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‫בעלון ללרופא‬
‫בטיחות) בעלון‬
)‫מידע בטיחות‬
‫החמרה (( מידע‬
‫על החמרה‬
‫הודעה על‬
‫הודעה‬
)).102.50
.102.50 ‫(מעודכן‬
‫(מעודכן‬
_____________11.07.13__________ ‫תאריך‬
DACOGEN, ___ ‫שם תכשיר באנגלית ומספר הרישום‬
143-65-31633-00
____J-C Health Care Ltd.__ ‫שם בעל הרישום‬
! ‫טופס זה מיועד לפרוט ההחמרות בלבד‬
‫ההחמרות המבוקשות‬
‫טקסט חדש‬
‫טקסט נוכחי‬
DACOGEN is indicated for the treatment of patients with DACOGEN is indicated for the
myelodysplastic syndromes (MDS) including previously treated and
treatment
of
patients
with
untreated, de novo and secondary MDS of all French-American-British
myelodysplastic syndromes (MDS)
(FAB) subtypes (refractory anemia, refractory anemia with ringed
including previously treated and
sideroblasts, refractory anemia with excess blasts, refractory anemia
untreated, de novo and secondary
with excess blasts in transformation, and chronic myelomonocytic
MDS of all French-American-British
leukemia)and Intermediate-1, Intermediate-2, and High-Risk
(FAB) subtypes (refractory anemia,
refractory anemia
with
ringed
International Prognostic Scoring System groups.
sideroblasts, refractory anemia with
excess blasts, refractory anemia with
DACOGEN is indicated for the treatment of adult patients aged 65 years
and above with newly diagnosed de novo or secondary acute myeloid
excess blasts in transformation, and
leukaemia (AML), according to the World Health Organisation (WHO)
chronic myelomonocytic leukemia)and
classification, who are not candidates for standard induction
Intermediate-1, Intermediate-2, and
chemotherapy.
High-Risk International Prognostic
Scoring System groups.
‫פרק בעלון‬
Indication
contraindications
Posology and Method of Administration DOSAGE AND
ADMINISTRATION
Dacogen must be administered under the supervision of
physicians experienced in the treatment of MDS.
DACOGEN administration must be initiated under the supervision of
physicians experienced in the use of chemotherapeutic agents.
Posology
There are 2 regimens recommended for DACOGEN administration. A
5-Day dosing regimen in the treatment of AML, and a 3-Day or 5-Day
dosing regimen in the treatment of MDS.
Pre-medication for the prevention of nausea and vomiting is not
routinely recommended but may be administered if required.
MDS
There are two regimens for Dacogen administration for MDS.
With either regimen It is recommended that patients be treated
for a minimum of 4 cycles; however, a complete or partial
remission response may take longer than 4 cycles to be
obtained.
Complete blood counts and platelet counts should be performed
as needed to monitor response and toxicity, but at a minimum,
prior to each cycle. Liver chemistries and serum creatinine
should be obtained prior to initiation of treatment.
In the AML Phase 3 study, the median time to response
(complete and partial remission) according to the International
Working Group criteria (IWG 2000), which includes transfusion
independence, was 3 treatment cycles. (complete remission [CR]
2 DOSAGE AND
ADMINISTRATION
Dacogen must be administered
under the supervision of physicians
experienced in the treatment of
MDS.
Pre-medication for the prevention
of nausea and vomiting is not
routinely recommended but may
be administered if required.
There are two regimens for
Dacogen administration. With
either regimen It is recommended
that patients be treated for a
minimum of 4 cycles; however, a
complete or partial remission may
take longer than 4 cycles to be
obtained.
In Phase 3 study, the median time
to response (complete and partial
remission) according to the
International Working Group
criteria (IWG 2000), which includes
transfusion independence, was 3
treatment cycles. Treatment may
be continued as long as the patient
shows response, continues to
benefit or exhibits stable disease,
i.e., in the absence of overt
progression.
If after 4 cycles, the patient’s
hematological values (e.g., platelet
counts or absolute neutrophil count
[ANC]), have not returned to pretreatment levels or if disease
progression occurs (peripheral
blast counts are increasing or bone
marrow blast counts are
worsening), the patient may be
Posology, dosage &
administration
or CR with incomplete platelet recovery [CRp]) was 4.3 months.
In MDS, the median time to response (CR+PR) in the Phase 2
MDS studies with the 5-Day dosing
regimen was 3.5 cycles. In the Phase 3 MDS study with the 3Day dosing regimen, the median time to response was 3 cycles.
Treatment may be continued as long as the patient shows
response, continues to benefit or exhibits stable disease, i.e., in
the absence of overt progression.
If after 4 cycles, the patient’s hematological values (e.g., platelet
counts or absolute neutrophil count [ANC]), have not returned to
pre-treatment levels or if disease progression occurs (peripheral
blast counts are increasing or bone marrow blast counts are
worsening), the patient may be considered to be a nonresponder and alternative therapeutic options to Dacogen should
be considered.
2.1 Treatment Regimen – Option 1
Dacogen is administered at a dose of 15 mg/m2 body surface by
continuous intravenous infusion over 3 hours repeated every 8
hours for 3 days. This cycle should be repeated every 6 weeks
depending on the patient's clinical response and observed
toxicity. The total daily dose must not exceed 45 mg/m2 and the
total dose per treatment cycle must not exceed 135 mg/m2. If a
dose is missed, treatment should be resumed as soon as
possible. Patients may be premedicated with standard antiemetic therapy.
2.2 Treatment Regimen – Option 2
Dacogen is administered at a dose of 20 mg/m2 by continuous
intravenous infusion over 1 hour repeated daily for 5 days. This
cycle should be repeated every 4 weeks. Patients may be
premedicated with standard anti-emetic therapy.
If myelosuppression is present, subsequent treatment cycles of
Dacogen should be delayed until there is hematologic recovery
(ANC ≥ 1,000/μL platelets ≥ 50,000/μL ).
Patients with Non-hematologic Toxicity
Following treatment with either DACOGEN regimen, if the
following non-hematological toxicities occur, the next cycle of
DACOGEN therapy should be withheld until levels return to
within the normal range or baseline:

Serum creatinine greater than or equal to 2 mg/dL.
Serum glutamate pyruvate transaminase (SGPT) or alanine
aminotransferase (ALT) or total bilirubin greater than or equal to
2 times the upper limit of normal.
considered to be a non-responder
and alternative therapeutic options
to Dacogen should be considered.
Complete blood counts and
platelet counts should be
performed as needed to monitor
response and toxicity, but at a
minimum, prior to each cycle. Liver
chemistries and serum creatinine
should be obtained prior to
initiation of treatment.
2.1 Treatment Regimen – Option
1
Dacogen is administered at a dose
of 15 mg/m2 body surface by
continuous intravenous infusion
over 3 hours repeated every 8
hours for 3 days. This cycle should
be repeated every 6 weeks
depending on the patient's clinical
response and observed toxicity.
The total daily dose must not
exceed 45 mg/m2 and the total
dose per treatment cycle must not
exceed 135 mg/m2. If a dose is
missed, treatment should be
resumed as soon as possible.
Patients may be premedicated with
standard anti-emetic therapy.
2.2 Treatment Regimen – Option
2
Dacogen is administered at a dose
of 20 mg/m2 by continuous
intravenous infusion over 1 hour
repeated daily for 5 days. This
cycle should be repeated every 4
weeks. Patients may be
premedicated with standard antiemetic therapy.
If myelosuppression is present,
subsequent treatment cycles of
Dacogen should be delayed until
there is hematologic recovery
(ANC ≥ 1,000/μL platelets ≥
50,000/μL ).

Active viral or bacterial infection that is not controlled
by concomitant anti-infective therapy.
Management of Grade 3-4
Myelosuppression in the First
3Treatment Cycles
AML
In a treatment cycle, Dacogen is administered at a dose of 20 mg/m2
body surface area by intravenous infusion over 1 hour repeated daily
for 5 consecutive days (i.e., a total of 5 doses per treatment cycle). The
total daily dose must not exceed 20 mg/m2 and the total dose per
treatment cycle must not exceed 100 mg/m2. If a dose is missed,
treatment should be resumed as soon as possible. The cycle should be
repeated every 4 weeks depending on the patient's clinical response and
observed toxicity. It is recommended that patients be treated for a
minimum of 4 cycles; however, a complete or partial remission may
take longer than 4 cycles to be obtained. Treatment may be continued
as long as the patient shows response, continues to benefit or exhibits
stable disease, i.e., in the absence of overt progression.
During the first cycles of treatment,
Grade 3-4 cytopenias are common
and may not represent progression
of MDS. Pre-treatment cytopenias
may not improve until after Cycle
3.
If after 4 cycles, the patient’s haematological values (e.g., platelet
counts or absolute neutrophil count), have not returned to pre-treatment
levels or if disease progression occurs (peripheral blast counts are
increasing or bone marrow blast counts are worsening), the patient may
be considered to be a non responder and alternative therapeutic options
to Dacogen should be considered.
Management of myelosuppression and associated complications
Myelosuppression and adverse events related to myelosuppression
(thrombocytopenia, anaemia, neutropenia, and febrile neutropenia) are
common in both treated and untreated patients with AML and MDS.
Complications of myelosuppression include infections and bleeding.
Treatment may be modified in patients experiencing myelosuppression
and associated complications as described below:
For the first 3 cycles, to optimize
patient benefit in the setting of
moderate neutropenia (absolute
neutrophil count < 1000/µL), all
attempts should be made to
maintain full dose treatment at the
standard treatment cycle interval.
Concomitant
antimicrobial
prophylaxis as per institutional
guidelines can be administered
until recovery of granulocytes to
above 500/µL. Clinicians should
also consider the need for early
administration of growth factors
during this time for the prevention
or treatment of infections in
patients with MDS.
Similarly, to optimize patient
benefit in the setting of moderate
thrombocytopenia (platelet count
<25,000/µL), all attempts should be
made to maintain full dose
treatment
at
the
standard
In AML
Treatment may be delayed at the discretion of the treating physician, if
the patient experiences myelosuppression-associated complications,
such as those described below:

Febrile neutropenia (temperature ≥ 38.5°C and absolute
neutrophil count < 1,000/μL)

Active viral, bacterial or fungal infection (i.e., requiring
intravenous anti-infectives or extensive supportive care)

Haemorrhage (gastrointestinal, genito-urinary, pulmonary
with platelets < 25,000/μL or any central nervous system haemorrhage)
Treatment with DACOGEN may be resumed once these conditions
have improved or have been stabilized with adequate treatment (antiinfective therapy, transfusions, or growth factors).
In clinical studies, approximately one-third of patients receiving
DACOGEN required a dose-delay. Dose reduction is not
recommended.
In MDS
3-Day Dosing Regimen
Dose Regimen Modifications in the First 3 Cycles
Management of Grade 3-4 Myelosuppression in the First
3Treatment Cycles
During the first cycles of treatment, Grade 3-4 cytopenias are
common and may not represent progression of MDS. Pretreatment cytopenias may not improve until after Cycle 3.
For the first 3 cycles, to optimize patient benefit in the setting of
moderate neutropenia (absolute neutrophil count < 1000/µL), all
attempts should be made to maintain full dose treatment at the
standard treatment cycle interval. Concomitant antimicrobial
prophylaxis as per institutional guidelines can be administered
until recovery of granulocytes to above 500/µL. Clinicians should
also consider the need for early administration of growth factors
during this time for the prevention or treatment of infections in
patients with MDS.
Similarly, to optimize patient benefit in the setting of moderate
thrombocytopenia (platelet count <25,000/µL), all attempts
should be made to maintain full dose treatment at the standard
treatment cycle interval with concomitant administration of
platelet transfusions in case of bleeding events.
Management of Grade 3-4 Myelosuppression Beyond the
First 3 Treatment Cycles
Dose Modifications After Cycle 3
If hematologic recovery (ANC absolute neutrophil count ≥
1,000/μL and platelets ≥ 50,000/μL) from a previous Dacogen
treatment cycle with persistent cytopenia(s) being considered
related to drug administration, requires more than 6 weeks, then
the next cycle of Dacogen therapy should be delayed and dosing
reduced by the algorithm below. All dose reductions that occur
should remain in effect for the duration of the chemotherapy;
there should be no dose re-escalation.
• Recovery requiring more than 6, but less than 8 weeks −
Dacogen dosing to be delayed for
up to 2 weeks and the dose reduced to 11 mg/m2 every 8
hours (33 mg/m2/day,
99 mg/m2/cycle) upon restarting therapy.
• Recovery requiring more than 8, but less than 10 weeks – the
Dacogen dose should be delayed up to 2 more weeks and the
dose reduced to 11 mg/m2 every 8 hours (33 mg/m2/day, 99
mg/m2/cycle) upon restarting therapy, then maintained in
subsequent cycles as clinically indicated.
• Recovery requiring more than 10 weeks – Patient should be
discontinued from the treatment
of the drug and assessed for disease progression (by bone
marrow aspirate) within 7 days
after the end of 10 weeks. However, for patients who have
been treated for at least 6 cycles,
and who continue to derive benefit from the therapy, a
prolonged delay beyond 10 weeks
can be allowed, in the absence of progression at the direction
of the treating physician.
treatment cycle interval with
concomitant
administration
of
platelet transfusions in case of
bleeding events.
Management of Grade 3-4
Myelosuppression Beyond the
First 3 Treatment Cycles
Dose Modifications After Cycle 3
If hematologic recovery (ANC ≥
1,000/μL and platelets ≥
50,000/μL) from a previous
Dacogen treatment cycle with
persistent cytopenia(s) being
considered related to drug
administration, requires more than
6 weeks, then the next cycle of
Dacogen therapy should be
delayed and dosing reduced by the
algorithm below. All dose
reductions that occur should
remain in effect for the duration of
the chemotherapy; there should be
no dose re-escalation.
• Recovery requiring more than 6,
but less than 8 weeks − Dacogen
dosing to be delayed for
up to 2 weeks and the dose
reduced to 11 mg/m2 every 8 hours
(33 mg/m2/day,
99 mg/m2/cycle) upon restarting
therapy.
• Recovery requiring more than 8,
but less than 10 weeks − The
Dacogen dose should be delayed
up to 2 more weeks and the dose
reduced to 11 mg/m2 every 8
hours
(33 mg/m2/day, 99 mg/m2/cycle)
upon restarting therapy, then
maintained in subsequent cycles
as clinically indicated.
• Recovery requiring more than 10
weeks – Patient should be
discontinued from the treatment
of the drug and assessed for
disease progression (by bone
marrow aspirate) within 7 days
after the end of 10 weeks.
However, for patients who have
been treated for at least 6 cycles,
and who continue to derive
benefit from the therapy, a
prolonged delay beyond 10 weeks
can be allowed, in the absence of
progression at the direction of the
treating physician.
Subsequent Treatment Cycles
The above cycle should be
repeated every 6 weeks depending
on the patient's clinical response
and observed toxicity. The total
daily dose must not exceed 45
mg/m2 and the total dose per
treatment cycle must not exceed
135 mg/m2. If a dose is missed,
treatment should be resumed as
soon
as
possible.
It
is
recommended that patients be
treated for a minimum of 4 cycles;
however, a complete or partial
response may take longer than 4
cycles.
Treatment
may
be
continued as long as the patient
continues to benefit.
In Phase 3 study, the median time
to response (complete and partial
remission) according to the
Subsequent Treatment Cycles
The above cycle should be repeated every 6 weeks depending
on the patient's clinical response and observed toxicity. The total
daily dose must not exceed 45 mg/m2 and the total dose per
treatment cycle must not exceed 135 mg/m2. If a dose is missed,
treatment should be resumed as soon as possible. It is
recommended that patients be treated for a minimum of 4 cycles;
however, a complete or partial response may take longer than 4
cycles. Treatment may be continued as long as the patient
continues to benefit.
In Phase 3 study, the median time to response (complete and
partial remission) according to the International Working Group
criteria (IWG 2000), which includes transfusion independence,
was 3 treatment cycles. Treatment may be continued as long as
the patient shows response, continues to benefit or exhibits
stable disease, i.e., in the absence of overt progression. If after
4 cycles, the patient’s hematological values (e.g., platelet counts
or absolute neutrophil count [ANC]), have not returned to pretreatment levels or if disease progression occurs (peripheral
blast counts are increasing or bone marrow blast counts are
worsening), the patient may be considered to be a nonresponder and alternative therapeutic options to Dacogen should
be considered.
5-Day Dosing Regimen
Dose reduction is not recommended in this clinical setting to optimize
patient benefit, dose should be delayed as follows:
Management of Grade 3-4 Myelosuppression in the First
3Treatment Cycles
Dose Regimen Modifications in the first 3 Cycles
During the first cycles of treatment, Grade 3 and - 4 cytopenias
are common and may not represent progression of MDS. Pretreatment cytopenias may not improve until after Cycle 3.
For the first 3 cycles, to optimize patient benefit in the setting of
moderate neutropenia (absolute neutrophil count < 1000/µL), all
attempts should be made to maintain full dose treatment at the
standard treatment cycle interval. Concomitant antimicrobial
prophylaxis as per institutional guidelines can be administered
until recovery of granulocytes to above 500/µL. Clinicians should
also consider the need for early administration of growth factors
during this time for the prevention or treatment of infections in
patients with MDS.
Similarly, to optimize patient benefit in the setting of moderate
thrombocytopenia (platelet count <25,000/µL), all attempts
should be made to maintain full dose treatment at the standard
treatment cycle interval with concomitant administration of
platelet transfusions in case of bleeding events.
Management of Grade 3-4 Myelosuppression Beyond the
First 3 Treatment Cycles
Dose Regimen Modifications After Cycle 3
International Working Group
criteria (IWG 2000), which includes
transfusion independence, was 3
treatment cycles. Treatment may
be continued as long as the patient
shows response, continues to
benefit or exhibits stable disease,
i.e., in the absence of overt
progression. If after 4 cycles, the
patient’s hematological values
(e.g., platelet counts or absolute
neutrophil count [ANC]), have not
returned to pre-treatment levels or
if disease progression occurs
(peripheral blast counts are
increasing or bone marrow blast
counts are worsening), the patient
may be considered to be a nonresponder and alternative
therapeutic options to Dacogen
should be considered.
Management of Grade 3-4
Myelosuppression in the First
3Treatment Cycles
During the first cycles of treatment,
Grade 3-4 cytopenias are common
and may not represent progression
of MDS. Pre-treatment cytopenias
may not improve until after Cycle
3.
For the first 3 cycles, to optimize
patient benefit in the setting of
moderate neutropenia (absolute
neutrophil count < 1000/µL), all
attempts should be made to
maintain full dose treatment at the
standard treatment cycle interval.
Concomitant
antimicrobial
prophylaxis as per institutional
guidelines can be administered
until recovery of granulocytes to
above 500/µL. Clinicians should
also consider the need for early
administration of growth factors
during this time for the prevention
or treatment of infections in
patients with MDS.
Similarly, to optimize patient
benefit in the setting of moderate
thrombocytopenia (platelet count
<25,000/µL), all attempts should be
made to maintain full dose
treatment
at
the
standard
treatment cycle interval with
concomitant
administration
of
platelet transfusions in case of
bleeding events.
Dose reduction is not recommended in this clinical setting to
optimize patient benefit. Dose should be delayed in case of the
following toxicities considered to be at least possibly related to
Management of Grade 3-4
Myelosuppression Beyond the
First 3 Treatment Cycles
the treatment:

Grade 3-4 non-myelosuppressive toxicities

Severe myelosuppression-associated complications
Dose
Regimen
(infections not resolving with adequate anti-infective therapy,
Dose
bleeding not resolving with adequate treatment)
recommended

Modifications
After Cycle 3
reduction
in
is
this
not
clinical
setting to optimize patient benefit.
Prolonged
myelosuppression
defined
as
a
hypocellular marrow (5% or less cellularity) without evidence of
disease progression for 6 weeks or more after the start of a
course of therapy
Dose should be delayed in case of
the following toxicities considered
to be at least possibly related to
the treatment:

Grade 3-4 non-
If recovery (ANC absolute neutrophil count >1,000/µL and
myelosuppressiv
platelets >50,000/µL) requires more than 8 weeks, the patient
e toxicities
should be discontinued from the treatment of drug and assessed

for disease progression (by bone marrow aspirate) within 7 days
Severe
after the end of 8 weeks. For patients who have been treated for
myelosuppressio
at least 6 cycles, and who continue to derive benefit from the
n-associated
therapy, a prolonged delay beyond 8 weeks can be allowed, in
complications
the absence of progression, at the discretion of the treating
(infections
not
physician.
resolving
with
adequate
anti-
infective therapy,
Special Populations:
Paediatric population
The safety and efficacy of Dacogen in children aged < 18 years have
not yet been established. No data are available.
bleeding
not
resolving
with
adequate
treatment)
Pediatric Use
The safety and effectiveness of Dacogen in pediatric patients
have not been established.

Prolonged
myelosuppressio
Hepatic impairment
n defined as a
Studies in patients with hepatic impairment have not been conducted.
The need for dose adjustment in patients with hepatic impairment has
not been evaluated. There are no data on the use of Dacogen in
patients with hepatic dysfunction; therefore, Dacogen should be
used with caution in these patients. If worsening hepatic function
occurs, patients should be carefully monitored (see sections 4.4 and
5.2).
hypocellular
marrow (5%
less
or
cellularity)
without evidence
of
disease
progression for 6
Renal impairment
weeks or more
Studies in patients with renal impairment have not been conducted.
There are no data on the use of Dacogen in patients with renal
dysfunction; therefore, Dacogen should be used with caution in
these patients.
after the start of a
course of therapy
If recovery (ANC >1,000/µL and
The need for dose adjustment in patients with renal impairment has not
been evaluated (see section 4.4 and 5.2).
The use of Dacogen in patients with renal or hepatic impairment
has not been established. Caution should be exercised in the
administration of Dacogen to patients with hepatic or renal
impairment and patients should be monitored closely for signs of
toxicity.
platelets >50,000/µL) requires
more than 8 weeks, the patient
should be discontinued from the
treatment of drug and assessed for
disease progression (by bone
marrow aspirate) within 7 days
after the end of 8 weeks. For
patients who have been treated for
Geriatric Use
Of the total number of MDS patients exposed to Dacogen in the
controlled clinical trial, 61 of 83 patients were age 65 and over,
while 21 of 83 patients were age 75 and over. No overall
differences in safety or effectiveness were observed between
these subjects and younger subjects, and other reported clinical
experience has not identified differences in responses between
the elderly and younger patients, but greater sensitivity of some
older individuals cannot be ruled out.
at least 6 cycles, and who continue
to derive benefit from the therapy,
a prolonged delay beyond 8 weeks
can be allowed, in the absence of
progression, at the discretion of the
treating physician.
2.3 Patients with Nonhematologic Toxicity
Method of Administration
DACOGEN is administered by intravenous infusion. A central venous
catheter is not required. For instructions on reconstitution and dilution
of the medicinal product before administration, see Section 6.6.
Following treatment with either
DACOGEN
regimen,
if
the
following
non-hematological
toxicities occur, the next cycle of
DACOGEN therapy should be
withheld until levels return to within
the normal range or baseline:

Serum creatinine greater
than or equal to 2 mg/dL.
Serum glutamate pyruvate
transaminase (SGPT) or
alanine
aminotransferase
(ALT) or total bilirubin greater
than or equal to 2 times the
upper limit of normal.

Active viral or bacterial
infection that is not controlled
by concomitant anti-infective
therapy.
2.4 Instructions for Intravenous
Administration
Dacogen is a cytotoxic drug and
caution should be exercised when
handling and preparing Dacogen.
Procedures for proper handling
and disposal of antineoplastic
drugs should be applied. Several
guidances on this subject have
been published.
Dacogen product is for single use
only.
Dacogen is administered by
intravenous infusion. A central
venous catheter is not required.
Dacogen should be aseptically
reconstituted with 10 mL of Sterile
Water for Injection; upon
reconstitution, each mL contains
approximately 5.0 mg of decitabine
at pH 6.7-to7.3.
Immediately after reconstitution,
the solution should be further
diluted with 0.9% Sodium Chloride
Injection, 5% Dextrose Injection, or
Lactated Ringer’s Injection to a
final drug concentration of 0.1 - 1.0
mg/mL. Unless used within 15
minutes of reconstitution, the
diluted
solution must be prepared using
cold (2°C - 8°C) infusion fluids and
stored at 2°C - 8°C for up to a
maximum of 7 hours until
administration.
Myelosuppresion
Myelosuppression and complications of myelosuppression, including
infections and bleeding that occur in patients with MDS or AML may
be exacerbated with DACOGEN treatment. In AML clinical studies,
the majority of patients had baseline Grade 3/4 myelosuppression. In
patients with baseline Grade 2 abnormalities, worsening of
myelosuppression was seen in most patients and more frequently than
in patients with baseline Grade 1 or 0 abnormalities. Myelosuppression
caused by DACOGEN is reversible.
Complete blood and platelet counts should be performed regularly, as
clinically indicated and prior to each treatment cycle. In the presence
of myelosuppression or its complications, treatment with DACOGEN
may be interrupted or supportive measures instituted (see sections 4.2
and 4.8).
Myelosuppression and complications of myelosuppression that
occur in patients with MDS may be exacerbated with Dacogen
treatment. Myelosuppression caused by Dacogen is reversible.
Complete blood and platelet counts should be performed
regularly, as clinically indicated and prior to each treatment
cycle. In the presence of myelosuppression or its complications,
treatment with DACOGEN may be interrupted or the dose
reduced as recommended in Section dosage and
administration.
The use of Dacogen in patients with renal or hepatic impairment
has not been established. Caution should be exercised in the
administration of Dacogen to patients with hepatic or renal
impairment and patients should be monitored closely for signs of
toxicity.
Neutropenia and Thrombocytopenia
Treatment with Dacogen is associated with neutropenia and
thrombocytopenia. Complete blood and platelet counts should
be performed as needed to monitor response and toxicity, but at
a minimum, prior to each dosing cycle. After administration of
the recommended dosage for the first cycle, treatment for
subsequent cycles should be adjusted [see Posoloy Dosage
and Administration (2.1, 2.2)].
Clinicians should consider the need for early institution of growth
factors and/or antimicrobial agents for the prevention or
treatment of infections in patients with MDS. Myelosuppression
and worsening neutropenia may occur more frequently in the
first or second treatment cycles, and may not necessarily
indicate progression of underlying MDS.
Hepatic impairment
Myelosuppression
and
complications of myelosuppression
that occur in patients with MDS
may be exacerbated with Dacogen
treatment.
Myelosuppression
caused by Dacogen is reversible.
Complete blood and platelet
counts should be performed
regularly, as clinically indicated
and prior to each treatment cycle.
In
the
presence
of
myelosuppression
or
its
complications,
treatment
with
DACOGEN may be interrupted or
the
dose
reduced
as
recommended in Section dosage
and administration.
The use of Dacogen in patients
with renal or hepatic impairment
has not been established. Caution
should be exercised in the
administration of Dacogen to
patients with hepatic or renal
impairment and patients should be
monitored closely for signs of
toxicity.
5.1 Neutropenia and
Thrombocytopenia
Treatment with Dacogen is
associated with neutropenia and
thrombocytopenia. Complete blood
and platelet counts should be
performed as needed to monitor
response and toxicity, but at a
minimum, prior to each dosing
cycle. After administration of the
recommended dosage for the first
cycle, treatment for subsequent
cycles should be adjusted [see
Dosage and Administration (2.1,
2.2)].
Clinicians should consider the
need for early institution of growth
factors and/or antimicrobial agents
for the prevention or treatment of
infections in patients with MDS.
Myelosuppression and worsening
Special Warnings and
Special Precautions
for Use
The use of Dacogen in patients with hepatic impairment has not been
established. Caution should be exercised in the administration of
Dacogen to patients with hepatic impairment and patients should be
monitored closely (see sections 4.2 and 5.2).
Renal impairment
The use of DACOGEN in patients with severe renal impairment has not
been studied. Caution should be exercised in the administration of
DACOGEN to patients with severe renal impairment (Creatinine
Clearance [CrCl] <30 ml/min) and these patients should be monitored
closely (see section 4.2).
Cardiac disease
Patients with a history of severe congestive heart failure or clinically
unstable cardiac disease were excluded from clinical studies and
therefore the safety and efficacy of DACOGEN in these patients has
not been established.
Excipients
This medicine contains 0.5 mmol potassium per vial. After
reconstitution and dilution of the solution for intravenous infusion, this
medicine contains between 1-10 mmol potassium per dose depending
on the infusion fluid for dilution. To be taken into consideration by
patients with reduced kidney function or patients on a controlled
potassium diet.
This medicine contains 0.29 mmol sodium per vial. After reconstitution
and dilution of the solution for intravenous infusion, this medicine
contains between 0.6-6 mmol sodium per dose depending on the
infusion fluid for dilution. To be taken into consideration by patients
on a controlled sodium diet.
Use in Pregnancy
Dacogen can cause fetal harm when administered to a pregnant
woman. Based on its mechanism of action, Dacogen is
expected to result in adverse reproductive effects. In preclinical
studies in mice and rats, decitabine was teratogenic, fetotoxic,
and embryotoxic.
There are no adequate and well-controlled studies of Dacogen in
pregnant women. If this drug is used during pregnancy, or if a
patient becomes pregnant while receiving this drug, the patient
should be apprised of the potential hazard to the fetus. Women
of childbearing potential should be advised to avoid becoming
pregnant while taking Dacogen [see Use in Specific Populations
(8.1)]
Use in Women of Childbearing Potential
Women of childbearing potential should be advised to avoid
becoming pregnant while receiving Dacogen and for 1 month
following completion of treatment. The time period following
treatment with Dacogen where it is safe to become pregnant is
unknown. Women of childbearing potential should be counseled
to use effective contraception during this time [see Use in
Specific Populations (8.1)]. Based on its mechanism of action,
Dacogen can cause fetal harm if used during pregnancy.
Decitabine is teratogenic in rats and mice. There are no
adequate and well-controlled studies from the use of DACOGEN
in pregnant women. DACOGEN is contraindicated during
pregnancy. If women become pregnant while receiving
DACOGEN, treatment should stop immediately, and the patient
should be apprised of the potential hazard to the fetus.
Use in Men
Men should be advised not to father a child while receiving
treatment with Dacogen, and for 2 3 months following
completion of treatment [see Nonclinical Toxicology (13.1)].
Men with female partners of childbearing potential should use
effective contraception during this time. Based on its mechanism
of action, Dacogen alters DNA synthesis and can cause fetal
harm.
Because of the possibility of infertility as a consequence of
Dacogen therapy, men should seek advice on conservation of
sperm prior to any treatment.
neutropenia may occur more
frequently in the first or second
treatment cycles, and may not
necessarily indicate progression of
underlying MDS.
5.2 Use in Pregnancy
Dacogen can cause fetal harm
when administered to a pregnant
woman. Based on its mechanism
of action, Dacogen is expected to
result in adverse reproductive
effects. In preclinical studies in
mice and rats, decitabine was
teratogenic, fetotoxic, and
embryotoxic.
There are no adequate and wellcontrolled studies of Dacogen in
pregnant women. If this drug is
used during pregnancy, or if a
patient becomes pregnant while
receiving this drug, the patient
should be apprised of the potential
hazard to the fetus. Women of
childbearing
potential should be advised to
avoid becoming pregnant while
taking Dacogen [see Use in
Specific Populations (8.1)]
5.3 Use in Women of
Childbearing Potential
Women of childbearing potential
should be advised to avoid
becoming pregnant while receiving
Dacogen and for 1 month following
completion of treatment. Women of
childbearing potential should be
counseled to use effective
contraception during this time [see
Use in Specific Populations (8.1)].
Based on its mechanism of action,
Dacogen can cause fetal harm if
used during pregnancy.
Decitabine is teratogenic in rats
and mice. There are no adequate
and well-controlled studies from
the use of DACOGEN in pregnant
women.
DACOGEN
is
contraindicated during pregnancy.
If women become pregnant while
receiving DACOGEN, treatment
should stop immediately, and the
patient should be apprised of the
potential hazard to the fetus.
5.4 Use in Men
Men should be advised not to
father a child while receiving
treatment with Dacogen, and for 2
months following completion of
treatment [see Nonclinical
Toxicology (13.1)]. Men with
female partners of childbearing
potential should use effective
contraception during this time.
Based on its mechanism of action,
Dacogen alters DNA synthesis and
can cause fetal harm.
Because of the possibility of
infertility as a consequence of
Dacogen therapy, men should
seek advice on conservation of
sperm prior to any treatment.
5.5 Effects on Ability to drive
and Use Machines
No studies have been performed
on the effects of Dacogen on the
ability to drive or use machines. If
patients experience asthenia,
fatigue, dizziness, or anemia,
caution should be exercised when
driving or operating machinery.
Impact of co-administered drugs on decitabine
Impact of co-administered drugs
on decitabine
Displacement of decitabine from its
plasma
protein
binding
by
Interaction with
Other Medicaments
Displacement of decitabine from its plasma protein binding
by co-administered drugs is unlikely given the negligible in
vitro plasma protein binding ( 1%) of decitabine. There is
the potential for a pharmacokinetic drug-drug interaction
with other agents, such as cytarabine, which are also
activated by sequential phosphorylation (via intracellular
phosphokinase activities) and/or metabolized by enzymes
implicated in the inactivation of decitabine (e.g., cytidine
deaminase). In vitro data indicated that decitabine is a poor
P-glycoprotein (P-gp) substrate and is therefore not prone
to interaction with P-gp inhibitors.
Impact of decitabine on co-administered drugs
Given its low in vitro plasma protein binding ( 1%),
decitabine is unlikely to displace co-administered drugs
from their plasma protein binding. Decitabine is a weak
inhibitor of the major human cytochrome P450 enzymes
(CYP): in vitro IC50 values towards inhibition of CYP1A2,
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 were
in excess of 5700 ng/mL. In each case, these IC50-values
are much higher than the maximum plasma concentrations
of decitabine achieved in patients (plasma Cmax-values <
100 ng/mL) treated as described in Section 4.2. Similarly,
decitabine does not induce major CYPs (CYP1A2, 2B6,
2C9, and 3A4/5) in vitro at concentrations of decitabine up
to 2280 ng/mL; i.e., a concentration that substantially
exceeds clinical plasma Cmax-values at the proposed
clinical dose. Decitabine, at concentrations up to 2280
ng/mL, was also shown to be a weak inhibitor of P-gp
mediated transport in vitro and is therefore also not
expected to affect P-gp mediated transport of coadministered drugs.
No formal clinical drug interaction studies with decitabine have
been conducted.
There is the potential for a drug-drug interaction with other agents
which are also activated by sequential phosphorylation (via
intracellular phosphokinase activities) and/or metabolized by
enzymes implicated in the inactivation of decitabine (e.g.,
cytidine deaminase). Therefore, caution should be exercised if
these drugs are combined with DACOGEN.
Impact of co-administered drugs on decitabine
Cytochrome (CYP) 450-mediated metabolic interactions are not
anticipated as decitabine metabolism is not mediated by this
system but by oxidative deamination.
Displacement of decitabine from its plasma protein binding by
co-administered drugs is unlikely given the negligible in vitro
plasma protein binding (<1%) of decitabine. In vitro data
indicated that decitabine is a poor P-glycoprotein (P-gp) substrate
and is therefore not prone to interaction with P-gp inhibitors.
co-administered drugs is unlikely
given the negligible in vitro plasma
protein binding ( 1%) of
decitabine. There is the potential
for a pharmacokinetic drug-drug
interaction with other agents, such
as cytarabine, which are also
activated
by
sequential
phosphorylation (via intracellular
phosphokinase activities) and/or
metabolized
by
enzymes
implicated in the inactivation of
decitabine
(e.g.,
cytidine
deaminase). In vitro data indicated
that decitabine is a poor Pglycoprotein (P-gp) substrate and
is therefore not prone to interaction
with P-gp inhibitors.
and Other Forms of
Interaction
Impact of decitabine on coadministered drugs
Given its low in vitro plasma
protein binding ( 1%), decitabine
is unlikely to displace coadministered drugs from their
plasma protein binding. Decitabine
is a weak inhibitor of the major
human cytochrome P450 enzymes
(CYP): in vitro IC50 values towards
inhibition of CYP1A2, CYP2C8,
CYP2C9, CYP2C19, CYP2D6, and
CYP3A4 were in excess of 5700
ng/mL. In each case, these IC50values are much higher than the
maximum plasma concentrations
of decitabine achieved in patients
(plasma Cmax-values < 100
ng/mL) treated as described in
Section 4.2. Similarly, decitabine
does not induce major CYPs
(CYP1A2, 2B6, 2C9, and 3A4/5) in
vitro
at
concentrations
of
decitabine up to 2280 ng/mL; i.e., a
concentration that substantially
exceeds clinical plasma Cmaxvalues at the proposed clinical
dose. Decitabine, at concentrations
up to 2280 ng/mL, was also shown
to be a weak inhibitor of P-gp
mediated transport in vitro and is
therefore also not expected to
affect P-gp mediated transport of
co-administered drugs.
Impact of decitabine on co-administered drugs
Given its low in vitro plasma protein binding (1%), decitabine is
unlikely to displace co-administered drugs from their plasma
protein binding. In vitro studies show that decitabine does not
inhibit nor induce CYP 450 enzymes up to more than 20-fold of
the therapeutic maximum observed plasma concentration (Cmax).
Thus, CYP-mediated metabolic drug interactions are not
anticipated and is unlikely to interact with agents metabolized
through these pathways.
Decitabine has been shown to be a weak inhibitor of P-gp
mediated transport in vitro and is therefore also not expected to
affect P-gp mediated transport of co-administered medicinal
products (see Section 5.2).
Pregnancy
Pregnancy Category D [see Special Warnings and Special
Precautions for Use Warnings and Precautions (5.2)] Dacogen
can cause fetal harm when administered to a pregnant woman.
There are no adequate and well-controlled studies of Dacogen
in pregnant women.
The developmental toxicity of decitabine was examined in mice
exposed to single IP (intraperitoneal) injections (0, 0.9 and 3.0
mg/m2, approximately 2% and 7% of the recommended daily
clinical dose, respectively) over gestation days 8, 9, 10 or 11.
No maternal toxicity was observed but reduced fetal survival
8.1 Pregnancy
Pregnancy Category D [see
Warnings and Precautions (5.2)]
Dacogen can cause fetal harm
when administered to a pregnant
woman. There are no adequate
and well-controlled studies of
Dacogen in pregnant women.
The developmental toxicity of
decitabine was examined in mice
exposed to single IP
pregnancy Fertility,
and Lactation
was observed after treatment
at 3 mg/m2 and decreased fetal weight was observed at both
dose levels. The 3 mg/m2 dose elicited characteristic fetal
defects for each treatment day, including supernumerary ribs
(both dose levels), fused vertebrae and ribs, cleft palate,
vertebral defects, hind-limb defects and digital defects of foreand hind-limbs. In rats given a single IP injection of 2.4, 3.6 or 6
mg/m2 (approximately 5, 8, or 13% the daily recommended
clinical dose, respectively) on gestation days 9-12, no maternal
toxicity was observed. No live fetuses were seen at any dose
when decitabine was injected on gestation day 9. A significant
decrease in fetal survival and reduced fetal weight at doses
greater than 3.6 mg/m2 was seen when decitabine was given on
gestation day 10. Increased incidences of vertebral and rib
anomalies were seen at all dose levels, and induction of
exophthalmia, exencephaly, and cleft palate were observed at
6.0 mg/m2. Increased incidence of foredigit defects was seen in
fetuses at doses greater than 3.6 mg/m 2. Reduced size and
ossification of long bones of the fore-limb and hindlimb were
noted at 6.0 mg/m2. If this drug is used during pregnancy, or if
the patient becomes pregnant while taking this drug, the patient
should be apprised of the potential hazard to the fetus. Women
of child bearing potential should be advised to avoid becoming
pregnant while taking Dacogen.
Contraception in males and females
Women of childbearing potential must use effective contraceptive
measures and avoid becoming
pregnant while being treated with Dacogen. The time period following
treatment with Dacogen where it is safe to become pregnant is
unknown. Men should use effective contraceptive measures and be
advised to not father a child while receiving Dacogen, and for 3
months following completion of treatment (see section 5.3).
The use of Dacogen with hormonal contraceptives has not been studied.
Nursing Mothers Lactation
It is not known whether decitabine or its metabolites are excreted
in human milk. Because many drugs are excreted in human
milk, and because of the potential for serious adverse reactions
from Dacogen in nursing infants, a decision should be made
whether to discontinue
nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
DACOGEN is contraindicated during lactation; therefore if
treatment with DACOGEN is required, breast-feeding must be
discontinued.
Fertility
No human data on the effect of decitabine on fertility are available. In
non-clinical animal studies,
decitabine alters male fertility and is mutagenic. Because of the
possibility of infertility as a
consequence of Dacogen therapy, men should seek advice on
conservation of sperm and female
patients of childbearing potential should seek consultation regarding
oocyte cryopreservation prior to initiation of treatment with Dacogen.
(intraperitoneal) injections (0, 0.9
and 3.0 mg/m2, approximately 2%
and 7% of the recommended daily
clinical dose, respectively) over
gestation days 8, 9, 10 or 11. No
maternal toxicity was observed but
reduced fetal survival was
observed after treatment
at 3 mg/m2 and decreased fetal
weight was observed at both dose
levels. The 3 mg/m2 dose elicited
characteristic fetal defects for each
treatment day, including
supernumerary ribs (both dose
levels), fused vertebrae and ribs,
cleft palate, vertebral defects, hindlimb defects and digital defects of
fore- and hind-limbs. In rats given
a single IP injection of 2.4, 3.6 or 6
mg/m2 (approximately 5, 8, or 13%
the daily recommended clinical
dose, respectively) on gestation
days 9-12, no maternal toxicity was
observed. No live fetuses were
seen at any dose when decitabine
was injected on gestation day 9. A
significant decrease in fetal
survival and reduced fetal weight
at doses greater than 3.6 mg/m2
was seen when decitabine was
given on gestation day 10.
Increased incidences of vertebral
and rib anomalies were seen at all
dose levels, and induction of
exophthalmia, exencephaly, and
cleft palate were observed at 6.0
mg/m2. Increased incidence of
foredigit defects was seen in
fetuses at doses greater than 3.6
mg/m2. Reduced size and
ossification of long bones of the
fore-limb and hindlimb were noted
at 6.0 mg/m2. If this drug is used
during pregnancy, or if the patient
becomes pregnant while taking this
drug, the patient should be
apprised of the potential hazard to
the fetus. Women of
child bearing potential should be
advised to avoid becoming
pregnant while taking Dacogen.
8.3 Nursing Mothers
It is not known whether decitabine
or its metabolites are excreted in
human milk. Because many drugs
are excreted in human milk, and
because of the potential for serious
adverse reactions from Dacogen in
nursing infants, a decision should
be made whether to discontinue
nursing or to discontinue the drug,
taking into account the importance
of the drug to the mother.
DACOGEN is contraindicated
during lactation; therefore if
treatment with DACOGEN is
required, breast-feeding must be
discontinued.
See bellow
Adverse events
MDS
Clinical Studies Experience
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.
Most Commonly Occurring Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae,
constipation, diarrhea, and hyperglycemia.
Adverse Reactions Most Frequently (≥ 1%) Resulting in Clinical Intervention in the Phase 3 Trial in the Dacogen Arm:
• Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium
complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial
hemorrhage, abnormal liver function tests.
• Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile
neutropenia.
• Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia,
depression, pharyngitis.
Discussion of Adverse Reactions Information
Dacogen was studied in 3 single-arm studies (N = 66, N = 98, N= 99) and 1 controlled supportive care study (N = 83 Dacogen, N = 81
supportive care ). The data described below reflect exposure to Dacogen in 83 patients in the MDS trial. In the trial, patients received 15
mg/m2 intravenously every 8 hours for 3 days every 6 weeks. The median number of Dacogen cycles was 3 (range 0 to 9).
Table 1 presents all adverse events regardless of causality occurring in at least 5% of patients in the Dacogen group and at a rate
greater than supportive care.
Table 1 Adverse Events Reported in ≥ 5% of Patients in the Dacogen Group and at a Rate Greater than
Supportive Care in Phase 3 MDS Trial Dacogen
Dacogen
N = 83 (%)
Blood and lymphatic system disorders
Neutropenia
75 (90)
Thrombocytopenia
74 (89)
Anemia NOS
68 (82)
Febrile neutropenia
24 (29)
Leukopenia NOS
23 (28)
Lymphadenopathy
10 (12)
Thrombocythemia
4 (5)
Cardiac disorders
Pulmonary edema NOS
5 (6)
Eye disorders
Vision blurred
5 (6)
Gastrointestinal disorders
Nausea
Constipation
Diarrhea NOS
Vomiting NOS
Abdominal pain NOS
Oral mucosal petechiae
Stomatitis
Dyspepsia
Ascites
Gingival bleeding
Hemorrhoids
Loose stools
Tongue ulceration
Dysphagia
Oral soft tissue disorder NOS
Supportive Care
N = 81 (%)
58 (72)
64 (79)
60 (74)
5 (6)
11 (14)
6 (7)
1 (1)
0 (0)
0 (0)
35 (42)
29 (35)
28 (34)
21 (25)
12 (14)
11 (13)
10 (12)
10 (12)
8 (10)
7 (8)
7 (8)
6 (7)
6 (7)
5 (6)
5 (6)
13 (16)
11 (14)
13 (16)
7 (9)
5 (6)
4 (5)
5 (6)
1 (1)
2 (2)
5 (6)
3 (4)
3 (4)
2 (2)
2 (2)
1 (1)
Dacogen
N = 83 (%)
Supportive Care
N = 81 (%)
Lip ulceration
4 (5)
Abdominal distension
4 (5)
Abdominal pain upper
4 (5)
Gastro-esophageal reflux Disease
4 (5)
Glossodynia
4 (5)
General disorders and administrative site disorders
3 (4)
1 (1)
1 (1)
0 (0)
0 (0)
Pyrexia
Edema peripheral
Rigors
Edema NOS
Pain NOS
Lethargy
Tenderness NOS
Fall
Chest discomfort
Intermittent pyrexia
Malaise
Crepitations NOS
Catheter site erythema
Catheter site pain
Injection site swelling
Hepatobiliary Disorders
44 (53)
21 (25)
18 (22)
15 (18)
11 (13)
10 (12)
9 (11)
7 (8)
6 (7)
5 (6)
4 (5)
4 (5)
4 (5)
4 (5)
4 (5)
23 (28)
13 (16)
14 (17)
5 (6)
5 (6)
3 (4)
0 (0)
3 (4)
3 (4)
3 (4)
1 (1)
1 (1)
1 (1)
0 (0)
0 (0)
Hyperbilirubinemia
Infections and Infestations
12 (14)
4 (5)
Pneumonia NOS
Cellulitis
Candidal infection NOS
Catheter related infection
Urinary tract infection NOS
18 (22)
10 (12)
8 (10)
7 (8)
6 (7)
11 (14)
6 (7)
1 (1)
0 (0)
1 (1)
Staphylococcal infection
6 (7)
Oral candidiasis
5 (6)
Sinusitis NOS
4 (5)
Bacteremia
4 (5)
Injury, poisoning and procedural complications
0 (0)
2 (2)
2 (2)
0 (0)
Transfusion reaction
Abrasion NOS
Investigations
6 (7)
4 (5)
3 (4)
1 (1)
Cardiac murmur NOS
Blood alkaline phosphatase
NOS increased
Aspartate aminotransferase
increased
Blood urea increased
Blood lactate dehydrogenase
Increased
13 (16)
9 (11)
9 (11)
7 (9)
8 (10)
7 (9)
8 (10)
7 (8)
1 (1)
5 (6)
Blood albumin decreased
Blood bicarbonate increased
6 (7)
5 (6)
0 (0)
1 (1)
Dacogen
N = 83 (%)
Supportive Care
N = 81 (%)
Blood chloride decreased
5 (6)
Protein total decreased
4 (5)
Blood bicarbonate decreased
4 (5)
Blood bilirubin decreased
4 (5)
Metabolism and nutrition disorders
Hyperglycemia NOS
27 (33)
Hypoalbuminemia
20 (24)
Hypomagnesemia
20 (24)
Hypokalemia
18 (22)
Hyponatremia
16 (19)
Appetite decreased NOS
13 (16)
Anorexia
13 (16)
Hyperkalemia
11 (13)
Dehydration
5 (6)
Musculoskeletal and connective tissue disorders
1 (1)
3 (4)
1 (1)
1 (1)
Arthralgia
Pain in limb
Back pain
Chest wall pain
Musculoskeletal discomfort
Myalgia
Nervous system disorders
17 (20)
16 (19)
14 (17)
6 (7)
5 (6)
4 (5)
8 (10)
8 (10)
5 (6)
1 (1)
0 (0)
1 (1)
Headache
Dizziness
Hypoesthesia
Psychiatric disorders
23 (28)
15 (18)
9 (11)
11 (14)
10 (12)
1 (1)
Insomnia
Confusional state
Anxiety
Renal and urinary disorders
23 (28)
10 (12)
9 (11)
11 (14)
3 (4)
8 (10)
16 (20)
14 (17)
6 (7)
10 (12)
13 (16)
12 (15)
8 (10)
3 (4)
4 (5)
Dysuria
5 (6)
Urinary frequency
4 (5)
Respiratory, thoracic and Mediastinal disorders
3 (4)
1 (1)
Cough
33 (40)
Pharyngitis
13 (16)
Crackles lung
12 (14)
Breath sounds decreased
8 (10)
Hypoxia
8 (10)
Rales
7 (8)
Postnasal drip
4 (5)
Skin and subcutaneous tissue disorders
25 (31)
6 (7)
1 (1)
7 (9)
4 (5)
2 (2)
2 (2)
Ecchymosis
Rash NOS
Erythema
Skin lesion NOS
Pruritis
Alopecia
Urticaria NOS
12 (15)
7 (9)
5 (6)
3 (4)
2 (2)
1 (1)
1 (1)
18 (22)
16 (19)
12 (14)
9 (11)
9 (11)
7 (8)
5 (6)
Swelling face
5 (6)
0 (0)
Dacogen
N = 83 (%)
Supportive Care
N = 81 (%)
Vascular disorders
Petechiae
Pallor
Hypotension NOS
Hematoma NOS
32 (39)
19 (23)
5 (6)
4 (5)
13 (16)
10 (12)
4 (5)
3 (4)
Discussion of Clinically Important Adverse Reactions
In the controlled trial using Dacogen dosed at 15 mg/m 2, administered by continuous intravenous infusion over 3 hours
repeated every 8 hours for 3 days, the highest incidence of Grade 3 or Grade 4 adverse events in the Dacogen arm were
neutropenia (87%),
thrombocytopenia (85%), febrile neutropenia (23%) and leucopenia (22%). Bone marrow suppression was the most
frequent cause of dose reduction, delay and discontinuation. Six patients had fatal events associated with their
underlying disease and myelosuppression (anemia, neutropenia, and thrombocytopenia) that were considered at least
possibly related to drug treatment [See Warnings and Precautions (5.1)]. Of the 83 Dacogen-treated patients,
8 permanently discontinued therapy for adverse events; compared to 1 of 81 patients in the supportive care arm.
In a single-arm study (N=99) Dacogen was dosed at 20 mg/m 2 intravenous, infused over one hour daily for 5 consecutive
days of a 4 week cycle. Table 2 presents all adverse events regardless of causality occurring in at least 5% of patients.
Table 2 Adverse Events Reported in ≥ 5% of Patients in a Single-arm Study* Dacogen
Dacogen
N = 99 (%)
Blood and lymphatic system disorders
Anemia
Febrile neutropenia
Leukopenia
Neutropenia
Pancytopenia
Thrombocythemia
Thrombocytopenia
Cardiac disorders
31 (31% )
20 (20% )
6 (6% )
38 (38% )
5 (5% )
5 (5% )
27 (27% )
Cardiac failure congestive
Tachycardia
Ear and labyrinth disorders
5 (5% )
8 (8% )
Ear pain
Gastrointestinal disorders
6 (6% )
Abdominal pain
Abdominal pain upper
Constipation
Diarrhea
Dyspepsia
Dysphagia
Gastro-esophageal reflux disease
14 (14% )
6 (6% )
30 (30% )
28 (28% )
10 (10% )
5 (5% )
5 (5% )
Dacogen
N = 99 (%)
Nausea
40 (40% )
Oral pain
5 (5% )
Stomatitis
11 (11% )
Toothache
6 (6% )
Vomiting
16 (16% )
General disorders and administration site conditions
Asthenia
Chest pain
Chills
Fatigue
Mucosal inflammation
Edema
Edema peripheral
Pain
Pyrexia
Infections and infestations
15 (15% )
6 (6% )
16 (16% )
46 (46% )
9 (9% )
5 (5% )
27 (27% )
5 (5% )
36 (36%)
Cellulitis
Oral candidiasis
Pneumonia
Sinusitis
9 (9% )
6 (6% )
20 (20% )
6 (6% )
Staphylococcal bacteremia
8 (8% )
Tooth abscess
5 (5% )
Upper respiratory tract infection
10 (10% )
Urinary tract infection
7 (7% )
Injury, poisoning and procedural complications
Contusion
Investigations
9 (9% )
Blood bilirubin increased
Breath sounds abnormal
Weight decreased
Metabolism and nutrition disorders
6 (6% )
5 (5% )
9 (9% )
Anorexia
23 (23% )
Decreased appetite
8 (8% )
Dehydration
8 (8% )
Hyperglycemia
6 (6% )
Hypokalemia
12 (12% )
Hypomagnesemia
5 (5% )
Musculoskeletal and connective tissue disorders
Arthralgia
Back pain
Bone pain
Muscle spasms
Muscular weakness
Musculoskeletal pain
Myalgia
Pain in extremity
Nervous system disorders
17 (17% )
18 (18% )
6 (6% )
7 (7% )
5 (5% )
5 (5% )
9 (9% )
18 (18% )
Dacogen
N = 99 (%)
Dizziness
Headache
21 (21% )
23 (23% )
Psychiatric disorders
Anxiety
9 (9% )
Confusional state
8 (8% )
Depression
9 (9% )
Insomnia
14 (14% )
Respiratory, thoracic and mediastinal disorders
Cough
27 (27% )
Dyspnea
29 (29% )
Epistaxis
13 (13% )
Pharyngolaryngeal pain
8 (8% )
Pleural effusion
5 (5% )
Sinus congestion
5 (5% )
Skin and subcutaneous tissue disorders
Dry skin
Ecchymosis
Erythema
Night sweats
Petechiae
Pruritus
Rash
Skin lesion
Vascular disorders
8 (8% )
9 (9% )
5 (5% )
5 (5% )
12 (12% )
9 (9% )
11 (11% )
5 (5% )
Hypertension
Hypotension
6 (6% )
11 (11% )
* In this single arm study, investigators reported adverse events based on clinical signs and symptoms rather than
predefined laboratory abnormalities. Thus not all laboratory abnormalities were recorded as adverse events.
Discussion of Clinically Important Adverse Reactions
In the single-arm study (N=99) when Dacogen was dosed at 20mg/m 2 intravenous, infused over one hour daily for 5
consecutive days, the highest incidence of Grade 3 or Grade 4 adverse events were neutropenia (37%),
thrombocytopenia (24%) and anemia (22%).
Seventy-eight percent of patients had dose delays, the median duration of this delay was 7 days and the largest
percentage of delays were due to hematologic toxicities. Hematologic toxicities and infections were the most frequent
causes of dose delays and discontinuation. Eight patients had fatal events due to infection and/or bleeding (seven of
which occurred in the clinical setting of myelosuppression) that were considered at least possibly related to
drug treatment. Nineteen of 99 patients permanently discontinued therapy for adverse events.
No overall difference in safety was detected between patients >65 years of age and younger patients in these
myelodysplasia trials. No significant gender differences in safety or efficacy were detected. Patients with renal or hepatic
dysfunction were not studied. Insufficient numbers of non-white patients were available to draw conclusions in these
clinical trials.
Serious Adverse Events that occurred in patients receiving Dacogen regardless of causality, not previously reported in
Tables 1 and 2 include:
• Blood and Lymphatic System Disorders: myelosuppression,splenomegaly.
• Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial
fibrillation, supraventricular tachycardia.
• Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage.
• General Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage.
• Hepatobiliary Disorders: cholecystitis.
• Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis,
peridiverticular abscess, respiratory tract infection, pseudomonal lung infection,
Mycobacterium avium complex infection.
• Injury, Poisoning and Procedural Complications: post procedural pain, post procedural
hemorrhage.
• Nervous System Disorders: intracranial hemorrhage.
• Psychiatric Disorders: mental status changes.
• Renal and Urinary Disorders: renal failure, urethral hemorrhage.
• Respiratory, Thoracic and Mediastinal Disorders: hemoptysis,lung infiltration, pulmonary
embolism, respiratory arrest,pulmonary mass.
• Allergic Reaction: Hypersensitivity (anaphylactic reaction) to Dacogen has been reported in
a Phase 2 trial.
Additional ADRs
Table 3 includes additional ADRs that occurred in Phase 1 and 2 open-label clinical studies for hematological
malignancies—myelodysplastic syndrome and acute myeloid leukemia and non-hematological malignancies (in which
DACOGEN was administered in combination with other cytotoxic drugs) that were not identified in Table 1 & 2.
Table 3. Additional Adverse Drug Reactions Reported by at Least 1 DACOGEN-treated Subject in
Phase 1 and 2 Clinical Studies of DACOGEN for Myelodysplastic Syndrome, Acute
Myeloid Leukemia, and Non-hematological Malignancies
MedDRA System/Organ Class
Adverse Event (Preferred Term)
Blood and Lymphatic System Disorders
Pancytopenia**
Infections and Infestations
Sepsis**
Septic shock
Gastrointestinal disorders
Stomatitis
** Includes events with a fatal outcome.
MedDRA= Medical dictionary for regulatory activities
Post-marketing Experience
The following adverse reactions have been identified during post approval use of Dacogen. 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.
Cases of Sweet’s Syndrome (acute febrile neutrophilic dermatosis) have been reported.
AML
Summary of the safety profile
The most common adverse drug reactions (≥ 35%) reported during treatment with Dacogen are
pyrexia, anaemia and thrombocytopenia.
The most common Grade 3/4 adverse drug reactions (≥ 20%) included pneumonia, thrombocytopenia,
neutropenia, febrile neutropenia and anaemia.
In clinical studies, 30% of patients treated with Dacogen and 25% of patients treated in the comparator
arm had adverse events with an outcome of death during treatment or within 30 days after the last dose
of study drug.
In the Dacogen treatment group, there was a higher incidence of treatment discontinuation due to
adverse events in women compared to men (43% versus 32%).
Tabulated list of adverse drug reactions
Adverse drug reactions reported in 293 AML patients treated with Dacogen are summarised in
Table 3. The following table reflects data from AML clinical studies. The adverse drug reactions are
listed by frequency category. Frequency categories are defined as follows: Very common (≥ 1/10),
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very
rare (< 1/10,000).
Within each frequency grouping, adverse drug reactions are presented in order of decreasing
seriousness.
Table 3:
Adverse Drug Reactions Identified with DACOGEN
System Organ Class
Frequency
(all
Grades)
Infections and
infestations
Very
common
pneumonia*
urinary tract infection*
Common
septic shock*
sepsis*
sinusitis
febrile neutropenia*
neutropenia*
thrombocytopeniab*
anaemia
leukopenia
Pancytopenia*
Blood and lymphatic
disorders
Immune system
disorders
Nervous system
disorders
Respiratory, thoracic
and mediastinal
disorders
Gastrointestinal
disorders
Skin and
subcutaneous tissue
disorders
General disorders
and administration
site conditions
a
Very
common
Uncommon
Common
Adverse Drug Reaction
Hypersensitivity including
anaphylactic reaction c
Frequency
All
Grades 3-4a
a
Grades
(%)
(%)
24
20
15
7
6
9
3
34
32
41
4
8
1
32
30
38
38
20
<1
1
31
18
<1
<1
Very
common
Very
common
headache
16
1
epistaxis
14
2
Very
common
diarrhoea
vomiting
31
18
2
1
nausea
33
<1
Common
stomatitis
7
1
Uncommon
acute febrile neutrophilic
dermatosis (Sweet’s
syndrome)
pyrexia
<1
NA
48
9
Very
common
Worst National Cancer Institute Common Terminology Criteria for Adverse Events Grade
b
Including hemorrhage associated with thrombocytopenia, including fatal cases
C
Including preffered terms hypersensitivity, drug hypersensitivity, anaphylactic reaction, anaphylactic shock,
anaphylactoid reaction, anaphylactoid shock.
*Includes events with fatal outcome
NA=not applicable
Description of selected adverse drug reactions
Haematologic adverse drug reactions
The most commonly reported haematologic adverse drug reactions associated with Dacogen treatment
included febrile neutropenia, thrombocytopenia, neutropenia, anaemia and leukopenia.
Serious infection-related adverse drug reactions such as septic shock, sepsis and pneumonia were
reported in patients receiving Dacogen.
Serious bleeding-related adverse drug reactions, some of which lead to a fatal outcome, such as central
nervous system (CNS) haemorrhage (2%) and gastrointestinal (GI) haemorrhage (2%), in the context
of severe thrombocytopenia, were reported in patients receiving Dacogen.
Haematological adverse drug reactions should be managed by routine monitoring of complete blood
counts and early administration of supportive treatments as required. Supportive treatments include,
administration of prophylactic antibiotics and/or growth factor support (e.g., G-CSF) for neutropenia
and transfusions for anaemia or thrombocytopenia according to institutional guidelines. For situations
where decitabine administration should be delayed, see section 4.2.