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An Option for Newly Diagnosed Chronic Phase (CP) Ph+ CML Adult Patients…
Start With SPRYCEL (dasatinib)
SPRYCEL: Superior Response Rates vs Imatinib
s Phase III, open-label, international, multicenter, randomized* study of SPRYCEL 100 mg once daily (n=259)
vs imatinib 400 mg once daily (n=260) in adults with newly diagnosed Ph+ CML in chronic phase (N=519)
at a minimum follow-up of 12 months1,2
— Primary endpoint was confirmed complete cytogenetic response (CCyR) † by 12 months
MMR at Any Time
Major Molecular Response (MMR)‡ at Any Time1
52%
SPRYCEL (95% CI, 46-58)
P<0.0001§
34%
SPRYCEL (n=259)
Imatinib (n=260)
Imatinib (95% CI, 28-40)
0
10
20
30
40
50
60
MMR (%)
70
80
90
100
s Among responders, median time to MMR was 6.3 months with SPRYCEL (n=135) vs 9.2 months with imatinib (n=88)1
s Primary endpoint: A significantly higher rate of patients on SPRYCEL (77%) (95% CI, 71-82) achieved
confirmed CCyR by 12 months vs 66% (95% CI, 60-72) of patients on imatinib (P=0.007§)1
s Among responders, median time to confirmed CCyR with SPRYCEL was 3.1 months (n=199) vs 5.6 months with
imatinib (n=177)1
Select Important Safety Information
s SPRYCEL is associated with the following warnings and precautions: myelosuppression; bleeding-related
events; fluid retention; QT prolongation; congestive heart failure, left ventricular dysfunction, and myocardial
infarction; pulmonary arterial hypertension; and use in pregnancy
s The most frequently reported serious adverse events in patients with newly diagnosed CP CML included
pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%)
s The most frequently reported adverse reactions reported in •10% of patients with newly diagnosed CP CML
included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized
edema), diarrhea, headache, musculoskeletal pain, and rash
s Please see detailed Important Safety Information on adjacent pages
Indication
SPRYCEL® (dasatinib) is indicated for the treatment of adults with newly diagnosed Philadelphia chromosomepositive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of SPRYCEL is based on
cytogenetic and major molecular response rates. The trial is ongoing and further data will be required to
determine long-term outcome.
for Superior Response
vs Imatinib in 1st Line
Start With Convenient Once-Daily Dosing
1 pill
100 mg
1 time per day
One tablet taken consistently, either in
the morning or in the evening
Tablets should not be crushed or cut;
they should be swallowed whole
Tablet not actual size.
s In clinical studies, treatment with SPRYCEL was continued until disease progression or until no longer
tolerated by the patient1
SPRYCEL Can Be Taken Either With or Without Food1
SPRYCEL—the only treatment for adults with newly diagnosed Ph+ CML in
chronic phase with:
FASTING
s No fasting requirements
s No need to alter meal schedules
s No need to take with food
Important Safety Information About Drug Interactions
s Use of concomitant strong CYP3A4 inducers may decrease plasma concentrations of SPRYCEL and should
be avoided
s Strong CYP3A4 inhibitors may increase plasma concentrations of SPRYCEL and should be avoided
s Grapefruit juice may increase plasma concentrations of SPRYCEL and should be avoided
s Concomitant use of H 2 antagonists or proton pump inhibitors with SPRYCEL is not recommended
s Antacids should be considered instead. Antacids may decrease SPRYCEL drug levels. If antacid therapy
is needed, the dose should be given 2 hours before or after SPRYCEL
*Stratified by Hasford risk score.2
Confirmed CCyR is defined as a CCyR (0% Ph+ metaphases) noted on 2 consecutive assessments at least 28 days apart.1
‡
MMR (at any time) was defined as BCR-ABL ratios ”0.1% by real-time quantitative polymerase chain reaction (RQ-PCR) in peripheral blood samples
standardized on the International Scale.1
§
Adjusted for Hasford score and indicated statistical significance at a pre-defined nominal level of significance.1
†
Please see detailed Important Safety Information,
including Important Safety Information on Drug
Interactions, on adjacent pages.
Important Safety Information
Myelosuppression:
s Treatment with SPRYCEL® (dasatinib) can cause severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia,
and anemia. Myelosuppression was reported in patients with normal baseline laboratory values as well as in
patients with pre-existing laboratory abnormalities
— Perform complete blood counts (CBCs) weekly for the first 2 months and then monthly thereafter, or as
clinically indicated
— Myelosuppression was generally reversible and usually managed by dose interruption, dose reduction,
or discontinuation
— Hematopoietic growth factor has been used in patients with resistant myelosuppression
Bleeding-Related Events:
s SPRYCEL caused platelet dysfunction in vitro and thrombocytopenia in humans
— In all clinical trials, severe central nervous system (CNS) hemorrhage, including fatalities, occurred in 1% of
patients. Severe gastrointestinal (GI) hemorrhage, including fatalities, occurred in 4% of patients receiving
SPRYCEL, which generally required treatment interruptions and transfusions. Other cases of severe
hemorrhage occurred in 2% of patients
s Most bleeding events were associated with severe thrombocytopenia
— Exercise caution in patients required to take medications that inhibit platelet function or anticoagulants
Fluid Retention:
s SPRYCEL is associated with fluid retention
— In clinical trials, fluid retention was severe in up to 10% of patients. Ascites (<1%), generalized edema (<1%),
and severe pulmonary edema (1%) were also reported
s Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be
evaluated by chest X-ray
s Severe pleural effusion may require thoracentesis and oxygen therapy
s Fluid retention was typically managed by supportive care measures that included diuretics or short courses
of steroids
QT Prolongation:
s In vitro data suggest that SPRYCEL has the potential to prolong cardiac ventricular repolarization (QT interval)
s In 865 patients with leukemia treated with SPRYCEL in five phase 2 single-arm studies, the maximum mean
changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms
s In clinical trials of patients treated with SPRYCEL (N=2440), 15 patients (<1%) had QTc prolongation as an
adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms
s Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc, including patients
with hypokalemia, hypomagnesemia, or congenital long QT syndrome and patients taking anti-arrhythmic drugs,
other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy
— Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration
Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction:
Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients
with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular
dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.
Pulmonary Arterial Hypertension (PAH):
SPRYCEL may increase the risk of developing PAH, which may occur anytime after initiation, including after
more than one year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH
may be reversible on discontinuation of SPRYCEL. Evaluate patients for signs and symptoms of underlying
cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed SPRYCEL
should be permanently discontinued.
Use in Pregnancy:
SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and
well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised
of the potential hazard to the fetus and to avoid becoming pregnant when taking SPRYCEL.
Nursing Mothers:
It is unknown whether SPRYCEL is excreted in human milk. Because of the potential for serious adverse reactions
in nursing infants, a decision should be made whether to discontinue nursing or to discontinue SPRYCEL.
Drug Interactions:
SPRYCEL (dasatinib) is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4.
s Drugs that may increase SPRYCEL plasma concentrations are:
— CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If
administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL
dose reduction or temporary discontinuation should be considered
Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone,
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong
CYP3A4 inhibitor, a dose decrease should be considered
Grapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided
s Drugs that may decrease SPRYCEL plasma concentrations are:
— CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL
should be considered
Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital)
should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose
of SPRYCEL is increased, the patient should be monitored carefully for toxicity
St John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided
s Antacids. Antacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and antacids
should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to
or 2 hours after the dose of SPRYCEL
s H2 antagonists/proton pump inhibitors, such as famotidine and omeprazole. Long-term suppression of gastric
acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore,
concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended
s Drugs that may have their plasma concentration altered by SPRYCEL are:
— CYP3A4 substrates, such as simvastatin. CYP3A4 substrates with a narrow therapeutic index should be
administered with caution in patients receiving SPRYCEL
Adverse Reactions:
The safety data reflect exposure to SPRYCEL in 258 patients with newly diagnosed chronic phase CML in a clinical
study (median duration of therapy was 18 months).
The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Patients aged 65 years
and older are more likely to experience toxicity. In the newly diagnosed chronic phase CML study, SPRYCEL was
discontinued for adverse reactions in 6% of patients.
s In newly diagnosed chronic phase CML patients:
— The most frequently reported serious adverse reactions included pleural effusion (2%), hemorrhage (2%),
congestive heart failure (1%), and pyrexia (1%)
— The most frequently reported adverse reactions (reported in •10% of patients) included myelosuppression,
fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache,
musculoskeletal pain, and rash
— Grade 3/4 laboratory abnormalities included neutropenia (22%), thrombocytopenia (19%), anemia (11%),
hypophosphatemia (5%), hypocalcemia (3%), and elevated bilirubin (1%)
s Grade 3/4 elevations of transaminase or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and
hypophosphatemia were reported in patients with all phases of CML
— Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption
— Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with
oral calcium supplementation
Please see brief summary of full Prescribing Information on adjacent pages.
References: 1. SPRYCEL® (dasatinib) full Prescribing Information. Bristol-Myers Squibb.
2. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed
chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270.
SPRYCEL is a registered trademark of Bristol-Myers Squibb Company.
For more information online, visit www.sprycel.com.
© 2011 Bristol-Myers Squibb 729US10AB13513 10/11
SPRYCEL® (dasatinib) Tablet for Oral Use
Brief Summary of Prescribing Information. For complete prescribing information consult official
package insert.
INDICATIONS AND USAGE
SPRYCEL® (dasatinib) is indicated for the treatment of adults with
•
newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic
phase. The effectiveness of SPRYCEL is based on cytogenetic response and major molecular response
rates [see Clinical Studies (14.1) in Full Prescribing Information]. The trial is ongoing and further data
will be required to determine long-term outcome.
•
chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to
prior therapy including imatinib.
•
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or
intolerance to prior therapy.
CONTRAINDICATIONS: None.
WARNINGS AND PRECAUTIONS
Myelosuppression: Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase
CML or Ph+ ALL than in chronic phase CML. In a dose-optimization study in patients with resistance or
intolerance to prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less
frequently in patients treated with 100 mg once daily than in patients treated with other dosing regimens.
Perform complete blood counts weekly for the first 2 months and then monthly thereafter, or as clinically
indicated. Myelosuppression was generally reversible and usually managed by withholding SPRYCEL
temporarily or dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information and Adverse
Reactions].
Bleeding Related Events: In addition to causing thrombocytopenia in human subjects, dasatinib caused
platelet dysfunction in vitro. In all clinical studies, severe central nervous system (CNS) hemorrhages, including
fatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage, including
fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other
cases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with severe
thrombocytopenia.
Patients were excluded from participation in initial SPRYCEL clinical studies if they took medications that inhibit
platelet function or anticoagulants. In subsequent trials, the use of anticoagulants, aspirin, and non-steroidal
anti-inflammatory drugs (NSAIDs) was allowed concurrently with SPRYCEL if the platelet count was
>50,000–75,000 per microliter. Exercise caution if patients are required to take medications that inhibit platelet
function or anticoagulants.
Fluid Retention: SPRYCEL is associated with fluid retention. In clinical trials, severe fluid retention was
reported in up to 10% of patients. Ascites and generalized edema were each reported in <1% of patients.
Severe pulmonary edema was reported in 1% of patients. Patients who develop symptoms suggestive of
pleural effusion, such as dyspnea or dry cough, should be evaluated by chest X-ray. Severe pleural effusion
may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive
care measures that include diuretics or short courses of steroids. In dose-optimization studies, fluid retention
events were reported less frequently with once daily dosing than with other dosing regimens.
QT Prolongation: In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular
repolarization (QT interval). Of the 2440 patients with CML treated with SPRYCEL in clinical studies, 15 patients
(<1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF
>500 ms. In 865 patients with leukemia treated with SPRYCEL in five Phase 2 single-arm studies, the maximum
mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms.
Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc. These include
patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking
anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose
anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration.
Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adverse
reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy,
heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor
patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.
Pulmonary Arterial Hypertension: SPRYCEL may increase the risk of developing pulmonary arterial
hypertension (PAH) which may occur anytime after initiation, including after more than one year of treatment.
Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of
SPRYCEL. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating
SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued.
Use in Pregnancy: SPRYCEL may cause fetal harm when administered to a pregnant woman. In nonclinical
studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib,
embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits. There are no
adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be
advised to avoid becoming pregnant while receiving treatment with SPRYCEL [see Use in Specific Populations].
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
•
Myelosuppression [see Dosage and Administration (2.3) in Full Prescribing Information and Warnings
and Precautions].
•
Bleeding related events [see Warnings and Precautions].
•
Fluid retention [see Warnings and Precautions].
•
QT prolongation [see Warnings and Precautions].
•
Congestive heart failure, left ventricular dysfunction, and myocardial infarction [see Warnings and
Precautions].
•
Pulmonary Arterial Hypertension [see Warnings and Precautions].
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 SPRYCEL in clinical studies including 258 patients with newly
diagnosed chronic phase CML and in 2182 patients with imatinib resistant or intolerant CML or Ph+ ALL.
In the newly diagnosed chronic phase CML trial, the median duration of therapy was 18 months; the median
average daily dose was 99 mg.
In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, patients had a minimum of 2 years
follow-up (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily).
Among patients with chronic phase CML and resistance or intolerance to prior imatinib therapy, the median
duration of treatment with SPRYCEL 100 mg once daily was 24 months (range 1–33 months). The median
duration of treatment with SPRYCEL 140 mg once daily was 15 months (range 0.03–36 months) for
accelerated phase CML, 3 months (range 0.03–29 months) for myeloid blast phase CML, and 3 months
(range 0.1–10 months) for lymphoid blast CML.
The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the newly diagnosed
chronic phase CML trial, drug was discontinued for adverse reactions in 6% of SPRYCEL-treated patients.
Among patients with resistance or intolerance to prior imatinib therapy, the rates of discontinuation for adverse
reaction were 15% in chronic phase CML, 16% in accelerated phase CML, 15% in myeloid blast phase CML,
8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In a dose-optimization study in patients with resistance
or intolerance to prior imatinib therapy and chronic phase CML, the rate of discontinuation for adverse reaction
was lower in patients treated with 100 mg once daily than in patients treated with other dosing regimens (10%
and 16%, respectively).
The most frequently reported adverse reactions reported in ≥10% of patients in newly diagnosed chronic
phase CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema,
generalized edema), diarrhea, headache, musculoskeletal pain, and rash. Pleural effusions were reported in
31 patients (see Table 1).
The most frequently reported adverse reactions reported in ≥20% of patients with resistance or intolerance to
prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin
rash, fatigue, nausea, and hemorrhage.
The most frequently reported serious adverse reactions in patients with newly diagnosed chronic phase CML
included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%). The most
frequently reported serious adverse reactions in patients with resistance or intolerance to prior
imatinib therapy included pleural effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%),
dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%), congestive heart failure/cardiac
dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%).
Chronic Myeloid Leukemia (CML): Adverse reactions (excluding laboratory abnormalities) that were reported
in at least 10% of patients are shown in Table 1 for newly diagnosed patients with chronic phase CML and
Table 2 for CML patients with resistance or intolerance to prior imatinib therapy.
Table 1:
Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed Chronic
Phase CML
All Grades
Grade 3/4
SPRYCEL (dasatinib)
Imatinib
SPRYCEL
Imatinib
(n=258)
(n=258)
(n=258)
(n=258)
Preferred Term
Percent (%) of Patients
Fluid retention
23
43
1
1
Pleural effusion
12
0
<1
0
Superficial localized edema
10
36
0
<1
Generalized edema
3
7
0
0
Congestive heart failure/
2
1
<1
<1
cardiac dysfunctiona
Pericardial effusion
2
<1
<1
0
Pulmonary hypertension
1
0
0
0
Pulmonary edema
<1
0
0
0
Diarrhea
18
19
<1
1
Headache
12
10
0
0
Musculoskeletal pain
12
16
0
<1
b
Rash
11
17
0
1
Nausea
9
21
0
0
Fatigue
8
11
<1
0
Myalgia
6
12
0
0
Hemorrhagec
6
5
1
1
Gastrointestinal bleeding
2
<1
1
0
d
Other bleeding
5
5
0
1
CNS bleeding
0
<1
0
<1
Vomiting
5
10
0
0
Muscle inflammation
4
19
0
<1
a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction
decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized,
rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special
interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye
hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral
hemorrhage, uterine hemorrhage, and vaginal hemorrhage.
Table 2:
Adverse Reactions Reported in ≥10% of Patients with CML Resistant or Intolerant
to Prior Imatinib Therapy
100 mg Once Daily
140 mg Once Daily
Myeloid
Lymphoid
Blast
Blast
Chronic
Accelerated
(n=74)
(n=33)
(n=165)
(n=157)
All
Grade
All
Grade
All
Grade
All
Grade
Preferred Term
Grades
3/4
Grades
3/4
Grades
3/4
Grades
3/4
Percent (%) of Patients
Fluid Retention
34
4
35
8
34
7
21
6
Superficial
18
0
18
1
14
0
3
0
localized edema
Pleural effusion
18
2
21
7
20
7
21
6
Generalized edema
3
0
1
0
3
0
0
0
Pericardial effusion
2
1
3
1
0
0
0
0
Congestive heart failure/
0
0
0
0
4
0
0
0
cardiac dysfunctiona
Pulmonary edema
0
0
1
0
4
3
0
0
Headache
33
1
27
1
18
1
15
3
Diarrhea
27
2
31
3
20
5
18
0
Fatigue
24
2
19
2
20
1
9
3
Dyspnea
20
2
20
3
15
3
3
3
Musculoskeletal pain
19
2
11
0
8
1
0
0
Nausea
18
1
19
1
23
1
21
3
b
Skin rash
17
2
15
0
16
1
21
0
Myalgia
13
0
7
1
7
1
3
0
Arthralgia
12
1
10
0
5
1
0
0
Infection (including
12
1
10
6
14
7
9
0
bacterial, viral, fungal,
and non-specified)
Abdominal pain
12
1
6
0
8
3
3
0
Hemorrhage
11
1
26
8
19
9
24
9
Gastrointestinal bleeding
2
1
8
6
9
7
9
3
CNS bleeding
0
0
1
1
0
0
3
3
Vomiting
7
1
11
1
12
0
15
0
Pyrexia
5
1
11
2
18
3
6
0
Febrile neutropenia
1
1
4
4
12
12
12
12
a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy,
diastolic dysfunction, ejection fraction decreased, and ventricular failure. b Includes drug eruption, erythema, erythema
multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash
follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin
irritation, urticaria vesiculosa, and rash vesicular.
Laboratory Abnormalities
Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia,
thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML
(Tables 3 and 4). Myelosuppression was reported in patients with normal baseline laboratory values as well
as in patients with pre-existing laboratory abnormalities.
In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or
reduction; permanent discontinuation of treatment occurred in 2% of patients with newly diagnosed chronic phase
CML and 5% of patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions].
Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and
hypophosphatemia were reported in patients with all phases of CML but were reported with an increased
frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminase or bilirubin were
usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during
the course of SPRYCEL (dasatinib) therapy often had recovery with oral calcium supplementation.
Laboratory abnormalities reported in patients with newly diagnosed chronic phase CML are shown in Table 3. There
were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters.
Table 3:
CTC Grade 3/4 Laboratory Abnormalities in Patients with Newly Diagnosed Chronic
Phase CML
SPRYCEL
Imatinib
(n=258)
(n=258)
Percent (%) of Patients
Hematology Parameters
Neutropenia
22
20
Thrombocytopenia
19
10
Anemia
11
7
Biochemistry Parameters
Hypophosphatemia
5
24
Hypokalemia
0
2
Hypocalcemia
3
2
Elevated SGPT (ALT)
<1
1
Elevated SGOT (AST)
<1
1
Elevated Bilirubin
1
0
Elevated Creatinine
<1
1
9
9
CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 /L, Grade 4 <0.5 × 10 /L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L,
Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 ×
upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN);
elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4
<6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L,
Grade 4 <2.5 mmol/L).
Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the
recommended starting doses of SPRYCEL are shown by disease phase in Table 4.
Table 4:
CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML: Resistance or
Intolerance to Prior Imatinib Therapy
Chronic Phase CML
Advanced Phase CML
140 mg Once Daily
Accelerated
Myeloid
Lymphoid
100 mg
Phase
Blast Phase
Blast Phase
Once Daily
(n=157)
(n=74)
(n=33)
(n=165)
Percent (%) of Patients
Hematology Parameters
Neutropenia
36
58
77
79
Thrombocytopenia
23
63
78
85
Anemia
13
47
74
52
Biochemistry Parameters
Hypophosphatemia
10
13
12
18
Hypokalemia
2
7
11
15
Hypocalcemia
<1
4
9
12
Elevated SGPT (ALT)
0
2
5
3
Elevated SGOT (AST)
<1
0
4
3
Elevated Bilirubin
<1
1
3
6
Elevated Creatinine
0
2
8
0
9
9
CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 /L, Grade 4 <0.5 × 10 /L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L,
Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 ×
upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN);
elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4
<6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L,
Grade 4 <2.5 mmol/L).
Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
A total of 135 patients with Ph+ ALL were treated with SPRYCEL in clinical studies. The median duration of
treatment was 3 months (range 0.03–31 months). The safety profile of patients with Ph+ ALL was similar to
those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention
events such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders such as
diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and
dyspnea (16%) were also frequently reported. The most frequently reported serious adverse reactions included
pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), infection (5%), pyrexia (4%),
pneumonia (3%), diarrhea (3%), nausea (2%), vomiting (2%), and colitis (2%).
Additional Data From Clinical Trials
The following adverse reactions were reported in patients in the SPRYCEL clinical studies at a frequency of
1%–<10%, 0.1%–<1%, or <0.1%. These events are included on the basis of clinical relevance.
Gastrointestinal Disorders: 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia,
abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder;
0.1%–<1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis; <0.1% –
protein losing gastroenteropathy. General Disorders and Administration Site Conditions: 1%–<10% – asthenia,
pain, chest pain, chills; 0.1%–<1% – malaise, temperature intolerance. Skin and Subcutaneous Tissue
Disorders: 1%–<10% – pruritus, alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema);
0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acute febrile
neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome. Respiratory, Thoracic, and
Mediastinal Disorders: 1%–<10% – cough, lung infiltration, pneumonitis, pulmonary hypertension; 0.1%–<1%
– asthma, bronchospasm; <0.1% – acute respiratory distress syndrome. Nervous System Disorders: 1%–<10%
– neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1%–<1% – amnesia, tremor,
syncope; <0.1% – convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis. Blood and
Lymphatic System Disorders: 1%–<10% – pancytopenia; <0.1% – aplasia pure red cell. Musculoskeletal and
Connective Tissue Disorders: 1%–<10% – muscular weakness; 0.1%–<1% – musculoskeletal stiffness,
rhabdomyolysis; <0.1% – tendonitis. Investigations: 1%–<10% – weight increased, weight decreased;
0.1%–<1% – blood creatine phosphokinase increased. Infections and Infestations: 1%–<10% – pneumonia
(including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection,
enterocolitis infection; 0.1%–<1% – sepsis (including fatal outcomes). Metabolism and Nutrition Disorders:
1%–<10% – anorexia, appetite disturbances; 0.1%–<1% – hyperuricemia, hypoalbuminemia. Cardiac Disorders:
1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<1% – angina pectoris, cardiomegaly,
pericarditis, ventricular arrhythmia (including ventricular tachycardia); <0.1% – cor pulmonale, myocarditis, acute
coronary syndrome. Eye Disorders: 1%–<10% – visual disorder (including visual disturbance, vision blurred, and
visual acuity reduced), dry eye; 0.1%–<1% – conjunctivitis. Vascular Disorders: 1%–<10% – flushing,
hypertension; 0.1%–<1% – hypotension, thrombophlebitis; <0.1% – livedo reticularis. Psychiatric Disorders:
1%–<10% – insomnia, depression; 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased.
Reproductive System and Breast Disorders: 0.1%–<1% – gynecomastia, menstruation irregular. Injury,
Poisoning, and Procedural Complications: 1%–<10% – contusion. Ear and Labyrinth Disorders:
1%–<10% – tinnitus; 0.1%–<1% – vertigo. Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis,
hepatitis. Renal and Urinary Disorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria. Neoplasms
Benign, Malignant, and Unspecified: 0.1%–<1% – tumor lysis syndrome. Immune System Disorders:
0.1%–<1% – hypersensitivity (including erythema nodosum).
Postmarketing Experience
The following additional adverse reactions have been identified during post approval use of SPRYCEL (dasatinib).
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.
Cardiac disorders: atrial fibrillation/atrial flutter. Vascular disorders: thrombosis/embolism (including
pulmonary embolism, deep vein thrombosis). Respiratory, thoracic, and mediastinal disorders: interstitial
lung disease, pulmonary arterial hypertension.
DRUG INTERACTIONS
Drugs That May Increase Dasatinib Plasma Concentrations
CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a study of 18 patients with solid tumors, 20-mg
SPRYCEL once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax and
AUC by four- and five-fold, respectively. Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 may
increase exposure to dasatinib and should be avoided. In patients receiving treatment with SPRYCEL, close
monitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of a
potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.1) in Full Prescribing Information].
Drugs That May Decrease Dasatinib Plasma Concentrations
CYP3A4 Inducers: When a single morning dose of SPRYCEL was administered following 8 days of continuous
evening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib
were decreased by 81% and 82%, respectively. Alternative agents with less enzyme induction potential should
be considered. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should
be considered [see Dosage and Administration (2.1) in Full Prescribing Information].
Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. In a study of 24 healthy
subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg
dose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased
26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects
concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax
were observed. Simultaneous administration of SPRYCEL with antacids should be avoided. If antacid therapy is
needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL.
H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists
or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. In a study of
24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced
the AUC and Cmax of dasatinib by 61% and 63%, respectively. In a study of 14 healthy subjects, administration
of a single 100-mg dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state reduced
the AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or proton
pump inhibitors with SPRYCEL is not recommended. The use of antacids (at least 2 hours prior to or 2 hours
after the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors in
patients receiving SPRYCEL therapy.
Drugs That May Have Their Plasma Concentration Altered By Dasatinib
CYP3A4 Substrates: Single-dose data from a study of 54 healthy subjects indicate that the mean Cmax and AUC
of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was
administered in combination with a single 100-mg dose of SPRYCEL. Therefore, CYP3A4 substrates known to
have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl,
pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be
administered with caution in patients receiving SPRYCEL.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D: SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no
adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be
advised of the potential hazard to the fetus and to avoid becoming pregnant. If SPRYCEL is used during pregnancy, or if
the patient becomes pregnant while taking SPRYCEL, the patient should be apprised of the potential hazard to the fetus.
In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses
of dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In both
rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m2/day] and rabbit:
0.5 mg/kg/day [6 mg/m2/day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of
105 ng•hr/mL (0.3-fold the human AUC in females at a dose of 70 mg twice daily) and 44 ng•hr/mL (0.1-fold
the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at
multiple sites (scapula, humerus, femur, radius, ribs, clavicle), reduced ossification (sternum; thoracic, lumbar,
and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia.
Nursing Mothers: It is unknown whether SPRYCEL is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse reactions in nursing infants from
SPRYCEL, 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.
Pediatric Use: The safety and efficacy of SPRYCEL in patients less than 18 years of age have not been established.
Geriatric Use: In the newly diagnosed chronic phase CML study, 25 patients (10%) were 65 years of age and
over and 7 patients (3%) were 75 years of age and over. Of the 2182 patients in clinical studies of SPRYCEL with
resistance or intolerance to imatinib therapy, 547 (25%) were 65 years of age and over and 105 (5%) were
75 years of age and over. No differences in efficacy were observed between older and younger patients.
Compared to patients under age 65 years, patients aged 65 years and older are more likely to experience
toxicity.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of dasatinib was evaluated
in healthy volunteers with normal liver function and patients with moderate (Child-Pugh class B) and severe
(Child-Pugh class C) hepatic impairment. Compared to the healthy volunteers with normal hepatic function, the
dose normalized pharmacokinetic parameters were decreased in the patients with hepatic impairment.
No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.3)
in Full Prescribing Information]. Caution is recommended when administering SPRYCEL to patients with
hepatic impairment.
Renal Impairment: There are currently no clinical studies with SPRYCEL in patients with impaired renal
function. Less than 4% of dasatinib and its metabolites are excreted via the kidney.
OVERDOSAGE
Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. Overdosage of 280 mg
per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding.
Since SPRYCEL is associated with severe myelosuppression [see Warnings and Precautions and Adverse
Reactions], patients who ingested more than the recommended dosage should be closely monitored for
myelosuppression and given appropriate supportive treatment.
Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular
necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. There
was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg
(120 mg/m2).
Manufactured by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
1284903A0
DS-B0001A-10-11
Rev October 2011
Standard CML therapies.
Are we holding them to a high enough standard?
We know that current chronic myeloid leukemia (CML) treatments are efficacious.
But resistance still occurs. In fact, post-imatinib studies found approximately 65% of these
patients eventually discontinue use of nilotinib and dasatinib as second-line therapy.1,2
Maybe it’s time to reconsider our definition of success.
Visit CMLResponseProject.com to learn more.
References: 1. Le Coutre PD, Giles FJ, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or -intolerant patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 48-month follow-up results of
a phase 2 study. Poster presented at: 53rd ASH Annual Meeting and Exposition; December 10-13, 2011; San Diego, CA. 2. Shah NP, Cortes JE, Schiffer CA, et al. Five-year follow-up of patients with imatinibresistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2011; Chicago, IL.
©2012 ARIAD Pharmaceuticals, Inc. All rights reserved.
5343712
How well is your Ph+ CML patient responding to
therapy? International scale (IS) RQ-PCR can tell you...
RQ-PCR FACTS
• RQ-PCR tests measure BCR-ABL transcripts, the
key cause of Ph+ CML1
• Most sensitive test available to measure minimal
residual disease, detecting 1 in 1,000,000 cells1,2
— Cytogenetic testing detects ~100-fold reductions
in Ph+ CML cells, whereas RQ-PCR detects
~10,000-fold reductions in disease burden3,4
• Easy to perform blood test1
RQ-PCR can help you detect early trends in
response status5
BCR-ABL/ABL % (IS)
RQ-PCR testing enables you to detect trends, such as rising
levels of BCR-ABL, that would not be apparent through
cytogenetic
testing alone.5
Rising BCRABL levels
CCyR
have been
associated
MMR
with mutations
and resistance,
so the sooner
Time
you detect
and confirm rising levels of BCR-ABL, the sooner you can test
for mutations and evaluate adherence or tolerability issues to
manage treatment accordingly.1,3
Monitoring with RQ-PCR may help indicate the
durability of response1
Traditionally, complete cytogenetic response (CCyR) has been the
gold standard for evaluating the potential durability of response.
More recently, studies have shown that achievement of major
molecular response (MMR) also correlates with durability of
response.1 In fact, patients who achieve both CCyR and MMR are
less likely to progress to advanced disease phases than patients
who achieve CCyR alone.1
QUALITATIVE VS QUANTITATIVE PCR TESTS
• Qualitative tests are diagnostic, indicating whether
Ph+ CML is present1
• Quantitative tests measure the amount of disease
in the peripheral blood or bone marrow1
Why it’s important to monitor with RQ-PCR tests
standardized to the IS
An MMR can only be defined by IS measurement, and appropriate
assessment of patient response can only be performed by an IS
lab. This means that only IS results can tell you if your patient has
achieved MMR.6
Understanding how IS works—using international
currency as an example
IS normalizes the RQ-PCR results of different laboratories to a
unified scale by a conversion factor.6 As illustrated below, RQ-PCR
results from different laboratories are like different international
currencies (ie, Lab A=US dollars and Lab B=Euros).
$1000
$1
€1000
=
€1
The relative reductions
of $1000 and €1000
are the same—both
are 3-log reductions, or
1000-fold decreases.
However, the absolute
value of $1 and €1 are
NOT the same.
Through use of a conversion factor (ie, exchange rate), the absolute
value of residual BCR-ABL can be known among different labs. This
means you can compare IS RQ-PCR results between labs.6
IS-standardized RQ-PCR tests provide the most
consistent measure of residual BCR-ABL7
An additional benefit of IS-standardized results is that they have
a lower degree of fluctuation over time compared with nonstandardized
laboratory results.
0.12
This consistency
0.10
IS-standardized laboratory
can help avoid
Nonstandardized laboratory
0.08
overtreatment or
0.06
undertreatment of
0.04
a patient due to a
0.02
numeric fluctuation
0
8
in the test.
Time
BCR-ABL/ABL/Ctl (%)
Real-time quantitative polymerase chain reaction
(RQ-PCR) acts like an early warning system for
measuring response and identifying potential
relapse. This is why it is such an important tool
for Philadelphia chromosome–positive chronic
myeloid leukemia (Ph+ CML) response monitoring.
Summary: The importance of monitoring Ph+ CML
patients with IS RQ-PCR tests
• RQ-PCR is the most sensitive way to monitor BCR-ABL
fluctuations, which can act as an early warning signal for
potential relapse5
• Monitoring for achievement of MMR in addition to CCyR
may help predict response1
• IS-standardized RQ-PCR tests are the only way to know if your
patient has achieved MMR and to ensure consistency of test results6
For information about a free trial of IS RQ-PCR, call
877-459-4979 and ask about GET RQ-PCR NOW.
References: 1. The NCCN Chronic Myelogenous Leukemia Clinical Practice Guidelines in Oncology (Version 2.2012). © 2011 National Comprehensive Cancer
Network, Inc. http://www.nccn.org. Accessed September 16, 2011. To view the most recent and complete version of the guidelines, go online to
www.nccn.org. 2. Radich JP. How I monitor residual disease in chronic myeloid leukemia. Blood. 2009;114(16):3376-3381. 3. Baccarani M, Cortes J, Pane F,
et al; European LeukemiaNet. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol.
2009;27(35):6041-6051. 4. Baccarani M, Saglio G, Goldman J, et al; European LeukemiaNet . Evolving concepts in the management of chronic myeloid
leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108(6):1809-1820. 5. Hughes T, Deininger M,
Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current
methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108(1):28-37. 6. Branford S, Fletcher L,
Cross NC, et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of
individual patient response and comparison of response rates between clinical trials. Blood. 2008;112(8):3330-3338. 7. Müller MC, Cross NC, Erben P,
et al. Harmonization of molecular monitoring of CML therapy in Europe. Leukemia. 2009;23(11):1957-1963. 8. Akard LP, Wang YL. Translating trial-based
molecular monitoring into clinical practice: importance of international standards and practical considerations for community practitioners. Clin Lymphoma
Myeloma Leuk. 2011 May 10 (Epub ahead of print). doi:10.1016/j.clml.2011.01.001.
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936-1080
©2011 Novartis
11/11
CDE-1030011
More Choice, More Color
for Blood Cell Disorders
Welcome to a More Colorful World.SM
Flow cytometry allows you to analyze
multiple parameters simultaneously—and
by adding more colors you can open up a
whole new world of information and insight.
BD Biosciences makes it easy for you with
our ever-expanding portfolio of high-quality
conjugated antibody specificities that offer a
full spectrum of color choices including our
new BD HorizonTM V500-C violet-laser dyes
to simplify work and speed results.
BD, BD Logo and all other trademarks are property of Becton, Dickinson and Company. © 2012 BD
23-13669-01
BD Biosciences reagents are part of the
building blocks to support patient care for
blood cell disorders.
Go to bdbiosciences.com/go/color to
learn more about our proven solution, try
our BD FACSelectTM tools, and download a
free product catalog.
BD Biosciences
2350 Qume Drive
San Jose, CA 95131
bdbiosciences.com
ADCETRIS is the first approved CD30directed antibody-drug conjugate (ADC)
Indicated for the treatment of:
• Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1
• HL in patients who are not ASCT candidates after failure of at least 2 multiagent
chemotherapy regimens1
• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent
chemotherapy regimen1
The indications for ADCETRIS are based on response rate. There are no data available
demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1
A therapeutic alternative for relapsed patients
73% objective response rate (95% CI: 65%-83%) in HL1
86% objective response rate (95% CI: 77%-95%) in sALCL1
BOXED WARNING
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML
and death can occur in patients receiving ADCETRIS.1
Contraindication
Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.1
Peripheral neuropathy
ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of
peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy
is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as
hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain
or weakness and institute dose modifications accordingly.1
Infusion reactions
Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients
during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate
medical management instituted. If anaphylaxis occurs, the infusion should be immediately and
permanently discontinued and appropriate medical management instituted.1
Please see Brief Summary of full Prescribing Information, including Boxed WARNING,
on the last page of this ad. Please see full Prescribing Information at ADCETRIS.com.
ADCETRIS is an ADC designed to target cells
expressing CD301
Antibody
The antibody, brentuximab,
specific for CD301
Cytotoxic agent
Linker
A synthetic protease-cleavable linker
that covalently attaches MMAE to the
CD30-directed antibody and releases
the agent within the target cell1
The synthetic microtubuledisrupting agent, monomethyl
auristatin E (MMAE, vedotin),
that induces target cell death1
CD30 is prevalent in both HL and sALCL2
• Binding of ADCETRIS to CD30 on the cell surface initiates internalization
of the ADC-CD30 complex1
• Inside the cell, MMAE is released via proteolytic cleavage1
• Binding of released MMAE to tubulin disrupts the microtubule network,
inducing apoptotic cell death1
Single-agent ADCETRIS was
evaluated in two pivotal, phase 2,
open-label, single-arm,
multicenter trials:
• 102 patients with HL who relapsed
after ASCT1
Neutropenia
Monitor complete blood counts prior to each dose of ADCETRIS
and consider more frequent monitoring for patients with Grade 3
or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage
by dose delays, reductions or discontinuation. Prolonged (≥1 week)
severe neutropenia can occur with ADCETRIS.1
• 58 patients with relapsed sALCL1
Tumor lysis syndrome
ADCETRIS 1.8 mg/kg was administered
intravenously over 30 minutes every
3 weeks.1
Patients with rapidly proliferating tumor and high tumor burden
are at risk of tumor lysis syndrome and these patients should be
monitored closely and appropriate measures taken.1
Assessment of efficacy included objective
response rate (complete remission
plus partial remission) and duration of
response evaluated by an independent
review facility based on measures defined
in the 2007 Revised Response Criteria for
Malignant Lymphoma (modified).1,3
Progressive multifocal leukoencephalopathy (PML)
JC virus infection resulting in PML and death has been reported
in ADCETRIS-treated patients. In addition to ADCETRIS therapy,
other possible contributory factors include prior therapies and
underlying disease that may cause immunosuppression. Consider
the diagnosis of PML in any patient presenting with new-onset signs
and symptoms of central nervous system abnormalities. Evaluation
of PML includes, but is not limited to, consultation with a neurologist,
brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if
PML is suspected and discontinue ADCETRIS if PML is confirmed.1
Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last
page of this ad. Please see full Prescribing Information at ADCETRIS.com.
ADCETRIS induced complete and partial remissions
in clinical trials1
Efficacy in relapsed patients1
Relapsed HL
(N = 58)
Median treatment duration: 27 weeks
Median treatment duration: 24 weeks
Duration of response
in months
Response, %
(95% CI)
Complete remission (CR)
Partial remission (PR)
Objective response
rate (ORR)
Relapsed sALCL
(N = 102)
Median
(95% CI)
Range
32
20.5
1.4-21.9+
(23-42)
(12.0-NE*)
40
3.5
(32-49)
(2.2-4.1)
Median
(95% CI)
Range
57
13.2
0.7-15.9+
(44-70)
(10.8-NE*)
1.3-18.7
73
6.7
(65-83)
(4.0-14.8)
Duration of response
in months
Response, %
(95% CI)
29
2.1
(18-41)
(1.3-5.7)
1.3-21.9+
0.1-15.8+
86
12.6
(77-95)
(5.7-NE*)
0.1-15.9+
*Not estimable. +Follow-up was ongoing at the time of data submission.
• ADCETRIS demonstrated efficacy in sALCL patients with poor prognosis1
– 72% of sALCL patients had anaplastic lymphoma kinase (ALK)-negative disease,
which has a worse prognosis than ALK-positive disease1,4
Adverse reactions occurring in ≥20% of patients regardless of causality1
HL (N = 102)
sALCL (N = 58)
% of patients
Adverse Reaction
Neutropenia
% of patients
Any Grade
Grade 3
Grade 4
Any Grade
Grade 3
Grade 4
54
15
6
55
12
9
Peripheral sensory neuropathy
52
8
-
53
10
-
Fatigue
49
3
-
41
2
2
Nausea
42
-
-
38
2
-
Anemia
33
8
2
52
2
-
Upper respiratory tract infection
47
-
-
12
-
-
Diarrhea
36
1
-
29
3
-
Pyrexia
29
2
-
38
2
-
Rash
27
-
-
31
-
-
Thrombocytopenia
28
7
2
16
5
5
Cough
25
-
-
17
-
-
Vomiting
22
-
-
17
3
-
• 21% of patients discontinued therapy due to treatment-emergent adverse reactions1
Continue treatment until a maximum of 16 cycles,
disease progression or unacceptable toxicity1
Recommended dose is 1.8 mg/kg administered only as an IV infusion over
30 minutes every 3 weeks1
• Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions1
• Complete blood counts should be monitored prior to each dose of ADCETRIS1
Most PN was Grade 1 or 2—no Grade 4 PN events were observed1
• 54% of patients experienced peripheral neuropathy (PN) in the pivotal trials1
• Grade 3 PN (sensory) was reported by 8% and 10% of patients in the HL and sALCL trials, respectively1
– 8% discontinued due to peripheral sensory neuropathy1
• Grade 3 PN (motor) was reported by 4% and 3% of patients in the HL and sALCL trials, respectively1
– 3% discontinued due to peripheral motor neuropathy1
Monitor patients for PN and institute dose modification accordingly1
New or worsening
Grade 2 or 3
Hold dose until PN improves to Grade 1 or baseline and then
restart at 1.2 mg/kg
Grade 4
Discontinue ADCETRIS
Improvement or resolution of PN symptoms was observed in the majority
of patients during follow-up1:
• 49% had complete resolution
• 51% had residual PN at time of last evaluation (31% partial improvement, 20% no improvement)
Neutropenia should be managed by dose delay and reduction1
Grade 3 or 4
Recurrent Grade 4 despite
use of growth factors
Hold dose until resolution to baseline or Grade 2 or lower
Consider growth factor support for subsequent cycles
Discontinue or reduce dose to 1.2 mg/kg
Please see Brief Summary of full Prescribing Information, including Boxed WARNING,
on adjacent page. Please see full Prescribing Information at ADCETRIS.com.
REFERENCES: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012. 2. Haluska FG, Brufsky AM, Canellos GP. The cellular biology of the Reed-Sternberg cell.
Blood. 1994;84(4):1005-1019. 3. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol.
2007;25(5):579-586. 4. Savage KJ, Harris NL, Vose JM, et al; International Peripheral T-Cell Lymphoma Project. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically
different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111(12):5496-5504.
US/BV/2011/0029b
855.4SEAGEN (855.473.2436)
SeaGenSecure.com
Brief Summary of Prescribing Information
(see Package Insert for full Prescribing Information)
WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
JC virus infection resulting in PML and death can occur in patients
receiving ADCETRIS.
Indications and usage
ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the
recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median
duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions
(≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue,
nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced
by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity
(3%), and urinary tract infection (3%).
Drug interactions
These indications are based on response rate. There are no data available demonstrating
improvement in patient reported outcomes or survival with ADCETRIS.
ADCETRIS (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL)
after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent
chemotherapy regimens in patients who are not ASCT candidates.
ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL)
after failure of at least one prior multi-agent chemotherapy regimen.
In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.
Contraindications
Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE
does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected
to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.
Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to
pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination
regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence
reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported
cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and
computed tomographic imaging of the chest. Most patients responded to corticosteroids.
Warnings and precautions
Peripheral neuropathy
ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of
peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy
is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of
neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and
20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy
at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as
hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or
weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay,
change in dose, or discontinuation of ADCETRIS.
Infusion reactions
Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients
during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of
ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the
infusion should be interrupted and appropriate medical management instituted. Patients who have
experienced a prior infusion-related reaction should be premedicated for subsequent infusions.
Premedication may include acetaminophen, an antihistamine and a corticosteroid.
Neutropenia
Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent
monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged
(≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops,
manage by dose delays, reductions, or discontinuations.
Tumor lysis syndrome
Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden
may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.
Progressive multifocal leukoencephalopathy
JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients.
In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and
underlying disease that may cause immunosuppression.
Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of
central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation
with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any
suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.
Stevens-Johnson syndrome
Effect of other drugs on ADCETRIS
CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration
of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by
approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with
ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS
with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.
Effect of ADCETRIS on other drugs
Use in specific populations
Pregnancy
Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in
pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS
can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused
embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures
at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy,
or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the
potential hazard to the fetus.
In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3,
or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy
Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with
3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss
(≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and
malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg
is approximately the same exposure in patients with HL or sALCL who received the recommended
dose of 1.8 mg/kg every three weeks.
Nursing mothers
It is not known whether brentuximab vedotin is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse reactions in nursing infants
from ADCETRIS 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.
Pediatric use
The safety and effectiveness of ADCETRIS have not been established in the pediatric population.
Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to
determine whether they respond differently than adult patients.
Geriatric use
Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine
whether they respond differently from younger patients. Safety and efficacy have not been established.
Renal impairment
The kidney is a route of excretion for MMAE. The influence of renal impairment on the
pharmacokinetics of MMAE has not been determined.
Hepatic impairment
The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics
of MMAE has not been determined.
Overdosage
There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely
monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.
Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome
occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Dosage and administration
Use in pregnancy
The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes
every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on
a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a
maximum of 16 cycles, disease progression or unacceptable toxicity.
There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However,
based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when
administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including
significantly decreased embryo viability and fetal malformations, in animals at maternal exposures
that were similar to human exposures at the recommended doses for patients with HL and sALCL.
If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug,
the patient should be apprised of the potential hazard to the fetus.
Adverse reactions
ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials,
the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia,
thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy,
headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection,
nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry
skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle
spasms, insomnia, anxiety, decreased appetite and weight decreased.
ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended
starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment
was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of
causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection,
nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting.
The most common serious adverse reactions experienced by patients with HL include peripheral motor
neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax
(2%), pyelonephritis (2%), and pyrexia (2%).
General dosing information
Dose modification
Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose
delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be
held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4
peripheral neuropathy, ADCETRIS should be discontinued.
Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS
should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth
factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4
neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors,
discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.
ADCETRIS, SeaGen Secure and their logos are
trademarks and Seattle Genetics and are
US registered trademarks of Seattle Genetics, Inc.
© 2012 Seattle Genetics, Inc., Bothell, WA 98021
All rights reserved. Printed in USA
US/BVP/2011/0150
15+ YEARS*
EXPERIENCE
MATTERS
3000 IU IS HERE
More units. Single vial. Same 5-mL diluent.1,2
Streamline their infusion experience.
The individual depicted is not a hemophilia patient. For illustrative purposes only.
*BeneFIX was approved February 11, 1997.3
Indication for BeneFIX
BeneFIX® Coagulation Factor IX (Recombinant) is indicated for the IX has been associated with the development of
control and prevention of bleeding episodes in adult and pediatric thromboembolic complications, including patients receiving
patients with hemophilia B (congenital factor IX deficiency or
continuous infusion through a central venous catheter. The safety
Christmas disease), including peri-operative management.
and efficacy of BeneFIX administration by continuous infusion
have not been established.
BeneFIX is NOT indicated for the treatment of other factor
deficiencies (eg, factors II, VII, VIII and X), hemophilia A patients
detected in patients receiving factor IX products. If expected
with inhibitors to factor VIII, reversal of coumarin-induced
plasma factor IX activity levels are not attained, or if patient
anticoagulation, or bleeding due to low levels of liver-dependent
presents with allergic reaction, or if bleeding is not controlled
coagulation factors.
with an expected dose, an assay that measures factor IX inhibitor
Important Safety Information for BeneFIX
concentration should be performed.
IX is contraindicated in patients who have manifested
!
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life-threatening, immediate hypersensitivity reactions,
as BeneFIX contains trace amounts.
including anaphylaxis, to the product or its components,
'"*+/&
including hamster protein.
were nausea, injection site reaction, injection site pain, headache,
Should symptoms occur, treatment with the product should be
discontinued, and emergency treatment should be sought.
References: 1. BeneFIX®#04"6&!08:!0;;<=;;2. Lambert T, Recht M, Valentino LA, et al. Reformulated BeneFIX®: efficacy and
safety in previously treated patients with moderately severe to severe haemophilia B. Haemophilia.<==?@;DE<DD<GD3.#H68JK
$$K#H6
8#04"6&8N
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Please see brief summary of full Prescribing Information for BeneFIX on reverse side.
Manufactured by Wyeth Pharmaceuticals Inc.
BUS424818-01 © 2012 Pfizer Inc. All rights reserved.
Marketed by Pfizer Inc.
Printed in USA/February 2012
Brief Summary
ADVERSE REACTIONS
See package insert for full Prescribing Information. For further product information and current
package insert, please visit www.BeneFIX.com or call our medical communications department
toll-free at 1-800-934-5556.
The most serious adverse reactions are systemic hypersensitivity reactions, including
bronchospastic reactions and/or hypotension and anaphylaxis and the development of
high-titer inhibitors necessitating alternative treatments to factor IX replacement therapy.
INDICATIONS AND USAGE
The most common adverse reactions observed in clinical trials (frequency >5% of PTPs or
PUPs) were headaches, dizziness, nausea, injections site reaction, injection site pain and skinrelated hypersensitivity reactions (e.g., rash, hives).
Control and Prevention of Bleeding Episodes in Hemophilia B
BeneFIX® Coagulation Factor IX (Recombinant) is indicated for the control and prevention of
bleeding episodes in adult and pediatric patients with hemophilia B (congenital factor IX
deficiency or Christmas disease).
BeneFIX is NOT indicated for treatment of other factor deficiencies (e.g., factors II, VII, VIII, and
X), hemophilia A patients with inhibitors to factor VIII, reversal of coumarin-induced
anticoagulation, or bleeding due to low levels of liver-dependent coagulation factors.
Peri-operative Management in Patients with Hemophilia B
BeneFIX is indicated for peri-operative management in adult and pediatric patients with
hemophilia B.
CONTRAINDICATIONS
Clinical Trials 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 clinical practice.
During uncontrolled open-label clinical studies with BeneFIX conducted in previously treated
patients (PTPs), 113 adverse reactions with known or unknown relation to BeneFIX therapy
were reported among 38.5% (25 of 65) of subjects (with some subjects reporting more than
one event) who received a total of 7,573 infusions. The most frequently reported treatmentemergent adverse reactions were headache (10.8%), dizziness (7.7%), injection site reaction
(7.7%), nausea (6.2%), and injection site pain (6.2%).
WARNINGS AND PRECAUTIONS
In the 63 previously untreated patients (PUPs), who received a total of 5,538 infusions,
10 adverse reactions were reported among 9.5% of the patients (6 out of 63) having known or
unknown relationship to BeneFIX. Adverse reactions reported in ≥5% of subjects were: hives
(4.8%), factor IX inhibition (3.2%), dyspnea (3.2%), injection site reaction (1.6%), chills (1.6%),
and rash (1.6%).
Anaphylaxis and Severe Hypersensitivity Reactions
Immunogenicity
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with
BeneFIX and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness,
hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort
(generalized) and fatigue. Frequently, these events have occurred in close temporal association
with the development of factor IX inhibitors. Advise patients to discontinue use of the product
and contact their physician and/or seek immediate emergency care. Patients may develop
hypersensitivity to hamster (CHO) protein as BeneFIX contains trace amounts.
In clinical studies with 65 PTPs (defined as having more than 50 exposure days), a low-titer
inhibitor was observed in one patient. The inhibitor was transient, the patient continued on
study and had normal factor IX recovery pharmacokinetics at study completion (approximately
15 months after inhibitor detection).
BeneFIX is contraindicated in patients who have manifested life-threatening, immediate
hypersensitivity reactions, including anaphylaxis, to the product or its components, including
hamster protein.
Thromboembolic Complications
The safety and efficacy of BeneFIX administration by continuous infusion have not been
established. There have been post-marketing reports of thrombotic events in patients receiving
continuous-infusion BeneFIX through a central venous catheter, including life-threatening
superior vena cava (SVC) syndrome in critically ill neonates.
Nephrotic Syndrome
Nephrotic syndrome has been reported following immune tolerance induction with factor IX
products in hemophilia B patients with factor IX inhibitors and a history of allergic reactions to
factor IX. The safety and efficacy of using BeneFIX for immune tolerance induction have not
been established.
Neutralizing Antibodies (Immunogenicity)
Patients using BeneFIX should be monitored for the development of factor IX inhibitors by
appropriate clinical observations and laboratory tests. Inhibitors have been reported following
administration of BeneFIX. If expected plasma factor IX activity levels are not attained, or if
bleeding is not controlled with an expected dose, an assay that measures factor IX inhibitor
concentration should be performed.
Patients with factor IX inhibitors may be at an increased risk of anaphylaxis upon subsequent
challenge with factor IX. Patients experiencing allergic reactions should be evaluated for the
presence of an inhibitor. Patients should be observed closely for signs and symptoms of acute
hypersensitivity reactions, particularly during the early phases of initial exposure to product.
Because of the potential for allergic reactions with factor IX concentrates, the
initial (approximately 10 - 20) administrations of factor IX should be performed
under medical supervision where proper medical care for allergic reactions could
be provided.
Monitoring Laboratory Tests
Patients should be monitored for factor IX activity levels by the one-stage clotting assay
to confirm that adequate factor IX levels have been achieved and maintained, when
clinically indicated.
Patients should be monitored for the development of inhibitors if expected factor IX activity
plasma levels are not attained, or if bleeding is not controlled with the recommended dose of
BeneFIX. Assays used to determine if factor IX inhibitor is present should be titered in Bethesda
Units (BUs).
In clinical studies with pediatric PUPs, inhibitor development was observed in 2 out of 63
patients (3.2%), both were high-titer (>5 BU) inhibitors detected after 7 and 15 exposure days,
respectively. Both patients were withdrawn from the study.
DRUG INTERACTIONS—None known.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C—Animal reproduction and lactation studies have not been conducted
with BeneFIX. It is not known whether BeneFIX can affect reproductive capacity or cause fetal
harm when given to pregnant women. BeneFIX should be administered to pregnant women only
if needed.
Labor and Delivery
There is no information available on the effect of factor IX replacement therapy on labor and
delivery. Use only if needed.
Nursing Mothers
It is not known whether this drug is excreted into human milk. Because many drugs are
excreted into human milk, caution should be exercised if BeneFIX is administered to nursing
mothers. Use only if needed.
Pediatric Use
Safety, efficacy, and pharmacokinetics of BeneFIX have been evaluated in previously treated
(PTP) and previously untreated pediatric patients (PUP). On average, lower recovery has been
observed in pediatric patients (<15 years). A dose adjustment may be needed.
Geriatric Use
Clinical studies of BeneFIX did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Dose selection for an
elderly patient should be individualized.
STORAGE AND HANDLING
Product kit as packaged for sale: BeneFIX can be stored at room temperature or under
refrigeration, at a temperature of 2 to 30°C (36 to 86°F). Do not use BeneFIX after the expiration
date on the label.
Do not freeze to prevent damage to the diluent syringe.
Product after reconstitution: The product does not contain a preservative and should be used
within 3 hours.
This brief summary is based on the BeneFIX® Coagulation Factor IX (Recombinant) Prescribing
Information LAB-0464-8.0, revised 11/2011.
Manufactured by Wyeth Pharmaceuticals Inc.
BUS420430-01 © 2011 Pfizer Inc. All rights reserved.
Marketed by Pfizer Inc.
Printed in USA/November 2011
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For needs that go beyond medical care, refer your
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WARNINGS AND PRECAUTIONS:
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" ! " " ! 0 ! ." (" ADVERSE REACTIONS:
) $/1 # 234 " ! $ 56$6 714 7%4 664 /!" 84 94 1 51: 1:4 134
$94 784 /!"
6;4 & 6:4 #" ;4 94! ! #
# $ 56$6 1 51:- $ 73 6;4 & !
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374 374 " 364
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1%4 $;4DRUG INTERACTIONS:
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USE IN SPECIFIC POPULATIONS:
= " & ! ! # " ! ! " " " ! " . # / ," !
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ISTODAX® is a registered trademark of Celgene Corporation.
©2011 Celgene Corporation
10/11
IST11038
INDICATIONS
s4REATMENTOFPERIPHERAL4CELLLYMPHOMA04#,INPATIENTS
WHOHAVERECEIVEDATLEASTONEPRIORTHERAPY
s4REATMENTOFCUTANEOUS4CELLLYMPHOMA#4#,INPATIENTS
WHOHAVERECEIVEDATLEASTONEPRIORSYSTEMICTHERAPY
4HESEINDICATIONSAREBASEDONRESPONSERATE#LINICALBENElT
SUCHASIMPROVEMENTINOVERALLSURVIVALHASNOTBEENDEMONSTRATED
RECHARGE THE POSSIBILITIES
www.istodax.com
Please see Important Safety Information on adjacent page.
Please see Brief Summary of full Prescribing Information on following pages.
Only
ISTODAX® (romidepsin) for injection
For intravenous infusion only
The following is a brief summary only; see full prescribing information for
complete product information.
1 INDICATIONS AND USAGE
ISTODAX is indicated for:
M+D73F?7@FA85GF3@7AGE+57>>>K?B:A?3+#;@B3F;7@FEI:A:3H7
D757;H763F>73EFA@7BD;ADEKEF7?;5F:7D3BK
M+D73F?7@FA8B7D;B:7D3>+57>>>K?B:A?3'+#;@B3F;7@FEI:A:3H7
D757;H763F>73EFA@7BD;ADF:7D3BK
+:7E7;@6;53F;A@E3D743E76A@D7EBA@E7D3F7>;@;53>47@78;FEG5:3E
;?BDAH7?7@F;@AH7D3>>EGDH;H3>:3E@AF477@67?A@EFD3F76
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
+:7D75A??7@6766AE7A8DA?;67BE;@;E?9?2 36?;@;EF7D76
;@FD3H7@AGE>KAH7D3:AGDB7D;A6A@63KE3@6A8363K 5K5>7
K5>7EE:AG>647D7B73F767H7DK63KEBDAH;676F:3FF:7B3F;7@F
5A@F;@G7EFA47@78;F8DA?3@6FA>7D3F7EF:76DG9
2.2 Dose Modification
%A@:7?3FA>A9;5FAJ;5;F;7E7J57BF3>AB75;3
MD367ADFAJ;5;FK+D73F?7@FI;F:DA?;67BE;@E:AG>64767>3K76
G@F;>FAJ;5;FKD7FGD@EFA≤D367AD43E7>;@7F:7@F:7D3BK?3K47
D7EF3DF763F?9?2 8D367FAJ;5;FKD75GDEFD73F?7@FI;F:
DA?;67BE;@E:AG>64767>3K76G@F;>FAJ;5;FKD7FGD@EFA≤D367AD
43E7>;@73@6F:76AE7E:AG>647B7D?3@7@F>KD76G576FA
?9?2
MD367FAJ;5;FK+D73F?7@FI;F:DA?;67BE;@E:AG>64767>3K76G@F;>
FAJ;5;FKD7FGD@EFA≤D367AD43E7>;@7F:7@F:76AE7E:AG>647
B7D?3@7@F>KD76G576FA
?9?2
M)A?;67BE;@E:AG>6476;E5A@F;@G76;8D367ADFAJ;5;F;7ED75GD38F7D
6AE7D76G5F;A@
7?3FA>A9;5FAJ;5;F;7E
MD367AD@7GFDAB7@;3ADF:DA?4A5KFAB7@;3+D73F?7@FI;F:
DA?;67BE;@E:AG>64767>3K76G@F;>F:7EB75;8;55KFAB7@;3D7FGD@EFA
%≥P
9#3@6ADB>3F7>7F5AG@F≥P
9#AD43E7>;@7F:7@
F:7D3BK?3K47D7EF3DF763F?9?2
MD367874D;>7≥N@7GFDAB7@;3ADF:DA?4A5KFAB7@;3F:3F
D7CG;D7EB>3F7>7FFD3@E8GE;A@+D73F?7@FI;F:DA?;67BE;@E:AG>647
67>3K76G@F;>F:7EB75;8;55KFAB7@;3D7FGD@EFA≤D367AD43E7>;@7
3@6F:7@F:76AE7E:AG>647B7D?3@7@F>KD76G576FA
?9?2
2.3 Instructions for Preparation and Intravenous Administration
*+&/E:AG>647:3@6>76;@3?3@@7D5A@E;EF7@FI;F:D75A??7@676
E387BDA576GD7E8AD:3@6>;@95KFAFAJ;56DG9E
5 WARNINGS AND PRECAUTIONS
5.1 Hematologic
+D73F?7@FI;F: *+&/53@53GE7F:DA?4A5KFAB7@;3>7G=AB7@;3
@7GFDAB7@;33@6>K?B:AB7@;33@63@7?;3F:7D78AD7F:7E7:7?3FA>A9;53>
B3D3?7F7DEE:AG>647?A@;FAD766GD;@9FD73F?7@FI;F: *+&/3@6F:7
6AE7E:AG>647?A6;8;763E@757EE3DK1*77AE3973@66?;@;EFD3F;A@
3@66H7DE7)735F;A@E2
5.2 Infection
*7D;AGE3@6EA?7F;?7E83F3>;@875F;A@E;@5>G6;@9B@7G?A@;33@6E7BE;E
:3H7477@D7BADF76;@5>;@;53>FD;3>EI;F: *+&/+:7E753@A55GD
6GD;@9FD73F?7@F3@6I;F:;@
63KE38F7DFD73F?7@F3@6F:7D;E=A8>;87
F:D73F7@;@9;@875F;A@E?3K47:;9:7D;@B3F;7@FEI;F:3:;EFADKA87JF7@E;H7
AD;@F7@E;H75:7?AF:7D3BK1*776H7DE7)735F;A@E2
5.3 Electrocardiographic Changes
*7H7D3>FD73F?7@F7?7D97@F?ADB:A>A9;53>5:3@97E;@E;@5>G6;@9+I3H7
3@6*+E79?7@F5:3@97E:3H7477@D7BADF76;@5>;@;53>EFG6;7E+:75>;@;53>
E;9@;8;53@57A8F:7E75:3@97E;EG@=@AI@1*776H7DE7)735F;A@E2
@B3F;7@FEI;F:5A@97@;F3>>A@9(+EK@6DA?7B3F;7@FEI;F:3:;EFADKA8
E;9@;8;53@F53D6;AH3E5G>3D6;E73E73@6B3F;7@FEF3=;@93@F;3DD:KF:?;5
?76;5;@7EAD?76;5;@3>BDA6G5FEF:3F>736FAE;9@;8;53@F(+BDA>A@93F;A@
3BBDABD;3F753D6;AH3E5G>3D?A@;FAD;@9BD753GF;A@EE:AG>6475A@E;67D76
EG5:3EF:7?A@;FAD;@9A87>75FDA>KF7E3@6E3F43E7>;@73@6B7D;A6;53>>K
6GD;@9FD73F?7@F
'AF3EE;G?3@6?39@7E;G?E:AG>647I;F:;@F:7@AD?3>D3@97478AD7
36?;@;EFD3F;A@A8 *+&/1*776H7DE7)735F;A@E2
5.4 Tumor Lysis Syndrome
+G?AD>KE;EEK@6DA?7+#*:3E477@D7BADF76FAA55GD;@A8B3F;7@FE
I;F:FG?ADEF397+#3@6A8B3F;7@FEI;F:*F397 -'+#'3F;7@FE
I;F:36H3@576EF3976;E73E73@6AD:;9:FG?AD4GD67@E:AG>6475>AE7>K
?A@;FAD763BBDABD;3F7BD753GF;A@EE:AG>647F3=7@3@6FD73F?7@FE:AG>6
47;@EF;FGF763E3BBDABD;3F7
5.5 Use in Pregnancy
+:7D73D7@A367CG3F73@6I7>>5A@FDA>>76EFG6;7EA8 *+&/;@BD79@3@F
IA?7@AI7H7D43E76A@;FE?75:3@;E?A835F;A@3@68;@6;@9E;@3@;?3>E
*+&/?3K53GE787F3>:3D?I:7@36?;@;EF7D76FA3BD79@3@FIA?3@
@3@3@;?3>D7BDA6G5F;H7EFG6KDA?;67BE;@I3E7?4DKA5;63>3@6D7EG>F76
;@36H7DE778875FEA@F:767H7>AB;@987FGE3F7JBAEGD7E47>AIF:AE7;@
B3F;7@FE3FF:7D75A??7@6766AE7A8?9?2I77= 8F:;E6DG9;E
GE766GD;@9BD79@3@5KAD;8F:7B3F;7@F475A?7EBD79@3@FI:;>7F3=;@9
*+&/F:7B3F;7@FE:AG>6473BBD;E76A8F:7BAF7@F;3>:3L3D6FAF:7
87FGE1*77,E7;@*B75;8;5'ABG>3F;A@E2
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
753GE75>;@;53>FD;3>E3D75A@6G5F76G@67DI;67>KH3DK;@95A@6;F;A@E
36H7DE7D735F;A@D3F7EA4E7DH76;@F:75>;@;53>FD;3>EA836DG953@@AF47
6;D75F>K5A?B3D76FAD3F7E;@F:75>;@;53>FD;3>EA83@AF:7D6DG93@6?3K
@AFD78>75FF:7D3F7EA4E7DH76;@BD35F;57
Cutaneous T-Cell Lymphoma
+:7E387FKA8 *+&/I3E7H3>G3F76;@B3F;7@FEI;F:+#;@
E;@9>73D?5>;@;53>EFG6;7E;@I:;5:B3F;7@FED757;H763EF3DF;@96AE7A8
?9?2+:7?73@6GD3F;A@A8FD73F?7@F;@F:7E7EFG6;7EI3E
?A@F:ED3@97FA?A@F:E
A??A@6H7DE7)735F;A@E
+34>7EG??3D;L7EF:7?AEF8D7CG7@F36H7DE7D735F;A@E
D793D6>7EEA853GE3>;FKGE;@9F:7%3F;A@3>3@57D @EF;FGF7A??A@
+7D?;@A>A9KD;F7D;38AD6H7DE7H7@FE% +-7DE;A@
G7
FA?7F:A6A>A9;53>6;887D7@57E47FI77@F:7EFG6;7EF:763F33D7
BD7E7@F76E7B3D3F7>K8AD*FG6K3@6*FG6K6H7DE7D735F;A@E3D7
D3@=764KF:7;D;@5;67@57;@*FG6K#34AD3FADK34@AD?3>;F;7E5A??A@>K
D7BADF76
3E36H7DE7D735F;A@E3D7;@5>G676;@+34>7
Table 1. Adverse Reactions
Occurring in >20% of Patients in Either CTCL Study (N=185)
Study 1
Study 2
(n=102)
(n=83)
Grade 3
Grade 3
Adverse Reactions n (%)
All
or 4
All
or 4
@K36H7DE7D735F;A@
%3GE73
EF:7@;33F;9G7
@875F;A@E
-A?;F;@9
@AD7J;3
KBA?39@7E7?;3
;3DD:73
'KD7J;3
@7?;3
+:DA?4A5KFAB7@;3
KE97GE;3
A@EF;B3F;A@
%7GFDAB7@;3
KBAF7@E;A@
'DGD;FGE
KBA=3>7?;3
7D?3F;F;EJ8A>;3F;H7
67D?3F;F;E
KBA53>57?;3
#7G=AB7@;3
#K?B:AB7@;3
>3@;@73?;@AFD3@E87D3E7
;@5D73E76
EB3DF3F73?;@AFD3@E87D3E7
;@5D73E76
KBA3>4G?;@7?;3
>75FDA53D6;A9D3?
*++I3H75:3@97E
KB7D9>K57?;3
KBA@3FD7?;3
KB7D?39@7E7?;3
KBAB:AEB:3F7?;3
KB7DGD;57?;3
Serious Adverse Reactions
Infections were the most common type of SAE reported in both studies
with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2
experiencing a serious infection. Serious adverse reactions reported in
> 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2,
serious adverse reactions in > 2% of patients were fatigue (7%),
supraventricular arrhythmia, central line infection, neutropenia (6%),
hypotension, hyperuricemia, edema (5%), ventricular arrhythmia,
thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate
aminotransferase increased, sepsis, catheter related infection,
hypophosphatemia and dyspnea (4%).
Most deaths were due to disease progression. In Study 1, there were two
deaths due to cardiopulmonary failure and acute renal failure. In Study 2,
there were six deaths due to infection (4), myocardial ischemia, and acute
respiratory distress syndrome.
Discontinuations
Discontinuation due to an adverse event occurred in 21% of patients in
Study 1 and 11% in Study 2. Discontinuations occurring in at least 2%
of patients in either study included infection, fatigue, dyspnea,
QT prolongation, and hypomagnesmia.
Peripheral T-Cell Lymphoma
The safety of ISTODAX was evaluated in 178 patients with PTCL in a
sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored
study (Study 4) in which patients received a starting dose of 14 mg/m2.
The mean duration of treatment and number of cycles in these studies
were 5.6 months and 6 cycles.
Common Adverse Reactions
Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless
of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented
separately for Study 3 and Study 4. Laboratory abnormalities commonly
reported (≥ 10%) as adverse reactions are included in Table 2.
Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in
Study 3 and Corresponding Incidence in Study 4 (N=178)
Study 3
Study 4
(N=131)
(N=47)
Grade 3
Grade 3
Adverse Reactions n (%)
All
or 4
All
or 4
Any adverse reactions
127 (97)
86 (66)
47 (100)
40 (85)
Gastrointestinal disorders
Nausea
77 (59)
3 (2)
35 (75)
3 (6)
Vomiting
51 (39)
6 (5)
19 (40)
4 (9)
Diarrhea
47 (36)
3 (2)
17 (36)
1 (2)
Constipation
39 (30)
1 (<1)
19 (40)
1 (2)
Abdominal pain
18 (14)
3 (2)
6 (13)
1 (2)
Stomatitis
13 (10)
0
3 (6)
0
General disorders and
administration site conditions
Asthenia/Fatigue
72 (55)
11 (8)
36 (77)
9 (19)
Pyrexia
46 (35)
7 (5)
22 (47)
8 (17)
Chills
14 (11)
1 (<1)
8 (17)
0
Edema peripheral
13 (10)
1 (<1)
3 (6)
0
Blood and lymphatic
system disorders
Thrombocytopenia
53 (41)
32 (24)
34 (72)
17 (36)
Neutropenia
39 (30)
26 (20)
31 (66)
22 (47)
Anemia
32 (24)
14 (11)
29 (62)
13 (28)
Leukopenia
16 (12)
8 (6)
26 (55)
21 (45)
Metabolism and nutrition
disorders
Anorexia
37 (28)
2 (2)
21 (45)
1 (2)
Hypokalemia
14 (11)
3 (2)
8 (17)
1 (2)
Nervous system disorders
Dysgeusia
27 (21)
0
13 (28)
0
Headache
19 (15)
0
16 (34)
1 (2)
Respiratory, thoracic and
mediastinal disorders
Cough
23 (18)
0
10 (21)
0
Dyspnea
17 (13)
3 (2)
10 (21)
2 (4)
Investigations
Weight decreased
13 (10)
0
7 (15)
0
Cardiac disorders
Tachycardia
13 (10)
0
0
0
Serious Adverse Reactions
Infections were the most common type of SAE reported. In Study 3,
25 patients (19%) experienced a serious infection, including 6 patients
(5%) with serious treatment-related infections. In Study 4, 11 patients
(23%) experienced a serious infection, including 8 patients (17%) with
serious treatment-related infections. Serious adverse reactions reported
in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis,
vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia,
abdominal pain (3%), chest pain, neutropenia, pulmonary embolism,
dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in
≥ 2 of patients were pyrexia (17%), aspartate aminotransferase increased,
hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase
increased (11%), infection, dehydration, dyspnea (9%), lymphopenia,
neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile
neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity,
catheter related infection, hyperuricemia, hypoalbuminemia, syncope,
pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).
Deaths due to all causes within 30 days of the last dose of ISTODAX
occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In
Study 3, there were 5 deaths unrelated to disease progression that were
due to infections, including multi-organ failure/sepsis, pneumonia, septic
shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there
were 3 deaths unrelated to disease progression that were due to sepsis,
aspartate aminotransferase elevation in the setting of Epstein Barr virus
reactivation, and death of unknown cause.
Discontinuations
Discontinuation due to an adverse event occurred in 19% of patients in
Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia
and pneumonia were the only events leading to treatment discontinuation
in at least 2% of patients. In Study 4, events leading to treatment
discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia,
infection, and alanine aminotransferase increased (4%).
6.2 Postmarketing Experience
No additional safety signals have been observed from postmarketing
experience.
7 DRUG INTERACTIONS
7.1 Coumadin or Coumadin Derivatives
Prolongation of PT and elevation of INR were observed in a patient
receiving ISTODAX concomitantly with warfarin. Although the interaction
potential between ISTODAX and Coumadin or Coumadin derivatives has
not been formally studied, physicians should carefully monitor PT and
INR in patients concurrently administered ISTODAX and Coumadin or
Coumadin derivatives [See Clinical Pharmacology (12.3)].
7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes
Romidepsin is metabolized by CYP3A4. Although there are no formal
drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g.,
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone,
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase
concentrations of romidepsin. Therefore, co-administration with strong
CYP3A4 inhibitors should be avoided if possible. Caution should be
exercised with concomitant use of moderate CYP3A4 inhibitors.
Co-administration of potent CYP3A4 inducers (e.g., dexamethasone,
carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital)
may decrease concentrations of romidepsin and should be avoided if
possible. Patients should also refrain from taking St. John’s Wort.
7.3 Drugs that Inhibit Drug Transport Systems
Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp,
ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased
concentrations of romidepsin are likely, and caution should be exercised.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [See Warnings and Precautions (5.5)].
There are no adequate and well-controlled studies of ISTODAX in pregnant
women. However, based on its mechanism of action and findings in animals,
ISTODAX may cause fetal harm when administered to a pregnant woman.
In an animal reproductive study, romidepsin was embryocidal and resulted
in adverse effects on the developing fetus at exposures below those in
patients at the recommended dose. If this drug is used during pregnancy,
or if the patient becomes pregnant while taking ISTODAX, the patient
should be apprised of the potential hazard to the fetus.
Romidepsin was administered intravenously to rats during the period
of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial
resorption or post-implantation loss was observed at the high-dose of
0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were
noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures
(AUC) ≥0.2% of the human exposure at the recommended dose of
14 mg/m2/week. Drug-related fetal effects consisted of folded retina,
rotated limbs, and incomplete sternal ossification.
8.3 Nursing Mothers
It is not known whether romidepsin is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants from ISTODAX, a decision
should be made whether to discontinue nursing or discontinue the drug,
taking into account the importance of the drug to the mother.
8.4 Pediatric Use
The safety and effectiveness of ISTODAX in pediatric patients has not been
established.
8.5 Geriatric Use
Of the approximately 300 patients with CTCL or PTCL in trials, about 25%
were > 65 years old. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects; however, greater
sensitivity of some older individuals cannot be ruled out.
8.6 Hepatic Impairment
No dedicated hepatic impairment study for ISTODAX has been conducted.
Mild hepatic impairment does not alter pharmacokinetics of romidepsin
based on a population pharmacokinetic analysis. Patients with moderate
and severe hepatic impairment should be treated with caution [See
Clinical Pharmacology (12.3)].
8.7 Renal Impairment
No dedicated renal impairment study for ISTODAX has been conducted.
Based upon the population pharmacokinetic analysis, renal impairment
is not expected to significantly influence drug exposure. The effect of
end-stage renal disease on romidepsin pharmacokinetics has not been
studied. Thus, patients with end-stage renal disease should be treated
with caution [See Clinical Pharmacology (12.3)].
10 OVERDOSAGE
No specific information is available on the treatment of overdosage of
ISTODAX.
Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin
doses up to 2.2 fold the recommended human dose based on the body
surface area, included irregular respiration, irregular heart beat, staggering
gait, tremor, and tonic convulsions.
In the event of an overdose, it is reasonable to employ the usual supportive
measures, e.g., clinical monitoring and supportive therapy, if required.
There is no known antidote for ISTODAX and it is not known if ISTODAX
is dialyzable.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been performed with romidepsin.
Romidepsin was not mutagenic in vitro in the bacterial reverse mutation
assay (Ames test) or the mouse lymphoma assay. Romidepsin was not
clastogenic in an in vivo rat bone marrow micronucleus assay when
tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and
3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively).
These doses were up to 1.3-fold the recommended human dose, based
on body surface area.
Based on non-clinical findings, male and female fertility may be compromised
by treatment with ISTODAX. In a 26-week toxicology study, romidepsin
administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose
(2 mg/m2/dose) following the clinical dosing schedule. This dose resulted
in AUC0-inf. values that were approximately 2% the exposure level in patients
receiving the recommended dose of 14 mg/m2/dose. A similar effect was
seen in mice after 4 weeks of drug administration at higher doses. Seminal
vesicle and prostate organ weights were decreased in a separate study
in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day
(0.6 mg/m2/day), approximately 30% the estimated human daily dose
based on body surface area. Romidepsin showed high affinity for binding
to estrogen receptors in pharmacology studies. In a 26-week toxicology
study in rats, atrophy was seen in the ovary, uterus, vagina and mammary
gland of females administered doses as low as 0.1 mg/kg/dose
(0.6 mg/m2/dose) following the clinical dosing schedule. This dose
resulted in AUC0-inf. values that were 0.3% of those in patients receiving
the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian
follicles and decreased weight of ovaries were observed in a separate
study in rats after four weeks of daily drug administration at 0.1 mg/kg/day
(0.6 mg/m2/day). This dose is approximately 30% the estimated human
daily dose based on body surface area.
16 HOW SUPPLIED/STORAGE AND HANDLING
Keep out of reach of children.
Procedures for proper handling and disposal of anticancer drugs should be
considered. Several guidelines on this subject have been published1-4 [See
References (15)].
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling.
17.1 Instructions
M%3GE733@6-A?;F;@9
Nausea and vomiting are common following treatment with ISTODAX.
Prophylactic antiemetics are recommended to be used in all patients.
Advise patients to report these symptoms so that appropriate treatment
can be instituted [See Adverse Reactions (6)].
M#AI>AA6AG@FE
Patients should be informed that treatment with ISTODAX can cause low
blood counts and that frequent monitoring of hematologic parameters
is required. Patients should be instructed to report fever or other signs
of infection, significant fatigue, shortness of breath, or bleeding [See
Warnings and Precautions (5.1)].
M @875F;A@E
Patients should be informed that infections may occur during treatment
with ISTODAX. Patients should be instructed to report fever, cough,
shortness of breath with or without chest pain, burning on urination,
flu-like symptoms, muscle aches, or worsening skin problems [See
Warnings and Precautions (5.2)].
M+G?AD#KE;E*K@6DA?7
Patients at risk of tumor lysis syndrome (i.e, those with advanced stage
disease and/or high tumor burden) should be monitored closely for
TLS and appropriate measures taken if symptoms are observed [See
Warnings and Precautions (5.4)].
M,E7;@'D79@3@5K
If pregnancy occurs during treatment with ISTODAX, female patients
should be advised to seek immediate medical advice and counseling.
[See Warnings and Precautions (5.5)].
M'3F;7@FEE:AG>647;@EFDG5F76FAD736F:7B3F;7@F;@E7DF53D78G>>K
Manufactured for:
Celgene Corporation
Summit, NJ 07901
Manufactured by:
7@-7@G7#34AD3FAD;7E @5
Bedford, OH 44146
ISTODAX® is a registered trademark of Celgene Corporation
U.S. Patents: 4,977,138; 7,608,280; 7,611,724
*+-' '' Author guide
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scope of Blood. Papers on the immune response to specific microbioBLOOD, 8 MARCH 2012 䡠 VOLUME 119, NUMBER 10
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Author guide
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xxxii
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BLOOD, 8 MARCH 2012 䡠 VOLUME 119, NUMBER 10
NOW ENROLLING
Study Description
A multicenter, randomized, double-blind, placebo-controlled clinical trial of deferasirox in patients with myelodysplastic
syndromes (MDS) (low/intermediate-1 risk) and transfusional iron overload (Clinical Trial Protocol CICL670A2302).
The purpose of this study is to demonstrate in low/intermediate-1 risk MDS patients, treated as per standard practice,
the clinical superiority of deferasirox to placebo, while rigorously monitoring relevant clinical parameters (cardiac and
liver function, and transformation to acute leukemia [AML]) potentially affected by iron overload complications.
Study Design
Primary Endpoint*
Deferasirox
Screening
5y
Placebo
Expected
end of study
5andomization
(2:1=Deferasirox/Placebo)
The following dosing schedule is to be followed:
Ȼ 10 mg/kg/day (once daily) for 2 weeks, followed by 20 mg/kg/day
(once daily)
Ȼ After 3 months, the dose can be adjusted by 5 mg/kg/day or
10 mg/kg/day up to 40 mg/kg/day based on serum ferritin response
Two interim analyses for safety and efÀcacy are planned when
approximately 50 and 75 of the reTuired number of events (244)
have been observed.
Composite primary endpoint (event-free survival):
Ȼ Death
Ȼ 1onfatal event:
1. Echocardiographic evidence of worsening
cardiac function
2. Hospitalization for congestive heart failure
3. Liver function impairment
4. Liver cirrhosis
5. Progression to AML
Eligibility†
Inclusion criteria:
Ȼ Male or female patients, • 1 years of age
Ȼ Patient must weigh between 35 kg to 135 kg
Ȼ Patients with low or intermediate risk MDS, as
determined by IPSS score
Ȼ )erritin ! 1000 mcg/L and 3500 mcg/L at screening
Ȼ History of transfusion of 15 P5%C to 75 P5%C units
Ȼ Anticipated to be transfused with • units of P5%Cs
annually during the study
Endpoint details are deÀned in the protocol.
†
2ther protocol-deÀned inclusion/exclusion criteria may apply.
Exclusion criteria:
Ȼ More than 6 months of cumulative iron chelation
therapy (such as daily deferasirox or deferiprone or
5 ×/week deferoxamine)
Ȼ More than 3 years since patient began receiving
regular transfusions (2 units per weeks or 4 units
received in a 3-month period)
Ȼ Creatinine clearance 40 mL/min
Ȼ Serum creatinine ! 1.2 × 8L1 at screening
Ȼ SigniÀcant proteinuria
Ȼ EC2* performance status ! 2
Ȼ L9E) 50 by echocardiography
Ȼ History of hospitalization for congestive heart failure
Ȼ Systemic diseases which would prevent study
treatment (eg, uncontrolled hypertension,
cardiovascular, renal, hepatic, metabolic, etc)
Ȼ Evidence of active hepatitis % or hepatitis C
Ȼ History of HI9-positive test result
Ȼ ALT or AST ! 2.5 × 8L1 at screening
Ȼ Total bilirubin ! 8L1 at screening
Ȼ Diagnosis of liver cirrhosis
For more information
Ȼ Call 1ovartis 2ncology at 1-00-340-643
Ȼ Contact your local 1ovartis Medical Science Liaison (MSL)
Ȼ ClinicalTrials.gov identiÀer: 1CT0040602
Novartis Pharmaceuticals Corporation
East Hanover, 1- 0736-100
‹ 2012 1ovartis
1/12
I2E-103651
Indications and usage
Soliris is a complement inhibitor indicated for:
• The treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis
• The treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit
complement-mediated thrombotic microangiopathy
The effectiveness of Soliris in aHUS is based on the effects on thrombotic microangiopathy (TMA) and
renal function. Prospective clinical trials in additional patients are ongoing to confirm the benefit of
Soliris in patients with aHUS.
Limitation of Use
Soliris is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic
syndrome (STEC-HUS).
®
( e c u l i z u m a b )
®
( e c u l i z u m a b )
Concentrated solution for intravenous infusion
Brief summary—please see full prescribing information
IMPORTANT SAFETY INFORMATION
WARNING: SERIOUS MENINGOCOCCAL INFECTIONS
See full prescribing information for complete boxed warning
Life-threatening and fatal meningococcal infections have occurred
in patients treated with Soliris. Meningococcal infection may become
rapidly life-threatening or fatal if not recognized and treated early.
t$PNQMZXJUIUIFNPTUDVSSFOU"EWJTPSZ$PNNJUUFFPO*NNVOJ[BUJPO
1SBDUJDFT"$*1
SFDPNNFOEBUJPOTGPSNFOJOHPDPDDBMWBDDJOBUJPOJO
patients with complement deficiencies.
t*NNVOJ[FQBUJFOUTXJUIBNFOJOHPDPDDBMWBDDJOFBUMFBTUXFFLTQSJPS
UPBENJOJTUFSJOHUIFmSTUEPTFPG4PMJSJTVOMFTTUIFSJTLTPGEFMBZJOH
4PMJSJTUIFSBQZPVUXFJHIUIFSJTLTPGEFWFMPQJOHBNFOJOHPDPDDBM
infection. (See Serious Meningococcal Infections for additional
HVJEBODFPOUIFNBOBHFNFOUPGUIFSJTLPGNFOJOHPDPDDBMJOGFDUJPO
t.POJUPSQBUJFOUTGPSFBSMZTJHOTPGNFOJOHPDPDDBMJOGFDUJPOTBOE
evaluate immediately if infection is suspected.
4PMJSJTJTBWBJMBCMFPOMZUISPVHIBSFTUSJDUFEQSPHSBNVOEFSB3JTL
&WBMVBUJPOBOE.JUJHBUJPO4USBUFHZ3&.4
6OEFSUIF4PMJSJT3&.4
prescribers must enroll in the program. Enrollment in the Soliris
REMS program and additional information are available by telephone:
40-*3*4
INDICATIONS AND USAGE
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Soliris is indicated for the treatment of patients with paroxysmal nocturnal
IFNPHMPCJOVSJB1/)
UPSFEVDFIFNPMZTJT
Atypical Hemolytic Uremic Syndrome (aHUS)
Soliris is indicated for the treatment of patients with atypical hemolytic uremic
TZOESPNFB)64
UPJOIJCJUDPNQMFNFOUNFEJBUFEUISPNCPUJDNJDSPBOHJPQBUIZ
5IF FGGFDUJWFOFTT PG 4PMJSJT JO B)64 JT CBTFE PO UIF FGGFDUT PO UISPNCPUJD
NJDSPBOHJPQBUIZ5."
BOESFOBMGVODUJPO1SPTQFDUJWFDMJOJDBMUSJBMTJOBEEJUJPOBM
QBUJFOUTBSFPOHPJOHUPDPOmSNUIFCFOFmUPG4PMJSJTJOQBUJFOUTXJUIB)64
-JNJUBUJPOPG6TF: Soliris is not indicated for the treatment of patients with Shiga
toxin E. coliSFMBUFEIFNPMZUJDVSFNJDTZOESPNF45&$)64
CONTRAINDICATIONS
Soliris is contraindicated in:
t 1BUJFOUTXJUIVOSFTPMWFETFSJPVTNeisseria meningitidis infection
t 1BUJFOUT XIP BSF OPU DVSSFOUMZ WBDDJOBUFE BHBJOTU Neisseria meningitidis,
VOMFTTUIFSJTLTPGEFMBZJOH4PMJSJTUSFBUNFOUPVUXFJHIUIFSJTLTPGEFWFMPQJOHB
meningococcal infection [see Warnings and Precautions].
WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections
The use of Soliris increases a patient’s susceptibility to serious meningococcal
JOGFDUJPOT TFQUJDFNJB BOEPS NFOJOHJUJT
-JGFUISFBUFOJOH BOE GBUBM
meningococcal infections have occurred in patients treated with Soliris.
"ENJOJTUFSBQPMZWBMFOUNFOJOHPDPDDBMWBDDJOFBDDPSEJOHUPUIFNPTUDVSSFOU
"EWJTPSZ$PNNJUUFFPO*NNVOJ[BUJPO1SBDUJDFT"$*1
SFDPNNFOEBUJPOTGPS
patients with complement deficiencies. Revaccinate patients in accordance
XJUI"$*1SFDPNNFOEBUJPOTDPOTJEFSJOHUIFEVSBUJPOPG4PMJSJTUIFSBQZ
7BDDJOBUFQBUJFOUTXJUIPVUBIJTUPSZPGNFOJOHPDPDDBMWBDDJOBUJPOBUMFBTU
XFFLT QSJPS UP SFDFJWJOH UIF mSTU EPTF PG 4PMJSJT *G VSHFOU 4PMJSJT UIFSBQZ JT
indicated in an unvaccinated patient, administer the meningococcal vaccine
BTTPPOBTQPTTJCMF*ODMJOJDBMTUVEJFTQBUJFOUTXJUIB)64XFSFUSFBUFE
XJUI4PMJSJTMFTTUIBOXFFLTBGUFSNFOJOHPDPDDBMWBDDJOBUJPOBOEPGUIFTF
QBUJFOUT SFDFJWFE BOUJCJPUJDT GPS QSPQIZMBYJT PG NFOJOHPDPDDBM JOGFDUJPO
VOUJMBUMFBTUXFFLTBGUFSNFOJOHPDPDDBMWBDDJOBUJPO5IFCFOFmUTBOESJTLT
of antibiotic prophylaxis for prevention of meningococcal infections in patients
receiving Soliris have not been established.
7BDDJOBUJPO SFEVDFT CVU EPFT OPU FMJNJOBUF UIF SJTL PG NFOJOHPDPDDBM
JOGFDUJPOT *O DMJOJDBM TUVEJFT PVU PG 1/) QBUJFOUT EFWFMPQFE TFSJPVT
meningococcal infections while receiving treatment with Soliris; both had
been vaccinated [see Adverse Reactions>*ODMJOJDBMTUVEJFTBNPOHOPO1/)
QBUJFOUTNFOJOHPDPDDBMNFOJOHJUJTPDDVSSFEJOPOFVOWBDDJOBUFEQBUJFOU*O
BEEJUJPOBQSFWJPVTMZWBDDJOBUFEQBUJFOUXJUIB)64EFWFMPQFENFOJOHPDPDDBM
sepsis during the post-study follow-up period [see Adverse Reactions].
$MPTFMZ NPOJUPS QBUJFOUT GPS FBSMZ TJHOT BOE TZNQUPNT PG NFOJOHPDPDDBM
infection and evaluate patients immediately if an infection is suspected.
Meningococcal infection may become rapidly life-threatening or fatal if
not recognized and treated early. Discontinue Soliris in patients who are
undergoing treatment for serious meningococcal infections.
QBSBNFUFST NBZ JEFOUJGZ B 5." DPNQMJDBUJPO PDDVSSFODF PG UXP PS SFQFBUFE
NFBTVSFNFOUPGBOZPOFPGUIFGPMMPXJOHBEFDSFBTFJOQMBUFMFUDPVOUCZPS
NPSFDPNQBSFEUPCBTFMJOFPSUIFQFBLQMBUFMFUDPVOUEVSJOH4PMJSJTUSFBUNFOUBO
JODSFBTFJOTFSVNDSFBUJOJOFCZPSNPSFDPNQBSFEUPCBTFMJOFPSOBEJSEVSJOH
4PMJSJTUSFBUNFOUPSBOJODSFBTFJOTFSVN-%)CZPSNPSFPWFSCBTFMJOFPSOBEJS
during Soliris treatment.
*G5."DPNQMJDBUJPOTPDDVSBGUFS4PMJSJTEJTDPOUJOVBUJPODPOTJEFSSFJOTUJUVUJPOPG
Soliris treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh
GSP[FOQMBTNBJOGVTJPO1&1*
>PSBQQSPQSJBUFPSHBOTQFDJmDTVQQPSUJWFNFBTVSFT
TABLE 1 (CONT.): ADVERSE REACTIONS OCCURRING IN AT LEAST 15% OF
PATIENTS LESS THAN 18 YEARS OF AGE ENROLLED IN aHUS STUDY 3
MedDRA
Number (%) of Patients
ver. 11.0
< 2 yrs
2 to < 12 yrs 12 to<18 yrs
Total
(n=5)
(n=10)
(n=4)
(n=19)
Respiratory,
Thoracic and
Mediastinal
Disorders
$PVHI
Thrombosis Prevention and Management
The effect of withdrawal of anticoagulant therapy during Soliris treatment has not /BTBMDPOHFTUJPO
been established. Therefore, treatment with Soliris should not alter anticoagulant $BSEJBD%JTPSEFST
management.
5BDIZDBSEJB
a.
Laboratory Monitoring
includes the preferred terms upper respiratory tract infection and nasopharyngitis.
PNH: Serum LDH levels increase during hemolysis and may assist in monitoring
4PMJSJT FGGFDUT JODMVEJOH UIF SFTQPOTF UP EJTDPOUJOVBUJPO PG UIFSBQZ *O DMJOJDBM Immunogenicity
studies, six patients achieved a reduction in serum LDH levels only after a decrease in "TXJUIBMMQSPUFJOTUIFSFJTBQPUFOUJBMGPSJNNVOPHFOJDJUZ5IFJNNVOPHFOJDJUZPG
UIF4PMJSJTEPTJOHJOUFSWBMGSPNUPEBZT"MMPUIFSQBUJFOUTBDIJFWFEBSFEVDUJPO Soliris has been evaluated using two different immunoassays for the detection of
JOTFSVN-%)MFWFMTXJUIUIFEBZEPTJOHJOUFSWBM<TFFClinical Pharmacology and BOUJFDVMJ[VNBCBOUJCPEJFTBEJSFDUFO[ZNFMJOLFEJNNVOPTPSCFOUBTTBZ&-*4"
using the Fab fragment of eculizumab as target was used for the PNH indication;
Clinical Studies].
B)64 &BSMZ TJHOT PG UISPNCPUJD NJDSPBOHJPQBUIZ 5."
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CSJEHJOH BTTBZ VTJOH UIF FDVMJ[VNBC
platelet count, and increases in serum LDH and creatinine levels. Follow patients for XIPMFNPMFDVMBSBTUBSHFUXBTVTFEGPSUIFB)64JOEJDBUJPO-PXUJUFSTPGBOUJCPEJFT
TJHOTPG5."CZNPOJUPSJOHTFSJBMQMBUFMFUDPVOUTTFSVN-%)BOEDSFBUJOJOFEVSJOH UP4PMJSJTXFSFEFUFDUFEJO
PGBMM1/)QBUJFOUTUSFBUFEXJUI4PMJSJTCZ
UIF&-*4"BTTBZ*OQBUJFOUTXJUIB)64USFBUFEXJUI4PMJSJTBOUJCPEJFTUP4PMJSJT
Soliris therapy and following discontinuation of Soliris.
XFSFEFUFDUFEJO
CZUIF&$-BTTBZ"O&$-CBTFEOFVUSBMJ[JOH)")"
BTTBZ XJUI B MPX TFOTJUJWJUZ PG NDHN- XBT QFSGPSNFE UP EFUFDU OFVUSBMJ[JOH
Infusion Reactions
"TXJUIBMMQSPUFJOQSPEVDUTBENJOJTUSBUJPOPG4PMJSJTNBZSFTVMUJOJOGVTJPOSFBDUJPOT BOUJCPEJFT GPS UIF QBUJFOUT XJUI B)64 /P OFVUSBMJ[JOH BDUJWJUZ UP 4PMJSJT XBT
JODMVEJOH BOBQIZMBYJT PS PUIFS IZQFSTFOTJUJWJUZ SFBDUJPOT *O DMJOJDBM USJBMT OP EFUFDUFE JO QBUJFOUT XJUI B)64 USFBUFE XJUI 4PMJSJT /P BQQBSFOU DPSSFMBUJPO PG
patients experienced an infusion reaction which required discontinuation of Soliris. antibody development to clinical response was observed in both indications. The
*OUFSSVQU4PMJSJTJOGVTJPOBOEJOTUJUVUFBQQSPQSJBUFTVQQPSUJWFNFBTVSFTJGTJHOTPG immunogenicity data reflect the percentage of patients whose test results were
DPOTJEFSFEQPTJUJWFGPSBOUJCPEJFTUP4PMJSJTJOBO&-*4"CBTFEBTTBZBOEPSBO&$-
cardiovascular instability or respiratory compromise occur.
based assay are highly dependent on the sensitivity and specificity of the assay
ADVERSE REACTIONS
VTFE"EEJUJPOBMMZUIFPCTFSWFEJODJEFODFPGBOUJCPEZQPTJUJWJUZJOUIFBTTBZNBZCF
Clinical Trial Experience
influenced by several factors including sample handling, timing of sample collection,
Meningococcal infections are the most important adverse reactions experienced concomitant medications and underlying disease. For these reasons, comparison
CZ QBUJFOUT SFDFJWJOH 4PMJSJT *O 1/) DMJOJDBM TUVEJFT UXP QBUJFOUT FYQFSJFODFE of the incidence of antibodies to Soliris with the incidence of antibodies to other
meningococcal sepsis. Both patients had previously received a meningococcal products may be misleading.
WBDDJOF*ODMJOJDBMTUVEJFTBNPOHQBUJFOUTXJUIPVU1/)NFOJOHPDPDDBMNFOJOHJUJT
occurred in one unvaccinated patient. Meningococcal sepsis occurred in one Postmarketing Experience
QSFWJPVTMZWBDDJOBUFEQBUJFOUFOSPMMFEJOUIFSFUSPTQFDUJWFB)64TUVEZEVSJOHUIF $BTFTPGTFSJPVTPSGBUBMNFOJOHPDPDDBMJOGFDUJPOTIBWFCFFOSFQPSUFE
post-study follow-up period [see Warnings and Precautions].
USE IN SPECIFIC POPULATIONS
PNH 5IF EBUB EFTDSJCFE CFMPX SFnFDU FYQPTVSF UP 4PMJSJT JO BEVMU QBUJFOUT
XJUI1/)BHFPGXIPNXFSFGFNBMF"MMIBETJHOTPSTZNQUPNTPG Pregnancy
intravascular hemolysis. Soliris was studied in a placebo-controlled clinical study (in 1SFHOBODZ$BUFHPSZ$
XIJDIQBUJFOUTSFDFJWFE4PMJSJTBOEQMBDFCP
BTJOHMFBSNDMJOJDBMTUVEZBOE There are no adequate and well-controlled studies of Soliris in pregnant women.
BMPOHUFSNFYUFOTJPOTUVEZQBUJFOUTXFSFFYQPTFEGPSHSFBUFSUIBOPOFZFBS"MM 4PMJSJTBSFDPNCJOBOU*H(NPMFDVMFIVNBOJ[FEBOUJ$BOUJCPEZ
JTFYQFDUFEUP
DSPTTUIFQMBDFOUB"OJNBMTUVEJFTVTJOHBNPVTFBOBMPHVFPGUIF4PMJSJTNPMFDVMF
patients received the recommended Soliris dose regimen.
Because clinical trials are conducted under widely varying conditions, adverse NVSJOFBOUJ$BOUJCPEZ
TIPXFEJODSFBTFESBUFTPGEFWFMPQNFOUBMBCOPSNBMJUJFT
reaction rates observed in the clinical trials of a drug cannot be directly compared BOEBOJODSFBTFESBUFPGEFBEBOENPSJCVOEPGGTQSJOHBUEPTFTUJNFTUIFIVNBO
to rates in the clinical trials of another drug and may not reflect the rates observed dose. Soliris should be used during pregnancy only if the potential benefit justifies
UIFQPUFOUJBMSJTLUPUIFGFUVT
in practice.
The most frequently reported adverse reactions in the PNH randomized trial "OJNBM SFQSPEVDUJPO TUVEJFT XFSF DPOEVDUFE JO NJDF VTJOH EPTFT PG B NVSJOF
öPWFSBMMBOEHSFBUFSUIBOQMBDFCP
BSFIFBEBDIFOBTPQIBSZOHJUJTCBDLQBJO BOUJ$BOUJCPEZUIBUBQQSPYJNBUFEUJNFTMPXEPTF
BOEUJNFTIJHIEPTF
the recommended human Soliris dose, based on a body weight comparison. When
and nausea.
animal exposure to the antibody occurred in the time period from before mating until
*OUIFQMBDFCPDPOUSPMMFEDMJOJDBMTUVEZTFSJPVTBEWFSTFSFBDUJPOTPDDVSSFEBNPOH early gestation, no decrease in fertility or reproductive performance was observed.
QBUJFOUT SFDFJWJOH 4PMJSJT BOE QBUJFOUT SFDFJWJOH QMBDFCP 5IF When maternal exposure to the antibody occurred during organogenesis, two cases
serious reactions included infections and progression of PNH. No deaths occurred PG SFUJOBM EZTQMBTJB BOE POF DBTF PG VNCJMJDBM IFSOJB XFSF PCTFSWFE BNPOH in the study and no patients receiving Soliris experienced a thrombotic event; one offspring born to mothers exposed to the higher antibody dose; however, the exposure
thrombotic event occurred in a patient receiving placebo.
did not increase fetal loss or neonatal death. When maternal exposure to the antibody
"NPOHQBUJFOUTXJUI1/)USFBUFEXJUI4PMJSJTJOUIFTJOHMFBSNDMJOJDBMTUVEZ occurred in the time period from implantation through weaning, a higher number of
or the follow-up study, the adverse reactions were similar to those reported in the NBMFPGGTQSJOHCFDBNFNPSJCVOEPSEJFEDPOUSPMTMPXEPTFHSPVQIJHI
QMBDFCPDPOUSPMMFEDMJOJDBMTUVEZ4FSJPVTBEWFSTFSFBDUJPOTPDDVSSFEBNPOHPG EPTFHSPVQ
4VSWJWJOHPGGTQSJOHIBEOPSNBMEFWFMPQNFOUBOESFQSPEVDUJWFGVODUJPO
the patients in these studies. The most common serious adverse reactions were: viral
Nursing Mothers
JOGFDUJPO
IFBEBDIF
BOFNJB
BOEQZSFYJB
B)64 5IF TBGFUZ PG 4PMJSJT UIFSBQZ JO QBUJFOUT XJUI B)64 XBT FWBMVBUFE JO UXP *U JT OPU LOPXO XIFUIFS 4PMJSJT JT FYDSFUFE JOUP IVNBO NJML *H( JT FYDSFUFE JO
QSPTQFDUJWFTJOHMFBSNTUVEJFTB)644UVEJFTBOE
BOEPOFSFUSPTQFDUJWFTUVEZ IVNBONJMLTPJUJTFYQFDUFEUIBU4PMJSJTXJMMCFQSFTFOUJOIVNBONJML)PXFWFS
B)644UVEZ
5IFEBUBEFTDSJCFECFMPXXFSFEFSJWFEGSPNBEVMUBOEBEPMFTDFOU QVCMJTIFEEBUBTVHHFTUUIBUBOUJCPEJFTJOIVNBONJMLEPOPUFOUFSUIFOFPOBUBM
QBUJFOUTXJUIB)64FOSPMMFEJOB)644UVEZBOEB)644UVEZ"MMQBUJFOUTSFDFJWFE BOEJOGBOUDJSDVMBUJPOJOTVCTUBOUJBMBNPVOUT$BVUJPOTIPVMECFFYFSDJTFEXIFO
UIFSFDPNNFOEFEEPTBHFPG4PMJSJT.FEJBOFYQPTVSFXBTXFFLTSBOHFXFFLT
4PMJSJTJTBENJOJTUFSFEUPBOVSTJOHXPNBO5IFVOLOPXOSJTLTUPUIFJOGBOUGSPN
gastrointestinal or limited systemic exposure to Soliris should be weighed against
Because clinical trials are conducted under widely varying conditions, adverse UIFLOPXOCFOFmUTPGIVNBONJMLGFFEJOH
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 Pediatric Use
in practice.
The safety and effectiveness of Soliris for the treatment of PNH in pediatric patients
5IFNPTUGSFRVFOUMZSFQPSUFEBEWFSTFSFBDUJPOTJOB)64TJOHMFBSNQSPTQFDUJWFUSJBMT below the age of 18 years have not been established.
öDPNCJOFEQFSQBUJFOUJODJEFODF
BSFIZQFSUFOTJPOVQQFSSFTQJSBUPSZUSBDU Three clinical studies assessing the safety and effectiveness of Soliris for the
infection, diarrhea, headache, anemia, vomiting, nausea, urinary tract infection, USFBUNFOUPGB)64JODMVEFEBUPUBMPGQFEJBUSJDQBUJFOUTBHFTNPOUITUP
BOEMFVLPQFOJB
ZFBST
5IFTBGFUZBOEFGGFDUJWFOFTTPG4PMJSJTGPSUIFUSFBUNFOUPGB)64BQQFBS
*OB)644UVEJFTBOEDPNCJOFE
PGQBUJFOUTFYQFSJFODFEBTFSJPVT similar in pediatric and adult patients [see Dosage and Administration, Adverse
BEWFSTFFWFOU4"&
5IFNPTUDPNNPOMZSFQPSUFE4"&TXFSFIZQFSUFOTJPO
Reactions, and Clinical Studies].
BOEJOGFDUJPOT
0OFQBUJFOUEJTDPOUJOVFE4PMJSJTEVFUPBEWFSTFFWFOUTEFFNFE "ENJOJTUFSWBDDJOBUJPOTGPSUIFQSFWFOUJPOPGJOGFDUJPOEVFUPNeisseria meningitidis,
unrelated to Soliris.
Streptococcus pneumoniae and Haemophilus influenzaUZQFC)JC
BDDPSEJOHUP"$*1
"OBMZTJTPGSFUSPTQFDUJWFMZDPMMFDUFEBEWFSTFFWFOUEBUBGSPNQFEJBUSJDBOEBEVMU guidelines [see Warnings and Precautions].
QBUJFOUTFOSPMMFEJOB)644UVEZ/
SFWFBMFEBTBGFUZQSPmMFUIBUXBTTJNJMBS
UPUIBUXIJDIXBTPCTFSWFEJOUIFUXPQSPTQFDUJWFTUVEJFTB)644UVEZJODMVEFE Geriatric Use
pediatric patients less than 18 years of age. Overall, the safety of Soliris in pediatric 4JYUFFOQBUJFOUTZFBSTPGBHFPSPMEFSXJUI1/)BOEXJUIB)64
XFSFUSFBUFE
QBUJFOUTXJUIB)64FOSPMMFEJO4UVEZBQQFBSFETJNJMBSUPUIBUPCTFSWFEJOBEVMU XJUI4PMJSJT"MUIPVHIUIFSFXFSFOPBQQBSFOUBHFSFMBUFEEJGGFSFODFTPCTFSWFEJO
QBUJFOUT5IFNPTUDPNNPOö
BEWFSTFFWFOUTPDDVSSJOHJOQFEJBUSJDQBUJFOUT UIFTFTUVEJFTUIFOVNCFSPGQBUJFOUTBHFEBOEPWFSJTOPUTVGmDJFOUUPEFUFSNJOF
whether they respond differently from younger patients.
are presented in Table 1.
Soliris REMS
#FDBVTFPGUIFSJTLPGNFOJOHPDPDDBMJOGFDUJPOT4PMJSJTJTBWBJMBCMFPOMZUISPVHIB
SFTUSJDUFEQSPHSBNVOEFSB3JTL&WBMVBUJPOBOE.JUJHBUJPO4USBUFHZ3&.4
6OEFS
the Soliris REMS, prescribers must enroll in the program.
1SFTDSJCFST NVTU DPVOTFM QBUJFOUT BCPVU UIF SJTL PG NFOJOHPDPDDBM JOGFDUJPO
provide the patients with the REMS educational materials, and ensure patients are
vaccinated with a meningococcal vaccine.
Enrollment in the Soliris REMS program and additional information are available by
Table 1: Adverse Reactions Occurring in at Least 15% of Patients Less
UFMFQIPOF40-*3*4
than 18 Years of Age Enrolled in aHUS Study 3
Other Infections
Number (%) of Patients
4PMJSJT CMPDLT UFSNJOBM DPNQMFNFOU BDUJWBUJPO UIFSFGPSF QBUJFOUT NBZ IBWF MedDRA
< 2 yrs 2 to < 12 yrs 12 to<18 yrs
Total
increased susceptibility to infections, especially with encapsulated bacteria. ver. 11.0
(n=5)
(n=10)
(n=4)
(n=19)
$IJMESFOUSFBUFEXJUI4PMJSJTNBZCFBUJODSFBTFESJTLPGEFWFMPQJOHTFSJPVTJOGFDUJPOT
due to Streptococcus pneumoniae and Haemophilus influenzaUZQFC)JC
"ENJOJTUFS General Disorders
vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus and Administration
influenzaUZQFC)JC
JOGFDUJPOTBDDPSEJOHUP"$*1HVJEFMJOFT6TFDBVUJPOXIFO
Site Conditions
administering Soliris to patients with any systemic infection.
1ZSFYJB
Monitoring After Soliris Discontinuation
Gastrointestinal
Treatment Discontinuation for PNH: Monitor patients after discontinuing Soliris for at
Disorders
MFBTUXFFLTUPEFUFDUIFNPMZTJT
5SFBUNFOU%JTDPOUJOVBUJPOGPSB)64"GUFSEJTDPOUJOVJOH4PMJSJTNPOJUPSQBUJFOUT %JBSSIFB
XJUI B)64 GPS TJHOT BOE TZNQUPNT PG UISPNCPUJD NJDSPBOHJPQBUIZ 5."
7PNJUJOH
DPNQMJDBUJPOTGPSBUMFBTUXFFLT*OB)64DMJOJDBMTUVEJFTQBUJFOUTJOUIF
Infections and
QSPTQFDUJWF TUVEJFT
EJTDPOUJOVFE 4PMJSJT USFBUNFOU 5." DPNQMJDBUJPOT PDDVSSFE
GPMMPXJOHBNJTTFEEPTFJOQBUJFOUTBOE4PMJSJTXBTSFJOJUJBUFEJOPGUIFTFQBUJFOUT Infestations
$MJOJDBMTJHOTBOETZNQUPNTPG5."JODMVEFDIBOHFTJONFOUBMTUBUVTTFJ[VSFT 6QQFSSFTQJSBUPSZ
BOHJOB EZTQOFB PS UISPNCPTJT *O BEEJUJPO UIF GPMMPXJOH DIBOHFT JO MBCPSBUPSZ tract infectiona
HOW SUPPLIED/STORAGE AND HANDLING
4PMJSJTFDVMJ[VNBC
JTTVQQMJFEBTNHTJOHMFVTFWJBMTDPOUBJOJOHN-PG
mg/mL sterile, preservative-free Soliris solution per vial.
Soliris vials must be stored in the original carton until time of use under refrigerated
DPOEJUJPOTBU$'
BOEQSPUFDUFEGSPNMJHIU%POPUVTFCFZPOEUIF
expiration date stamped on the carton. Refer to Dosage and Administration (2) for
information on the stability and storage of diluted solutions of Soliris.
DO NOT FREEZE. DO NOT SHAKE.
/%$4JOHMFVOJUNHDBSUPO$POUBJOTPOF
N-WJBMPG4PMJSJT
NHN-
.BOVGBDUVSFECZ"MFYJPO1IBSNBDFVUJDBMT*OD
,OPUUFS%SJWF$IFTIJSF$564"
Soliris® is a registered trademark of Alexion Pharmaceuticals, Inc.
Copyright © 2011, Alexion Pharmaceuticals, Inc.
All rights reserved. SOL 1175
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DACOGEN® (decitabine) for INJECTION
Brief Summary of Prescribing Information
Before prescribing, please see the full Prescribing Information for DACOGEN.
INDICATIONS AND USAGE
Dacogen is indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and
secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess
blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and
high-risk International Prognostic Scoring System groups.
WARNINGS AND PRECAUTIONS
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]. 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.
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]
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 [Use in Specific Populations]. Based
on its mechanism of action, Dacogen can cause fetal harm if used during pregnancy.
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]. 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.
ADVERSE REACTIONS
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.
The following Adverse Events were Reported in ≥ 5% of Patients in the Dacogen Group and at a Rate Greater than
Supportive Care in the Phase 3 MDS Trial for Dacogen [N = 83 (%)] and Supportive Care [N = 81 (%)], respectively:
Blood and lymphatic system disorders—Neutropenia 75(90), 58(72); Thrombocytopenia 74(89), 64 (79); Anemia NOS 68 (82), 60
(74); Febrile neutropenia 24 (29), 5 (6); Leukopenia NOS 23 (28),11 (14); Lymphadenopathy 10(12), 6 (7) Thrombocythemia 4(5),1(1);
Cardiac disorders—Pulmonary edema NOS 5(6),0(0); Eye disorders—Vision blurred 5(6),0(0); Gastrointestinal disorders—
Nausea 35(42),13(16); Constipation 29(35),11(14); Diarrhea NOS 28(34),13(16) ; Vomiting NOS 21(25), 7(9); Abdominal
pain NOS 12(14), 5(6); Oral mucosal petechiae 11(13), 4(5); Stomatitis 10(12), 5(6); Dyspepsia 10(12), 1(1); Ascites 8(10), 2(2); Gingival
bleeding 7(8), 5(6); Hemorrhoids 7(8), 3(4); Loose stools 6(7), 3(4); Tongue ulceration 6(7), 2(2); Dysphagia 5(6), 2(2); Oral soft tissue
disorder NOS 5(6), 1(1); Lip ulceration 4(5), 3(4); Abdominal distension 4(5), 1(1); Abdominal pain upper 4(5), 1(1); Gastro-esophageal reflux
disease 4(5), 0(0); Glossodynia 4(5), 0(0); General disorders and administrative site disorders—Pyrexia 44(53), 23(28); Edema
peripheral 21(25), 13(16); Rigors 18(22), 14(17); Edema NOS 15(18), 5(6); Pain NOS 11(13), 5(6); Lethargy 10(12), 3(4); Tenderness
NOS 9(11), 0(0); Fall 7(8), 3(4); Chest discomfort 6(7), 3(4); Intermittent pyrexia 5(6), 3(4); Malaise 4(5), 1(1); Crepitations NOS 4(5),
1(1); Catheter site erythema 4(5), 1(1); Catheter site pain 4(5), 0(0); Injection site swelling 4(5), 0(0); Hepatobiliary Disorders—
Hyperbilirubinemia 12(14), 4(5); Infections and Infestations—Pneumonia NOS 18(22), 11(14); Cellulitis 10(12), 6(7); Candidal
infection NOS 8(10), 1(1); Catheter related infection 7(8), 0(0); Urinary tract infection NOS 6(7), 1(1); Staphylococcal infection 6(7), 0(0); Oral
candidiasis 5(6), 2(2); Sinusitis NOS 4(5), 2(2); Bacteremia 4(5), 0(0); Injury, poisoning and procedural complications—Transfusion
reaction 6(7), 3(4); Abrasion NOS 4(5), 1(1); Investigations—Cardiac murmur NOS 13(16), 9(11); Blood alkaline phosphatase NOS
increased 9(11), 7(9); Aspartate aminotransferase increased 8(10), 7(9); Blood urea increased 8(10), 1(1); Blood lactate dehydrogenase
increased 7(8), 5(6); Blood albumin decreased 6(7), 0(0); Blood bicarbonate increased 5(6), 1(1); Blood chloride decreased 5(6), 1(1); Protein
total decreased 4(5), 3(4); Blood bicarbonate decreased 4(5), 1(1); Blood bilirubin decreased 4(5), 1(1); Metabolism and nutrition
disorders—Hyperglycemia NOS 27(33), 16(20); Hypoalbuminemia 20(24), 14(17); Hypomagnesemia 20(24), 6(7); Hypokalemia
18(22), 10(12); Hyponatremia 16(19), 13(16); Appetite decreased NOS 13(16), 12(15); Anorexia 13(16), 8(10); Hyperkalemia 11(13),
3(4); Dehydration 5(6), 4(5); Musculoskeletal and connective tissue disorders—Arthralgia 17(20), 8(10); Pain in limb 16(19),
8(10); Back pain 14(17); 5(6); Chest wall pain 6(7), 1(1); Musculoskeletal discomfort 5(6), 0(0); Myalgia 4(5), 1(1); Nervous system
disorders—Headache 23(28), 11(14); Dizziness 15(18), 10(12); Hypoesthesia 9(11), 1(1); Psychiatric disorders—Insomnia
23(28), 11(14); Confusional state 10(12), 3(4); Anxiety 9(11), 8(10); Renal and urinary disorders—Dysuria 5(6), 3(4); Urinary
frequency 4(5), 1(1); Respiratory, thoracic and Mediastinal disorders—Cough 33(40), 25(31); Pharyngitis 13(16), 6(7); Crackles
lung 12(14), 1(1); Breath sounds decreased 8(10), 7(9); Hypoxia 8(10), 4(5); Rales 7(8), 2(2); Postnasal drip 4(5), 2(2); Skin and
subcutaneous tissue disorders—Ecchymosis 18(22), 12(15); Rash NOS 16(19), 7(9); Erythema 12(14), 5(6); Skin lesion NOS 9(11),
3(4); Pruritis 9(11), 2(2); Alopecia 7(8), 1(1); Urticaria NOS 5(6), 1(1); Swelling face 5(6), 0(0); Vascular disorders—Petechiae
32(39), 13(16); Pallor 19(23), 10(12); Hypotension NOS 5(6), 4(5); Hematoma NOS 4(5), 3(4).
Discussion of Clinically Important Adverse Reactions
In the controlled trial using Dacogen dosed at 15 mg/m2, 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]. 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/m2 intravenous, infused over one hour daily for 5 consecutive days of a 4 week cycle.
The information below presents all adverse events regardless of causality occurring in at least 5% of patients.
The following Adverse Events were Reported in ≥ 5% of Patients in a Single-arm Study* for Dacogen [N = 99 (%)]:
Blood and lymphatic system disorders—Anemia 31(31%); Febrile neutropenia 20(20%); Leukopenia 6(6%); Neutropenia 38, (38%);
Pancytopenia 5 (5%); Thrombocythemia 5 (5%); Thrombocytopenia 27 (27%); Cardiac disorders—Cardiac failure congestive 5 (5%);
Tachycardia 8 (8%); Ear and labyrinth disorders—Ear pain 6 (6%); Gastrointestinal disorders—Abdominal pain 14 (14%);
Abdominal pain upper 6 (6%); Constipation 30 (30%); Diarrhea 28 (28%); Dyspepsia 10 (10%); Dysphagia 5 (5%); Gastro-esophageal reflux
disease 5 (5%); Nausea 40 (40%); Oral pain 5 (5%); Stomatitis 11 (11%); Toothache 6 (6%); Vomiting 16 (16%); General disorders and
administration site conditions—Asthenia 15 (15%); Chest pain 6 (6%); Chills 16 (16%); Fatigue 46 (46%); Mucosal inflammation 9
(9%); Edema 5 (5%); Edema peripheral 27 (27%); Pain 5 (5%); Pyrexia 36 (36%); Infections and infestations—Cellulitis 9 (9%); Oral
candidiasis 6 (6%); Pneumonia 20 (20%); Sinusitis 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 9 (9%);
Investigations—Blood bilirubin increased 6 (6%); Breath sounds abnormal 5 (5%); Weight decreased 9 (9%); Metabolism and nutrition
disorders—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 17 (17%); Back pain 18 (18%); Bone pain 6
(6%); Muscle spasms 7 (7%); Muscular weakness 5 (5%); Musculoskeletal pain 5 (5%); Myalgia 9 (9%); Pain in extremity 18 (18%); Nervous
system disorders—Dizziness 21 (21%); Headache 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 8 (8%); Ecchymosis 9 (9%); Erythema 5 (5%); Night sweats 5 (5%); Petechiae 12 (12%); Pruritus 9 (9%) ; Rash 11
(11%) ; Skin lesion 5 (5%) ; Vascular disorders—Hypertension 6 (6%); Hypotension 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 20 mg/m2 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 above 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.
Post-marketing Experience
The following adverse reactions have been identified during postapproval 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.
DRUG INTERACTIONS
Drug interaction studies with decitabine have not been conducted. In vitro studies in human liver microsomes suggest that decitabine is unlikely
to inhibit or induce cytochrome P450 enzymes. In vitro metabolism studies have suggested that decitabine is not a substrate for human liver
cytochrome P450 enzymes. As plasma protein binding of decitabine is negligible (<1%), interactions due to displacement of more highly protein
bound drugs from plasma proteins are not expected.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D [see Warnings and Precautions]
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 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 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.
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.
Pediatric Use
The safety and effectiveness of Dacogen in pediatric patients have not been established.
Geriatric Use
Of the total number of 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.
Renal Impairment
There are no data on the use of Dacogen in patients with renal dysfunction; therefore, Dacogen should be used with caution in these patients.
Hepatic Impairment
There are no data on the use of Dacogen in patients with hepatic dysfunction; therefore, Dacogen should be used with caution in these patients.
OVERDOSAGE
There is no known antidote for overdosage with Dacogen. Higher doses are associated with increased myelosuppression including prolonged
neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose.
DOSAGE AND ADMINISTRATION [See section 2 of full Prescribing Information for complete information on Dosage
and Administration for DACOGEN]
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.
Treatment Regimen – Option 1
Patients may be premedicated with standard anti-emetic therapy. If hematologic recovery (ANC ≥ 1,000/μL and platelets ≥50,000/μL) from a
previous Dacogen treatment cycle requires more than 6 weeks, then the next cycle of Dacogen therapy should be delayed and dosing temporarily
reduced.
Treatment Regimen – Option 2
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 the first cycle of Dacogen treatment, if any of the following non-hematologic toxicities are present, Dacogen treatment should not be
restarted until the toxicity is resolved: 1) serum creatinine ≥ 2 mg/dL; 2) SGPT, total bilirubin ≥ 2 times ULN; 3) and active or uncontrolled infection.
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. 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 (36°F–46°F) for up to a maximum of 7 hours until administration.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container
permit. Do not use if there is evidence of particulate matter or discoloration.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis and Impairment of Fertility
Carcinogenicity studies with decitabine have not been conducted. The mutagenic potential of decitabine was tested in several in vitro and in vivo
systems. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichia coli lac-I
transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies.
The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m2 IP injection
(approximately 7% the recommended daily clinical dose) on day 10 of gestation. Body weights of males and females exposed in utero to decitabine
were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in
utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at 3 and 5 months of age
(36% and 0% pregnancy rate, respectively). In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m2 decitabine (approximately 0.3% to
1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures
(hemoglobin and WBC counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were
found at doses ≥ 0.3 mg/m2. In females mated to males dosed with ≥ 0.3 mg/m2 decitabine, pregnancy rate was reduced and preimplantation
loss was significantly increased.
Instructions for Patients
Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Dacogen and for 1 month afterwards,
and to use effective contraception during this time, [See Warnings and Precautions].
Men should be advised not to father a child while receiving treatment with Dacogen, and for 2 months afterwards. During these times, men with
female partners of childbearing potential should use effective contraception [See Warnings and Precautions and Nonclinical Toxicology].
Patients should be advised to monitor and report any symptoms of neutropenia, thrombocytopenia, or fever to their physician as soon as possible
[See Warnings and Precautions].
Prescribing information as of March 2010.
Manufactured by Pharmachemie B.V. Haarlem, the Netherlands
DACOGEN® is a registered trademark of SuperGen, Inc., Dublin, CA,U.S.A. used under license.
Distributed and marketed by Eisai Inc. © 2010 Eisai Inc. All rights reserved. Printed in USA. DAC345
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Dacogen® is a registered trademark of SuperGen, Inc., Dublin, CA, USA, used under license.
Distributed and marketed by Eisai Inc.
© 2011 Eisai Inc.
All rights reserved. Printed in USA. DAC399 3/11