir
|
Biopsy
Cellularity at Time of Nadir
|
|
% decrease in
|
(%)
|
|
counts from
baseline
|
30 to 60
|
15 to 30
|
<15
|
|
|
|
|
|
% Dose in the
Next Course
|
|
50 to 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 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.
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)].
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)].
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.
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.
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).
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.
DOSAGE FORMS AND
STRENGTHS
Azacitidine
for Injection is supplied as lyophilized powder in 100 mg single-dose
vials.
CONTRAINDICATIONS
Advanced Malignant Hepatic Tumors
Azacitidine
for Injection is contraindicated in patients with advanced malignant hepatic
tumors [see Warnings
and Precautions (5.2)].
Hypersensitivity to Azacitidine
Azacitidine
for Injection is contraindicated in patients with a known hypersensitivity to
azacitidine.
WARNINGS AND
PRECAUTIONSAnemia, 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)].
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.
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.
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 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)].
ADVERSE REACTIONS
The
following adverse reactions are described in other labeling sections:
•
Anemia, neutropenia and
thrombocytopenia [see Warnings
and Precautions (5.1)]
•
Hepatic Toxicity in Patients
with Severe Pre-existing Hepatic Impairment [see Warnings
and Precautions (5.2)]
•
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.
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.
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
|
|
Adverse reactiona
|
(N=220)
|
(N=92)
|
|
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.
|
|
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)
|
|
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)
|
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 Reactiona
|
(N=175)
|
(N=102)
|
(N=175)
|
(N=102)
|
|
|
a Multiple reports of the same
preferred term from a patient were only counted once within each
treatment.
|
|
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)
|
|
|
|
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.
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.
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)
USE IN SPECIFIC
POPULATIONSPregnancy
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 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).
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.
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
Based
on animal data, advise males that Azacitidine for Injection may impair
fertility [see Nonclinical
Toxicology (13.1)].
Pediatric Use
Safety
and effectiveness in pediatric patients have not been established.
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)].
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)].
Gender
There
were no clinically relevant differences in safety and efficacy based on gender.
Race
Greater
than 90% of all patients in all trials were Caucasian. Therefore, no
comparisons between Caucasians and non-Caucasians were possible.
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.
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:
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.
CLINICAL PHARMACOLOGYMechanism 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.
Pharmacokinetics
The
pharmacokinetics of azacitidine were studied in 6 MDS patients following a
single 75 mg/m2subcutaneous 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 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.
NONCLINICAL TOXICOLOGYCarcinogenesis, 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.
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.
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 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
|
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 to 92
|
35 to 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 Response
|
Marrow
|
<5% blasts
|
|
Peripheral
|
Normal CBC if abnormal at baseline
|
|
|
(CR), duration
|
Blood
|
Absence of blasts in the peripheral circulation
|
|
≥4 weeks
|
|
|
|
Partial
|
Marrow
|
No marrow requirements
|
≥50% decrease in blasts
|
|
Response
|
|
|
Improvement of marrow dyspoiesis
|
|
(PR), duration
|
Peripheral
|
≥50% restoration in the deficit from normal levels
of baseline white cells,
|
|
≥4 weeks
|
Blood
|
hemoglobin and platelets if abnormal at baseline
|
|
|
|
|
|
|
|
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.
|
|
|
|
Azacitidine for
|
Observation Before
|
|
|
|
Injection
|
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 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 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)
|
|
|
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.
|
|
Number and percent of patients who were
|
50/111
(45.0%)
|
13/114
(11.4%)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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 were
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
transfusion-independent at baseline who
|
10/68
(14.7%)
|
28/65
(43.1%)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
became transfusion-dependent on
treatment
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
(95%
CI: 7.3%, 25.4%)
|
(95%
CI: 30.9%, 56.0%)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
REFERENCES
1.
“OSHA Hazardous Drugs.” OSHA.
http://www.osha.gov/SLTC/hazardousdrugs/index.html
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 68001-313-56).
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.
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
For
BluePoint Laboratories
Revised
– September 2016
PACKAGE LABEL.PRINCIPAL
DISPLAY PANEL
|
AZACITIDINE Azacitidine Injection,
powder, lyophilized, for solution
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:68001-313
|
|
Route of
Administration
|
INTRAVENOUS, SUBCUTANEOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
AZACITIDINE (AZACITIDINE)
|
AZACITIDINE
|
100 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
SUCROSE
|
|
|
SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE
|
|
|
SODIUM PHOSPHATE, DIBASIC, DIHYDRATE
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:68001-313-56
|
1 INJECTION,
POWDER, LYOPHILIZED, FOR SOLUTION in 1 CARTON
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA208216
|
07/01/2017
|
|
|
|
Labeler - BluePoint Laboratories (985523874)
|
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Sindan-Pharma
Srl
|
|
683754121
|
ANALYSIS(68001-313),
LABEL(68001-313), MANUFACTURE(68001-313), PACK(68001-313)
|
Revised: 07/2017
BluePoint Laboratories
