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TASIGNA for adult patients with newly
diagnosed Ph+ CML in chronic phase
TASIGNA DOUBLED THE MAJOR MOLECULAR
RESPONSE (MMR) RATE OF IMATINIB AT
12 MONTHS1
2 TASIGNA PATIENTS (<1%) PROGRESSED
TO ACCELERATED PHASE OR BLAST CRISIS*
(AP/BC) VS 17 IMATINIB PATIENTS (6%)1
MMR rates at 12 months1
Progression to AP/BC1
30
100
P<0.0001
60
25
20
44%
[95% CI, 38.4%-50.3%]
22%
40
[95% CI, 17.6%-27.6%]
Patients
Patients (%)
80
10
20
5
0
0
TASIGNA
300 mg bid (n=282)
n=17 (6%)
15
n=2 (0.7%)
TASIGNA
300 mg bid (n=282)
Imatinib
400 mg qd (n=283)
Imatinib
400 mg qd (n=283)
ENESTnd study design: A randomized, controlled, open-label, multicenter Phase III trial of 846 patients with newly
diagnosed Ph+ CML in chronic phase. Patients were randomized to receive either TASIGNA 400 mg bid (n=281),
TASIGNA 300 mg bid (n=282), or imatinib 400 mg qd (n=283). The daily dose of imatinib could be escalated to 800 mg
(400 mg bid), but no dose escalation was permitted with TASIGNA. A centralized laboratory was used for PCR testing.
The primary end point was MMR at 12 months. MMR was deﬁned as ≤0.1% BCR-ABL/ABL by international scale
measured by RQ-PCR, which corresponds to a ≥3-log reduction of BCR-ABL transcripts from standardized baseline.1,2
The distinct safety proﬁle of TASIGNA supports its use in adult patients with
newly diagnosed Ph+ CML in chronic phase1
■
Discontinuation for adverse events regardless of causality was observed in 7% of patients
■
In ENESTnd, most side effects associated with TASIGNA did not lead to discontinuation
in the ﬁrst year
*Deﬁnition includes patients with clonal evolution and CML-related death. Time was censored at last assessment on
treatment for patients without events.2,3
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936-1080 ©2011 Novartis Printed in USA
12/10
AM7-100030
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EXPLORING CARFILZOMIB
I N R E L A P S E D M U LT I P L E M Y E L O M A
ASPIRE: a Phase III trial investigating carfilzomib-based
combination therapy
• ASPIRE* compares carfilzomib plus lenalidomide and dexamethasone (CRd)
and lenalidomide and dexamethasone (Rd)
• The trial includes patients with multiple myeloma who have received 1 to 3
prior treatment regimens
ASPIRE is one of many ongoing trials investigating agents in the Onyx
proteasome inhibitor pipeline.
To learn more about the ASPIRE trial, visit www.clinicaltrials.gov .
*ASPIRE: cArﬁlzomib, lenalidomide, and dexamethaSone (CRd) versus lenalidomide and
dexamethasone (Rd) for the treatment of PatIents with Relapsed multiple myEloma.
©2010 Onyx Pharmaceuticals, Inc., Emeryville, CA 1110-CARF-043 December 2010
Greater efﬁcacy vs imatinib on
every end point at 12 months
TASIGNA (nilotinib) is indicated for the treatment of adult patients with newly
diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+
CML) in chronic phase. The effectiveness of TASIGNA is based on major molecular
response and cytogenetic response rates. The study is ongoing and further data will
be required to determine long-term outcome.
Boxed WARNING and Additional Important Safety Information
TASIGNA prolongs the QT interval. ECGs should be obtained to monitor the QTc at
baseline, 7 days after initiation, and periodically thereafter, as well as following any
dose adjustments. Sudden deaths have been reported in patients receiving TASIGNA.
TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long
QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA
administration and should be periodically monitored. The concomitant use of strong
CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone,
disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong
the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol,
methadone, moxiﬂoxacin, and pimozide) should be avoided. The concomitant use of strong
CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin,
carbamazepine, rifampin, rifabutin, rifapentin, and phenobarbital). Patients should avoid
food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in
patients with hepatic impairment as nilotinib exposure is increased in patients with impaired
hepatic function.
■
■
■
■
■
■
■
■
■
Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia
Caution is recommended in patients with a history of pancreatitis
The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase
TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and
hyponatremia (see Boxed WARNING)
The exposure of nilotinib is reduced in patients with total gastrectomy
Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary
problems of galactose intolerance, severe lactase deﬁciency with a severe degree of intolerance
to lactose-containing products, or of glucose-galactose malabsorption
Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and
should be advised of the potential hazard to the fetus if they do
In chronic phase patients, the most commonly reported nonhematologic adverse drug reactions
(>10%) were rash, pruritus, nausea, fatigue, myalgia, headache, constipation, diarrhea, and vomiting
In accelerated phase patients, the most commonly reported nonhematologic adverse drug reactions
(>10%) were rash, pruritus, and fatigue
References: 1. TASIGNA® (nilotinib) capsules prescribing
information. East Hanover, NJ: Novartis Pharmaceuticals
Corporation; January 2011. 2. Saglio G, Kim D-W, Issaragrisil S,
et al; for ENESTnd investigators. Nilotinib versus imatinib for
newly diagnosed chronic myeloid leukemia. N Engl J Med.
2010;362(24):2251-2259. 3. Data on ﬁle. Novartis Pharmaceuticals
Corporation. East Hanover, NJ.
Please see brief summary of Prescribing Information on the following pages.
Tasigna® (nilotinib) Capsules
Initial U.S. Approval: 2007
BRIEF SUMMARY: Please see package insert for full prescribing information.
WARNING: QT PROLONGATION AND SUDDEN DEATHS
Tasigna prolongs the QT interval (5.2). Sudden deaths have been
reported in patients receiving nilotinib (5.3). Tasigna should not be used
in patients with hypokalemia, hypomagnesemia, or long QT syndrome
(4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna
administration and should be periodically monitored (5.2). Drugs known
to prolong the QT interval and strong CYP3A4 inhibitors should be
avoided (5.7). Patients should avoid food 2 hours before and 1 hour after
taking dose (5.8). A dose reduction is recommended in patients with
hepatic impairment (5.9). ECGs should be obtained to monitor the QTc at
baseline, seven days after initiation, and periodically thereafter, as well
as following any dose adjustments. (5.2, 5.3, 5.6, 5.12)
1 INDICATIONS AND USAGE
1.1 Newly Diagnosed Ph+ CML-CP
Tasigna (nilotinib) is indicated for the treatment of adult patients with newly
diagnosed Philadelphia chromosome positive chronic myeloid leukemia
(Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major
molecular response and cytogenetic response rates [see Clinical Studies
(14.1) in the full prescribing information]. The study is ongoing and further
data will be required to determine long-term outcome.
1.2 Resistant or Intolerant Ph+ CML-CP and CML-AP
Tasigna is indicated for the treatment of chronic phase and accelerated
phase Philadelphia chromosome positive chronic myelogenous leukemia
(Ph+ CML) in adult patients resistant or intolerant to prior therapy that
included imatinib. The effectiveness of Tasigna is based on hematologic
and cytogenetic response rates [see Clinical Studies (14.2) in the full prescribing information].
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
Tasigna should be taken twice daily at approximately 12 hour intervals and
must not be taken with food. The capsules should be swallowed whole with
water. No food should be consumed for at least 2 hours before the dose is
taken and no food should be consumed for at least one hour after the dose
is taken [see Boxed Warning, Warnings and Precautions (5.8), Clinical
Pharmacology (12.3) in the full prescribing information].
For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in one teaspoon of applesauce (puréed apple). The
mixture should be taken immediately (within 15 minutes) and should not be
stored for future use [see Clinical Pharmacology (12.3) in the full prescribing information].
Tasigna may be given in combination with hematopoietic growth factors
such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given
with hydroxyurea or anagrelide if clinically indicated.
Newly Diagnosed Ph+ CML-CP
The recommended dose of Tasigna is 300 mg orally twice daily [see Clinical Pharmacology (12.3) in the full prescribing information].
Resistant or Intolerant Ph+ CML-CP and CML-AP
The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily
[see Clinical Pharmacology (12.3) in the full prescribing information].
2.2 Dose Adjustments or Modifications
QT interval prolongation:
Table 1: Dose Adjustments for QT Prolongation
ECGs with a QTc
>480 msec
1. Withhold Tasigna, and perform an analysis of serum
potassium and magnesium, and if below lower limit of
normal, correct with supplements to within normal
limits. Concomitant medication usage must be reviewed.
2. Resume within 2 weeks at prior dose if QTcF returns to
<450 msec and to within 20 msec of baseline.
3. If QTcF is between 450 msec and 480 msec after 2 weeks,
reduce the dose to 400 mg once daily.
4. If, following dose-reduction to 400 mg once daily, QTcF
returns to >480 msec, Tasigna should be discontinued.
5. An ECG should be repeated approximately 7 days after
any dose adjustment.
Myelosuppression
Tasigna may need to be withheld and/or dose reduced for hematological
toxicities (neutropenia, thrombocytopenia) that are not related to underlying
leukemia (Table 2).
Table 2: Dose Adjustments for Neutropenia and Thrombocytopenia
Newly diagnosed Ph+ ANC* <1.0 x 109/L 1. Stop Tasigna, and monitor
CML in chronic phase and/or platelet
blood counts
at 300 mg twice daily counts <50 x 109/L 2. Resume within 2 weeks at
prior dose if ANC >1.0 x 109/L
Resistant or intolerant
and platelets >50 x 109/L
Ph+ CML in chronic
phase or accelerated
3. If blood counts remain low for
phase at 400 mg
>2 weeks, reduce the dose to
twice daily
400 mg once daily
*ANC = absolute neutrophil count
See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin,
and/or hepatic transaminases [see Adverse Reactions (6.1)].
Table 3: Dose Adjustments for Selected Non-hematologic
Laboratory Abnormalities
Elevated serum lipase 1. Withhold Tasigna, and monitor serum lipase or
or amylase ≥Grade 3
amylase
2. Resume treatment at 400 mg once daily if serum
lipase or amylase return to ≤Grade 1
Elevated bilirubin
1. Withhold Tasigna, and monitor bilirubin
≥Grade 3
2. Resume treatment at 400 mg once daily if bilirubin
return to ≤Grade 1
Elevated hepatic
1. Withhold Tasigna, and monitor hepatic transaminases
transaminases
2. Resume treatment at 400 mg once daily if hepatic
≥Grade 3
transaminases return to ≤Grade 1
Other Non-hematologic Toxicities
If other clinically significant moderate or severe non-hematologic toxicity
develops, withhold dosing, and resume at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose back to
300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant
Ph+ CML-CP and CML-AP) twice daily should be considered. For Grade 3
to 4 lipase elevations, dosing should be withheld, and may be resumed at
400 mg once daily. Test serum lipase levels monthly or as clinically indicated.
For Grade 3 to 4 bilirubin or hepatic transaminase elevations, dosing should
be withheld, and may be resumed at 400 mg once daily. Test bilirubin and
hepatic transaminases levels monthly or as clinically indicated [see Warnings and Precautions (5.4, 5.5), Use in Specific Populations (8.7) in the full
prescribing information].
Hepatic Impairment
If possible, consider alternative therapies. If Tasigna must be administered
to patients with hepatic impairment, consider the following dose reduction:
Table 4: Dose Adjustments for Hepatic Impairment (At Baseline)
Newly diagnosed
Mild, Moderate
An initial dosing regimen of
Ph+ CML in chronic
or Severe*
200 mg twice daily followed
phase at 300 mg
by dose escalation to 300 mg
twice daily
twice daily based on
tolerability
Resistant or intolerant
Mild or Moderate* An initial dosing regimen of
Ph+ CML in chronic phase
300 mg twice daily followed
or accelerated phase at
by dose escalation to 400 mg
400 mg twice daily
twice daily based on
tolerability
Severe*
A starting dose of 200 mg
twice daily followed by a
sequential dose escalation to
300 mg twice daily and then
to 400 mg twice daily based
on tolerability
*Mild = mild hepatic impairment (Child-Pugh Class A); Moderate = moderate
hepatic impairment (Child-Pugh Class B); Severe = severe hepatic impairment
(Child-Pugh Class C) [see Boxed Warning, Warnings and Precautions (5.9),
Use in Specific Populations (8.7) in the full prescribing information].
Concomitant Strong CYP3A4 Inhibitors
Avoid the concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole,
itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir,
ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit products may
also increase serum concentrations of nilotinib and should be avoided. Should
treatment with any of these agents be required, it is recommended that
therapy with Tasigna be interrupted. If patients must be co-administered a
strong CYP3A4 inhibitor, based on pharmacokinetic studies, consider a
dose reduction to 300 mg once daily in patients with resistant or intolerant
Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+
CML-CP. However, there are no clinical data with this dose adjustment in
patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period should be allowed before the Tasigna dose is
adjusted upward to the indicated dose. Close monitoring for prolongation
of the QT interval is indicated for patients who cannot avoid strong CYP3A4
inhibitors [see Boxed Warning, Warnings and Precautions (5.2, 5.7), Drug
Interactions (7.2) in the full prescribing information].
Concomitant Strong CYP3A4 Inducers
Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone,
phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital).
Patients should also refrain from taking St. John’s Wort. Based on the nonlinear pharmacokinetic profile of nilotinib, increasing the dose of Tasigna
when co-administered with such agents is unlikely to compensate for the loss
of exposure [see Drug Interactions (7.2) in the full prescribing information].
3 DOSAGE FORMS AND STRENGTHS
150 mg red opaque hard gelatin capsules with black axial imprint “NVR/BCR”.
200 mg light yellow opaque hard gelatin capsules with a red axial imprint
“NVR/TKI”.
4 CONTRAINDICATIONS
Do not use in patients with hypokalemia, hypomagnesemia, or long
QT syndrome [see Boxed Warning].
5 WARNINGS AND PRECAUTIONS
5.1 Myelosuppression
Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every two weeks for
the first 2 months and then monthly thereafter, or as clinically indicated.
Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction [see Dosage and Administration (2.2)].
5.2 QT Prolongation
Tasigna has been shown to prolong cardiac ventricular repolarization as
measured by the QT interval on the surface ECG in a concentrationdependent manner [see Adverse Reactions (6.1), Clinical Pharmacology
(12.4) in the full prescribing information]. Prolongation of the QT interval
can result in a type of ventricular tachycardia called torsade de pointes, which
may result in syncope, seizure, and/or death. ECGs should be performed at
baseline, seven days after initiation, periodically as clinically indicated and
following dose adjustments [see Warnings and Precautions (5.12)].
Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia or hypomagnesemia must be
corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)].
Significant prolongation of the QT interval may occur when Tasigna is
inappropriately taken with food and/or strong CYP3A4 inhibitors and/or
medicinal products with a known potential to prolong QT. Therefore,
co-administration with food must be avoided and concomitant use with
strong CYP3A4 inhibitors and/or medicinal products with a known potential
to prolong QT should be avoided [see Warnings and Precautions (5.7, 5.8)].
The presence of hypokalemia and hypomagnesemia may further enhance
this effect [see Warnings and Precautions (5.6, 5.12)].
5.3 Sudden Deaths
Sudden deaths have been reported in patients with CML treated with nilotinib
in clinical studies (n= 5,661; 0.3%). The relative early occurrence of some
of these deaths relative to the initiation of nilotinib suggests the possibility
that ventricular repolarization abnormalities may have contributed to their
occurrence.
5.4 Elevated Serum Lipase
The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. If lipase elevations
are accompanied by abdominal symptoms, interrupt dosing and consider
appropriate diagnostics to exclude pancreatitis. Test serum lipase levels
monthly or as clinically indicated.
5.5 Hepatotoxicity
The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as
clinically indicated [see Warnings and Precautions (5.12)].
5.6 Electrolyte Abnormalities
The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia,
hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected
prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)].
5.7 Drug Interactions
The administration of Tasigna with agents that are strong CYP3A4 inhibitors or
anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide,
procainamide, quinidine and sotalol) and other drugs that may prolong QT
interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide) should be avoided. Should
treatment with any of these agents be required, it is recommended that
therapy with Tasigna be interrupted. If interruption of treatment with Tasigna
is not possible, patients who require treatment with a drug that prolongs
QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning, Dosage and Administration
(2.2), Drug Interactions (7.2) in the full prescribing information].
5.8 Food Effects
The bioavailability of nilotinib is increased with food. Tasigna must not be
taken with food. No food should be taken at least 2 hours before and at
least one hour after the dose is taken. Grapefruit products and other foods
that are known to inhibit CYP3A4 should be avoided [see Boxed Warning,
Drug Interactions (7.2) and Clinical Pharmacology (12.3) in the full prescribing information].
5.9 Hepatic Impairment
Nilotinib exposure is increased in patients with impaired hepatic function.
A lower starting dose is recommended for patients with mild to severe
hepatic impairment (at baseline) and QT interval should be monitored
closely [see Boxed Warning, Dosage and Administration (2.2) and Use in
Specific Populations (8.7) in the full prescribing information].
5.10 Total Gastrectomy
The exposure of nilotinib is reduced in patients with total gastrectomy. More
frequent follow-up of these patients should be considered. Dose increase
or alternative therapy may be considered in patients with total gastrectomy
[see Clinical Pharmacology 12.3) in the full prescribing information].
5.11 Lactose
Since the capsules contain lactose, Tasigna is not recommended for patients
with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products
or of glucose-galactose malabsorption.
5.12 Monitoring Laboratory Tests
Complete blood counts should be performed every two weeks for the first
two months and then monthly thereafter. Chemistry panels, including the
lipid profile, should be checked periodically. ECGs should be obtained at
baseline, seven days after initiation and periodically thereafter, as well as
following dose adjustments [see Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed
more or less frequently at the physician’s discretion.
5.13 Use in Pregnancy
There are no adequate and well controlled studies of Tasigna in pregnant
women. However, Tasigna may cause fetal harm when administered to a
pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at
maternal exposures that were lower than the expected human exposure at
the recommended doses of nilotinib. 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 avoid becoming pregnant while taking Tasigna [see Use in
Specific Populations (8.1) in the full prescribing information].
6 ADVERSE REACTIONS
The following serious adverse reactions can occur with Tasigna and are
discussed in greater detail in other sections of the package insert [see
Boxed Warning, Warnings and Precautions (5)].
Myelosuppression [see Warnings and Precautions (5.1)]
QT prolongation [see Boxed Warning, Warnings and Precautions (5.2)]
Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3)]
Elevated serum lipase [see Warnings and Precautions (5.4)]
Hepatotoxicity [see Warnings and Precautions (5.5)]
Electrolyte abnormalities [see Boxed Warning, Warnings and Precautions (5.6)]
6.1 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 practice.
Newly diagnosed Ph+ CML-CP
The data below reflect exposure to Tasigna from a randomized trial in newly
diagnosed patients with Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment
in the nilotinib 300 mg twice daily group was 18.6 months. The median actual
dose intensity was 593 mg/day in the nilotinib 300 mg twice daily group.
The most common (>10%) non-hematologic adverse drug reactions were
rash, pruritus, headache, nausea, fatigue and myalgia. Upper abdominal
pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia,
abdominal pain, peripheral edema and asthenia were observed less commonly
(≤10% and >5%) and have been of mild to moderate severity, manageable
and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported
in 0.4% of patients.
Table 5: Most Frequently Reported Non-hematologic Adverse Reactions
(Regardless of Relationship to Study Drug) in Patients with
Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily
or Gleevec 400 mg once daily groups)a
Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%)
in the 300 mg twice daily treatment group. No patient had an absolute QTcF
of >500 msec.
The most common hematologic adverse drug reactions (all grades) were
myelosuppression including: thrombocytopenia (17%), neutropenia (15%)
and anemia (7%) See Table 7 for Grade 3/4 laboratory abnormalities.
Discontinuation due to adverse events regardless of causality was observed
in 7% of patients.
Resistant or intolerant Ph+ CML-CP and CML-AP
In the single open-label multicenter clinical trial, a total of 458 patients with
Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior
therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the
recommended dose of 400 mg twice daily.
The median duration of exposure in days for CML-CP and CML-AP patients
is 561 (range 1-1096) and 264 (range 2-1160), respectively. The median
dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range
151–1110) and 780 mg/day (range 150-1149), respectively and corresponded
to the planned 400 mg twice daily dosing.
The median cumulative duration in days of dose interruptions for the CML-CP
patients was 20 (range 1-345), and the median duration in days of dose
interruptions for the CML-AP patients was 23 (range 1–234).
In patients with CML-CP, the most commonly reported non-hematologic adverse
drug reactions (>10%) were rash, pruritus, nausea, fatigue, headache, constipation,
diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (>1%) were thrombocytopenia, neutropenia and anemia.
In patients with CML-AP, the most commonly reported non-hematologic
adverse drug reactions (>10%) were rash, pruritus and fatigue. The common
serious adverse drug reactions (>1%) were thrombocytopenia, neutropenia,
febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.
Sudden deaths and QT prolongation were reported. The maximum mean
QTcF change from baseline at steady-state was 10 msec. Increase in
QTcF >60 msec from baseline was observed in 4.1% of the patients and
QTcF of >500 msec was observed in 4 patients (<1%) [see Boxed Warning,
Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.4) in the
full prescribing information].
Discontinuation due to drug-related adverse reactions was observed in 16%
of CML-CP and 10% of CML-AP patients.
Most Frequently Reported Adverse Reactions
Tables 5 and 6 show the percentage of patients experiencing treatmentemergent adverse reactions (excluding laboratory abnormalities) regardless
of relationship to study drug. Adverse reactions reported in greater than
10% of patients who received at least one dose of Tasigna are listed.
Table 5: Most Frequently Reported Non-hematologic Adverse Reactions
(Regardless of Relationship to Study Drug) in Patients with
Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily
or Gleevec 400 mg once daily groups)a
Patients with Newly Diagnosed Ph+ CML-CP
TASIGNA
GLEEVEC
TASIGNA GLEEVEC
300 mg
400 mg
300 mg
400 mg
twice
once
twice
once
daily
daily
daily
daily
N=279
N=280
N=279
N=280
Body System and
Preferred Term
All Grades
CTC Gradesb 3 / 4 (%)
Skin and
Rash
36
16
<1
1
subcutaneous Pruritus
19
7
<1
0
tissue
Alopecia
10
5
0
0
disorders
GastroNausea
19
38
1
1
intestinal
Constipation
15
4
0
0
disorders
Diarrhea
14
37
<1
2
Vomiting
9
22
0
<1
Abdominal
pain upper
15
10
<1
<1
Abdominal
pain
12
9
1
<1
Nervous
Headache
28
16
3
<1
system
disorders
(continued)
Patients with Newly Diagnosed Ph+ CML-CP
Body System and
Preferred Term
TASIGNA
300 mg
twice
daily
GLEEVEC
400 mg
once
daily
N=279
N=280
Fatigue
Pyrexia
Asthenia
Edema,
peripheral
19
10
11
14
12
9
8
Musculoskeletal and
connective
tissue
disorders
Myalgia
Arthralgia
Muscle
spasms
Pain in
extremity
Back pain
14
15
Infections Nasopharynand
gitis
infestations Upper
respiratory
tract infection
Eye disorders Eyelid edema
GLEEVEC
400 mg
once
daily
N=279
N=280
CTC Gradesb 3 / 4 (%)
All Grades
General
disorders
and administration site
conditions
Respiratory, Cough
thoracic and
mediastinal
disorders
TASIGNA
300 mg
twice
daily
<1
0
<1
1
0
0
17
0
0
16
13
<1
<1
0
0
10
29
0
<1
9
12
13
10
0
<1
<1
1
12
9
0
0
19
15
0
0
13
9
0
0
1
14
0
<1
aExcluding
bNCI
laboratory abnormalities
Common Terminology Criteria for Adverse Events, Version 3.0
Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in
Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg
Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a
CML-CP
CML-AP
N=321
Body System and
Preferred Term
N=137
All
Grades
(%)
CTC
Gradesb
3 / 4 (%)
All
Grades
(%)
CTC
Gradesb
3 / 4 (%)
Skin and
subcutaneous
tissue
disorders
Rash
Pruritus
Night sweat
Alopecia
36
32
12
11
2
<1
<1
0
29
20
27
12
0
0
0
0
Gastrointestinal
disorders
Nausea
Constipation
Diarrhea
Vomiting
Abdominal
pain
Abdominal
pain upper
Dyspepsia
37
26
28
29
1
<1
3
<1
22
19
24
13
<1
0
2
0
15
2
16
3
14
10
<1
<1
12
4
<1
0
Nervous
system
disorders
Headache
35
2
20
1
General
disorders
and administration site
Fatigue
Pyrexia
Asthenia
Edema,
peripheral
Myalgia
32
22
16
3
<1
0
23
28
14
<1
2
1
15
19
<1
2
12
16
0
<1
(continued)
Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in
Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg
Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a
Body System and
Preferred Term
Musculoskeletal and
connective
tissue
disorders
Respiratory,
thoracic and
mediastinal
disorders
Arthralgia
Muscle
spasms
Bone pain
Pain in
extremity
Back pain
Musculoskeletal pain
Cough
Dyspnea
Oropharyngeal pain
Infections and Nasopharyninfestations gitis
Upper
respiratory
tract
infection
CML-CP
CML-AP
N=321
N=137
All
Grades
(%)
CTC
Gradesb
3 / 4 (%)
All
Grades
(%)
CTC
Gradesb
3 / 4 (%)
26
2
16
0
13
14
<1
<1
15
15
0
2
20
17
2
2
18
15
1
<1
11
<1
12
1
27
15
<1
2
18
9
0
2
11
0
7
0
24
<1
15
0
12
0
10
0
Metabolism
and
nutritional
disorders
Anorexia
12
<1
15
<1
Psychiatric
disorders
Insomnia
12
1
7
0
Vascular
disorders
Hypertension
10
2
11
<1
aExcluding
bNCI
laboratory abnormalities
Common Terminology Criteria for Adverse Events, Version 3.0
Laboratory Abnormalities
Table 7 shows the percentage of patients experiencing treatment-emergent
Grade 3/4 laboratory abnormalities in patients who received at least one
dose of Tasigna.
Table 7: Percent Incidence of Clinically Relevant
Grade 3/4* Laboratory Abnormalities
Patient Population
Newly Diagnosed
Ph+ CML-CP
Hematologic
Parameters
Thrombocytopenia
Neutropenia
Anemia
Biochemistry
Parameters
Elevated lipase
Hyperglycemia
Hypophosphatemia
Elevated bilirubin (total)
Elevated SGPT (ALT)
Hyperkalemia
Hyponatremia
Hypokalemia
Elevated SGOT (AST)
Decreased albumin
Resistant or
Intolerant Ph+
CML-CP
CML-AP
TASIGNA
300 mg
twice
daily
N=279
(%)
GLEEVEC
400 mg
once
daily
N=280
(%)
TASIGNA
400 mg
twice
daily
N=321
(%)
TASIGNA
400 mg
twice
daily
N=137
(%)
10
12
4
9
20
5
301
312
11
423
424
27
7
6
5
4
4
2
<1
<1
1
0
3
0
8
<1
3
1
<1
1
1
0
18
12
17
7
4
6
7
2
3
4
18
6
15
9
4
4
7
9
2
3
(continued)
Table 7: Percent Incidence of Clinically Relevant
Grade 3/4* Laboratory Abnormalities
Patient Population
Newly Diagnosed
Ph+ CML-CP
Biochemistry
Parameters
Hypocalcemia
Elevated alkaline
phosphatase
Elevated creatinine
Resistant or
Intolerant Ph+
CML-CP
CML-AP
TASIGNA
300 mg
twice
daily
N=279
(%)
GLEEVEC
400 mg
once
daily
N=280
(%)
TASIGNA
400 mg
twice
daily
N=321
(%)
TASIGNA
400 mg
twice
daily
N=137
(%)
<1
0
2
5
0
0
<1
<1
<1
<1
1
<1
*NCI Common Terminology Criteria for Adverse Events, version 3.0
1 CML-CP: Thrombocytopenia: 12% were grade 3, 18% were grade 4
2CML-CP: Neutropenia: 16% were grade 3, 15% were grade 4
3CML-AP: Thrombocytopenia: 11% were grade 3, 32% were grade 4
4CML-AP: Neutropenia: 16% were grade 3, 26% were grade 4
6.2 Additional Data from Clinical Trials
The following adverse drug reactions were reported in patients in the
Tasigna clinical studies at the recommended doses. These adverse drug
reactions are ranked under a heading of frequency, the most frequent first
using the following convention: common (1%-10%), uncommon (0.1%-1%),
and unknown frequency (single events). For adverse drug reactions listed
under “Investigations”, very common events (≥10%), which were not
included in Tables 5 and 6, are also reported. These adverse reactions are
included based on clinical relevance and ranked in order of decreasing seriousness within each category.
Infections and Infestations: Common: folliculitis. Uncommon: upper respiratory tract infection (including sinusitis, nasopharyngitis, pharyngitis), bronchitis, herpes virus infection, candidiasis pneumonia, urinary tract infection,
gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal
abscess, furuncle, tinea pedis.
Neoplasms Benign, Malignant and Unspecified: Common: Skin papilloma.
Unknown frequency: papilloma.
Blood and Lymphatic System Disorders: Common: febrile neutropenia,
pancytopenia, lymphopenia. Unknown frequency: thrombocytosis,
leukocytosis.
Immune System Disorders: Unknown frequency: hypersensitivity.
Endocrine Disorders: Uncommon: hyperthyroidism hypothyroidism. Unknown
frequency: hyperparathyroidism secondary, thyroiditis.
Metabolism and Nutrition Disorders: Common: electrolyte imbalance
(including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia,
hypocalcemia, hypophosphatemia, hypercalcemia, hyperphosphatemia),
diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia.
Uncommon: dehydration, decreased appetite, increased appetite. Unknown
frequency: hyperuricemia, gout, hypoglycemia, dyslipidemia.
Psychiatric Disorders: Common: depression, insomnia. Uncommon: anxiety.
Unknown frequency: disorientation, confusional state, amnesia, dysphoria.
Nervous System Disorders: Common: dizziness, hypoesthesia, paresthesia.
Uncommon: intracranial hemorrhage, migraine, loss of consciousness
(including syncope), tremor, disturbance in attention, hyperesthesia.
Unknown frequency: brain edema, optic neuritis, peripheral neuropathy,
lethargy, dysesthesia.
Eye Disorders: Common: eye hemorrhage, periorbital edema, eye pruritus,
conjunctivitis, dry eye. Uncommon: vision impairment, vision blurred,
visual acuity reduced, photopsia, eye irritation. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctival hemorrhage, conjunctivitis allergic, conjunctival
hyperemia, ocular hyperemia, ocular surface disease, scleral hyperemia.
Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing
impaired, ear pain, tinnitus.
Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, bradycardia),
palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure,
pericardial effusion, coronary artery disease, cyanosis, cardiac murmur.
Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease.
Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis.
Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema,
pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing.
Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort,
abdominal distension, dyspepsia, flatulence. Uncommon: gastrointestinal
hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis,
esophageal pain, dysgeusia, dry mouth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer,
esophagitis ulcerative, subileus, gastritis, hemorrhoids, hiatus hernia, rectal
hemorrhage, sensitivity of teeth, gingivitis.
Hepatobiliary Disorders: Common: hepatic function abnormal. Uncommon:
hepatitis, jaundice. Unknown frequency: cholestasis, hepatotoxicity,
hepatomegaly.
Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema,
urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis, dry skin.
Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis,
swelling of face. Unknown frequency: erythema nodosum, skin ulcer, palmarplantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister,
dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin
exfoliation, skin hyperpigmentation, skin hypertrophy.
Musculoskeletal and Connective Tissue Disorders: Common: bone pain,
musculoskeletal chest pain, musculoskeletal pain, flank pain. Uncommon:
musculoskeletal stiffness, muscular weakness, joint swelling. Unknown
frequency: arthritis.
Renal and Urinary Disorders: Common: pollakiuria. Uncommon: dysuria,
micturition urgency, nocturia. Unknown frequency: renal failure, hematuria,
urinary incontinence, chromaturia.
Reproductive System and Breast Disorders: Uncommon: breast pain,
gynecomastia, erectile dysfunction. Unknown frequency: breast induration,
menorrhagia, nipple swelling.
General Disorders and Administration Site Conditions: Common: pyrexia,
chest pain, pain (including neck pain and back pain), chest discomfort,
malaise. Uncommon: face edema, gravitational edema, influenza-like illness,
chills. Unknown frequency: feeling hot, localized edema.
Investigations: Common: blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, weight decreased,
weight increased. Uncommon: hemoglobin decreased, blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: blood
insulin increased, very low density lipoprotein increased, blood parathyroid
hormone increased, blood pressure increased.
6.3 Postmarketing Experience
The following additional adverse reactions have been reported during post
approval use of Tasigna. 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 tumor lysis syndrome have been reported in Tasigna treated patients
with resistant or intolerant CML. Malignant disease progression, high WBC
counts and/or dehydration were present in the majority of these cases.
10 OVERDOSAGE
Overdose with nilotinib has been reported, where an unspecified number of
Tasigna capsules were ingested in combination with alcohol and other drugs.
Events included neutropenia, vomiting, and drowsiness. In the event of
overdose, the patient should be observed and appropriate supportive treatment given.
16 HOW SUPPLIED/STORAGE AND HANDLING
Tasigna (nilotinib) 150 mg capsules are red opaque hard gelatin capsules,
size 1 with black axial imprint “NVR/BCR”. Tasigna (nilotinib) 200 mg capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial
imprint “NVR/TKI.” Tasigna capsules are supplied in blister packs.
150 mg
Carton of 4 blister packs of (4x28) ..................................NDC 0078-0592-87
Blisters of 28 capsules ....................................................NDC 0078-0592-51
200 mg
Carton of 4 blister packs of (4x28) ..................................NDC 0078-0526-87
Blisters of 28 capsules ....................................................NDC 0078-0526-51
Each blister pack contains one folded blister card of 28 capsules each, for
dosing two in the morning and two in the evening at 12 hour intervals over
a 7 day period.
Tasigna (nilotinib) capsules should be stored at 25°C (77°F); excursions
permitted between 15°-30°C (59°-86°F) [see USP Controlled Room
Temperature].
T2010-104
Manufactured by:
Novartis Pharma Stein AG
Stein, Switzerland
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
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Printed in USA/November 2010
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© 2010 Bayer HealthCare Pharmaceuticals Inc. All rights reserved.
Bayer and the Bayer Cross are trademarks of Bayer.
KN10000510
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© 2010 Bayer Schering Pharma AG. All rights reserved.
Bayer and the Bayer Cross are trademarks of Bayer.
G.PH.SM.Hem.2010-08-03.0183
For more information: www.clinicaltrials.gov
A Phase III Study of an ADC,*
Brentuximab Vedotin (SGN-35),
in Patients at High Risk of
Residual Hodgkin Lymphoma
Post-ASCT
Now
enrolling
A randomized, double-blind, placebo-controlled, multicenter phase III trial to evaluate the efficacy and
safety of the CD30-targeted antibody-drug conjugate brentuximab vedotin (SGN-35) and best supportive
care (BSC) compared with placebo and BSC in treating residual Hodgkin lymphoma following autologous
stem cell transplant (ASCT).
SC
The primary end point is progression-free survival; secondary end points include overall survival, safety
and tolerability.
Patients with
relapsed/
refractory HL
SGN-35 1.8 mg/kg IV
q 3 wk + BSC
ASCT
in previous
30-45 days
Randomization
Up to
12 months
of therapy
Placebo (IV) + BSC
Key Inclusion Criteria:
Histologically confirmed HL
ECOG performance status of 0 or 1
ASCT after relapsed/refractory HL
Adequate organ function
For full inclusion and exclusion criteria, please visit www.clinicaltrials.gov (NCT01100502), contact
Seattle Genetics at 866-333-7436 (US only) or e-mail [email protected].
*Antibody-drug conjugate.
SGN-35 is an investigational drug; its efficacy and safety have not been established. There is no guarantee
that SGN-35 will become commercially available.
www.seattlegenetics.com
Seattle Genetics and
are registered trademarks of Seattle Genetics, Inc.
Other trademarks are property of their respective owners.
MILLENNIUM and
Other trademarks are property of their respective owners.
Seattle Genetics, Inc., Bothell, WA 98021
© 2010 Seattle Genetics, Inc.
Printed in USA
All rights reserved.
Millennium Pharmaceuticals, Inc., Cambridge, MA 02139
Copyright ©2010, Millennium Pharmaceuticals, Inc.
All rights reserved.
ATH0001
8/10
NO
W
EN
RO
First-line FLT3-mutant AML clinical trial
LL
CALGB 10603
(Novartis # CPKC412A 2301)
Rationale
FLT3 mutations are common in AML and are associated
with poor prognosis*
Study
Randomized, placebo-controlled study involving > 500 patients
with FLT3 mutations
Newly diagnosed AML patients < 60 years
Addition of oral midostaurin (or placebo) to induction therapy
with daunorubicin and cytarabine and consolidation therapy
with high-dose cytarabine
Includes midostaurin/placebo continuation therapy for up to 12 months
Primary endpoint: overall survival
PKC412 (Midostaurin)
Questions regarding the conduct of the trial
should be directed to the CALGB† Study Chair:
International Participants
AMLSG
EORTC
Richard M. Stone, M.D.
Dana Farber Cancer Institute
[email protected]
German Austrian Acute Myeloid
Leukemia Study Group
European Organization for
Ostdeutsche Studiengruppe
Research and Treatment of Cancer Haematologie und Onkologie
CETLAM
GIMEMA
PETHEMA
For more information please refer to:
Groupo Cooperativo de
Tratamiento de las Leucemias
Agudas y Mielodisplasias
Gruppo Italiano Malattie
Ematologiche dell’Adulto
Programa Español para el
Tratamiento de las Hemopatias
Malignas
#SB[JMt6OJUFE,JOHEPN
Hungary
North American Cooperative
Groups
SAL
www.calgb.org
www.ctsu.org
www.clinicaltrials.gov
OSHO
Study Alliance Leukemia
*Kottaridis PD, et al. Blood. 2001;98:1752–1759. Small D, et al. Hematology Am Soc Hematol Educ Program. 2006:178–184.
†Cancer and Leukemia Group B.
Midostaurin is investigational. Efficacy and safety have not been established. There is no guarantee that midostaurin will become commercially available.
Novartis Pharma AG
CH-4002 Basel, Switzerland
© Novartis 2010
November 2010
GCT8748
T-ONC-1006221
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936
IN
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urns...
t
e
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L
TC
When P
B
O
L
n)
io
O
t
c
F
je
in
WI T H (pralatrexate
Important Safety Information
Warnings and Precautions
FOLOTYN may suppress bone marrow function, manifested
by thrombocytopenia, neutropenia, and anemia. Monitor
blood counts and omit or modify dose for hematologic
toxicities.
Mucositis may occur. If rGrade 2 mucositis is observed,
omit or modify dose.
Patients should be instructed to take folic acid and
receive vitamin B12 to potentially reduce treatment-related
hematological toxicity and mucositis.
FOLOTYN can cause fetal harm. Women should avoid
becoming pregnant while being treated with FOLOTYN and
pregnant women should be informed of the potential harm
to the fetus.
Use caution and monitor patients when administering
FOLOTYN to patients with moderate to severe renal
function impairment.
Elevated liver function test abnormalities may occur and
require monitoring. If liver function test abnormalities are
rGrade 3, omit or modify dose.
Dermatologic reactions may occur. Patients with
dermatologic reactions should be monitored closely, and
if skin reactions are severe, FOLOTYN should be withheld
or discontinued.
Adverse Reactions
The most common adverse reactions were mucositis (70%),
thrombocytopenia (41%), nausea (40%), and fatigue (36%).
The most common serious adverse events are pyrexia,
mucositis, sepsis, febrile neutropenia, dehydration, dyspnea,
and thrombocytopenia.
Use in Specific Patient Populations
Nursing mothers should be advised to discontinue nursing
or the drug, taking into consideration the importance of the
drug to the mother.
Please see accompanying brief summary
of Prescribing Information.
The indication for FOLOTYN is based on overall response rate. Clinical benefit such as improvement
in progression-free survival or overall survival has not been demonstrated.
Demonstrated
response in relapsed
or refractory PTCL1
Y
27%
by central review (95% CI, 19–36)*
Of the responders
66%
responded within Cycle 1*
—Median time to Àrst response
was 45 days (range=37–349 days)
9.4 month
median duration of response by
central review (range=1–503 days)*
—12% (95% CI, 7–20) of patients had responses
lasting 14 weeks (range=98–503 days)
Drug Interactions
Co-administration of drugs subject to renal
clearance (e.g., probenecid, NSAIDs, and trimethoprim/
sulfamethoxazole) may result in delayed renal clearance.
*Per independent central review
Reference: 1. FOLOTYN Prescribing Information.
Allos Therapeutics, Inc., 2010.
©2010 Allos Therapeutics, Inc.
8/10
Printed in USA
FOL-1106-10
Demonstrated response in
PROPEL—
the largest prospective single-arm,
open-label clinical trial in PTCL
11080 CirclePoint Road, Suite 200
Westminster, CO 80020
www.allos.com
www.FOLOTYN.com
Brief summary of Full Prescribing Information for FOLOTYN®
(pralatrexate)—Please consult Full Prescribing Information.
INDICATIONS AND USAGE
FOLOTYN is indicated for the treatment of patients with relapsed or refractory
peripheral T-cell lymphoma (PTCL). This indication is based on overall response
rate. Clinical beneﬁt such as improvement in progression-free survival or
overall survival has not been demonstrated.
WARNINGS AND PRECAUTIONS
Bone Marrow Suppression
FOLOTYN can suppress bone marrow function, manifested by thrombocytopenia,
neutropenia, and anemia. Dose modiﬁcations are based on ANC and platelet
count prior to each dose.
Mucositis
Treatment with FOLOTYN may cause mucositis. If rGrade 2 mucositis is
observed, omit dose and follow guidelines in Table 1.
Folic Acid and Vitamin B12 Supplementation
Patients should be instructed to take folic acid and receive vitamin B12 to
potentially reduce treatment-related hematological toxicity and mucositis.
Pregnancy Category D
FOLOTYN can cause fetal harm when administered to a pregnant woman.
FOLOTYN was embryotoxic and fetotoxic in rats and rabbits. 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.
Decreased Renal Function
Although FOLOTYN has not been formally tested in patients with renal
impairment, caution is advised when administering FOLOTYN to patients
with moderate to severe impairment. Monitor patients for renal function and
systemic toxicity due to increased drug exposure.
Elevated Liver Enzymes
Liver function test abnormalities have been observed after FOLOTYN
administration. Persistent liver function test abnormalities may be indicators of
liver toxicity and require dose modiﬁcation. Monitor patients for liver function.
Dermatologic Reactions
Dermatologic reactions have been reported in clinical studies and postmarketing safety reports in patients treated with FOLOTYN. Dermatologic
reactions have included skin exfoliation, ulceration, and toxic epidermal
necrolysis (TEN). These reactions, as well as tumor lysis syndrome, may
involve skin and subcutaneous sites of known lymphoma. Skin reactions
may be progressive and increase in severity with further treatment. Severe
skin reactions have been associated with fatal outcomes. Patients with
skin reactions should be monitored closely, and if skin reactions are severe,
FOLOTYN should be withheld or discontinued.
ADVERSE REACTIONS
The most common adverse reactions observed in patients with peripheral t-cell
lymphoma (PTCL) treated with FOLOTYN were mucositis, thrombocytopenia,
nausea, and fatigue.
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions,
adverse reaction rates observed in the clinical studies of a drug cannot be
directly compared to rates in the clinical studies of another drug and may not
reﬂect the rates observed in practice.
The safety of FOLOTYN was evaluated in 111 PTCL patients in a single-arm
clinical study in which patients received a starting dose of 30 mg/m2 once weekly
for 6 weeks in 7-week cycles. The median duration of treatment was 70 days
(range 1-540 days).
Most Frequent Adverse Reactions
Table 4 summarizes the most frequent adverse reactions, regardless of
causality, using the National Cancer Institute-Common Terminology Criteria for
Adverse Events (NCI CTCAE, version 3.0).
Table 4 Adverse Reactions Occurring in PTCL Patients
(Incidence r10% of patients)
N
111
78
45
44
40
38
37
36
33
31
29
28
27
23
21
17
17
17
16
%
100
70
41
40
36
34
33
32
30
28
26
25
24
21
19
15
15
15
14
N=111
Grade 3
N
%
48
43
19
17
15
14
4
4
5
5
17
15
0
0
1
1
1
1
1
1
0
0
2
2
14
13
2
2
8
7
3
3
4
4
0
0
2
2
15
14
1
1
0
0
14
13
6
5
0
0
13
13
12
12
12
12
12
11
11
11
4
0
3
3
0
4
0
3
3
0
0
0
0
4
0
0
0
0
4
0
Total
Preferred Term
Any Adverse Event
Mucositisa
Thrombocytopeniab
Nausea
Fatigue
Anemia
Constipation
Pyrexia
Edema
Cough
Epistaxis
Vomiting
Neutropenia
Diarrhea
Dyspnea
Anorexia
Hypokalemia
Rash
Pruritus
Pharyngolaryngeal
pain
Liver function test
abnormalc
Abdominal pain
Pain in extremity
Back pain
Leukopenia
Night sweats
Grade 4
N
%
34
31
4
4
21
19b
0
0
2
2
2
2
0
0
1
1
0
0
0
0
0
0
0
0
8
7
0
0
0
0
0
0
1
1
0
0
0
0
Asthenia
Tachycardia
Upper respiratory
tract infection
a
b
c
11
11
10
10
1
0
1
0
0
0
0
0
11
10
1
1
0
0
Stomatitis or mucosal inﬂammation of the gastrointestinal and genitourinary tracts
Five patients with platelets <10,000/µL
Alanine aminotransferase, aspartate aminotransferase, and transaminases increased
Serious Adverse Events
Forty-four percent of patients (n=49) experienced a serious adverse event while
on study or within 30 days after their last dose of FOLOTYN. The most common
serious adverse events (>3%), regardless of causality, were pyrexia, mucositis,
sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia.
One death from cardiopulmonary arrest in a patient with mucositis and
febrile neutropenia was reported in this trial. Deaths from mucositis, febrile
neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated on
all FOLOTYN trials at doses ranging from 30 to 325 mg/m2.
Discontinuations
Twenty-three percent of patients (n=25) discontinued treatment with FOLOTYN
due to adverse reactions. The adverse reactions reported most frequently as
the reason for discontinuation of treatment were mucositis (6%, n=7) and
thrombocytopenia (5%, n=5).
Dose Modiﬁcations
The target dose of FOLOTYN was 30 mg/m2 once weekly for 6 weeks in 7-week
cycles. The majority of patients (69%, n=77) remained at the target dose for the
duration of treatment. Overall, 85% of scheduled doses were administered.
DRUG INTERACTIONS
In vitro studies indicate that pralatrexate is not a substrate, inhibitor, or
inducer of CYP450 isoenzymes and has low potential for drug-drug interactions
at CYP450 isoenzymes. No formal clinical assessments of pharmacokinetic
drug-drug interactions between FOLOTYN and other drugs have been
conducted. The effect of co-administration of the uricosuric drug probenecid
on pralatrexate pharmacokinetics was investigated in a Phase 1 clinical
study. Co-administration of increasing doses of probenecid resulted in delayed
clearance of pralatrexate and a commensurate increase in exposure.
Due to the contribution of renal excretion (approximately 34%) to the overall
clearance of pralatrexate, concomitant administration of drugs that are subject
to substantial renal clearance (eg, NSAIDs, trimethoprim/sulfamethoxazole)
may result in delayed clearance of pralatrexate.
USE IN SPECIFIC POPULATION
Pregnancy
Pregnancy Category D.
FOLOTYN can cause fetal harm when administered to a pregnant woman.
Pralatrexate was embryotoxic and fetotoxic in rats at IV doses of 0.06 mg/kg/
day (0.36 mg/m2/day or about 1.2% of the clinical dose on a mg/m2 basis)
given on gestation days 7 through 20. Treatment with pralatrexate caused
a dose-dependent decrease in fetal viability manifested as an increase in
late, early, and total resorptions. There was also a dose-dependent increase
in post-implantation loss. In rabbits, IV doses of 0.03 mg/kg/day (0.36 mg/
m2/day) or greater given on gestation days 8 through 21 also caused abortion
and fetal lethality. This toxicity manifested as early and total resorptions,
post-implantation loss, and a decrease in the total number of live fetuses.
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.
Nursing Mothers
It is not known whether pralatrexate 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 this drug, a decision should be made
whether to discontinue nursing or to discontinue FOLOTYN, taking into account
the importance of FOLOTYN to the mother.
Pediatric Use
Pediatric patients were not included in clinical studies with FOLOTYN. The safety
and effectiveness of FOLOTYN in pediatric patients have not been established.
Geriatric Use
In the PTCL efﬁcacy study, 36% of patients (n=40) were 65 years of age and
over. No overall differences in efﬁcacy and safety were observed in patients
based on age (<65 years compared with r65 years).
No dosage adjustment is required in elderly patients with normal renal function.
Hepatic Impairment
Formal studies have not been performed with FOLOTYN in patients with hepatic
impairment. Patients with the following laboratory values were excluded from
the pralatrexate lymphoma clinical trials: total bilirubin >1.5 mg/dL; aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × upper limit
of normal (ULN); and AST or ALT >5 × ULN if documented hepatic involvement
with lymphoma.
Renal Impairment
See Warnings and Precautions.
Pregnancy/Nursing
Patients should be instructed to tell their physician if they are pregnant or plan
to become pregnant due to the risk of fetal harm. Patients should be instructed
to tell their physician if they are nursing.
Dermatologic Reactions
Physicians should discuss with patients the signs and symptoms of
dermatologic reactions. Patients should be made aware to immediately notify
their physician if any untoward skin reactions occur.
DOSAGE AND ADMINISTRATION
FOLOTYN should be administered under the supervision of a qualiﬁed physician
experienced in the use of antineoplastic agents. Appropriate management
of complications is possible only when adequate diagnostic and treatment
facilities are readily available.
Peripheral T-cell Lymphoma
The recommended dose of FOLOTYN is 30 mg/m2 administered as an
intravenous (IV) push over 3-5 minutes via the side port of a free-ﬂowing 0.9%
Sodium Chloride Injection, USP IV line once weekly for 6 weeks in 7-week cycles
until progressive disease or unacceptable toxicity.
Vitamin Supplementation
Patients should take low-dose (1.0-1.25 mg) oral folic acid on a daily basis.
Folic acid should be initiated during the 10-day period preceding the ﬁrst dose
of FOLOTYN, and dosing should continue during the full course of therapy and
for 30 days after the last dose of FOLOTYN. Patients should also receive a
vitamin B12 (1 mg) intramuscular injection no more than 10 weeks prior to the
ﬁrst dose of FOLOTYN and every 8-10 weeks thereafter. Subsequent vitamin B12
injections may be given the same day as treatment with FOLOTYN.
Monitoring and Dose Modiﬁcations
Management of severe or intolerable adverse reactions may require dose
omission, reduction, or interruption of FOLOTYN therapy.
Monitoring
Complete blood cell counts and severity of mucositis should be monitored
weekly. Serum chemistry tests, including renal and hepatic function, should be
performed prior to the start of the ﬁrst and fourth dose of a given cycle.
Dose Modiﬁcation Recommendations
Prior to administering any dose of FOLOTYN:
s-UCOSITISSHOULDBEbGrade 1.
s0LATELETCOUNTSHOULDBEr100,000/µL for ﬁrst dose and r50,000/µL for all
subsequent doses.
s!BSOLUTENEUTROPHILCOUNT!.#SHOULDBEr1,000/µL.
Doses may be omitted or reduced based on patient tolerance. Omitted doses
will not be made up at the end of the cycle; once a dose reduction occurs for
toxicity, do not re-escalate. For dose modiﬁcations and omissions, use the
guidelines in Tables 1, 2, and 3.
Table 1 FOLOTYN Dose Modiﬁcations for Mucositis
a
Action
Dose upon Recovery
to bGrade 1
Grade 2
Omit dose
Continue prior dose
Grade 2 recurrence
Omit dose
20 mg/m2
Grade 3
Omit dose
20 mg/m2
Grade 4
Stop therapy
Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI
CTCAE, Version 3.0)
Table 2 FOLOTYN Dose Modiﬁcations for Hematologic Toxicities
Blood Count on
Day of Treatment
Platelet
<50,000/µL
Duration of
Toxicity
Action
Dose upon Restart
1 week
Omit dose
Continue prior dose
2 weeks
Omit dose
20 mg/m2
3 weeks
Stop therapy
ANC 500-1,000/µL
1 week
and no fever
1 week
ANC 500-1,000/µL
with fever
2 weeks or
or
recurrence
ANC
<500/µL
3 weeks or
2nd recurrence
OVERDOSAGE
No speciﬁc information is available on the treatment of overdosage of FOLOTYN.
If an overdose occurs, general supportive measures should be instituted as
deemed necessary by the treating physician. Based on FOLOTYN’S mechanism
of action the prompt administration of leucovorin should be considered.
PATIENT COUNSELING INFORMATION
Need for Folic Acid and Vitamin B12
Patients treated with FOLOTYN must be instructed to take folic acid and vitamin
B12 as a prophylactic measure to potentially reduce possible side effects
[see Dosage and Administration].
Mucositis
Physicians should discuss with patients the signs and symptoms of mucositis.
Patients should be instructed on ways to reduce the risk of its development, and/
or ways to maintain nutrition and control discomfort from mucositis if it occurs.
Low Blood Cell Counts
Patients should be adequately informed of the risk of low blood cell counts and
instructed to immediately contact their physician should any signs of infection
develop, including fever. Patients should also be instructed to contact their
physician if bleeding or symptoms of anemia occur.
Concomitant Medications
Patients should be instructed to inform their physician if they are taking any
concomitant medications including prescription drugs (such as trimethoprim/
sulfamethoxazole) and nonprescription drugs (such as nonsteroidal antiinﬂammatory drugs) [see Drug Interactions].
Mucositis Gradea on
Day of Treatment
Omit dose
Continue prior dose
Omit dose, give
G-CSF or GM-CSF
support
Continue prior
dose with G-CSF or
GM-CSF support
Omit dose, give
G-CSF or GM-CSF
support
20 mg/m2 with
G-CSF or GM-CSF
support
Stop therapy
Table 3 FOLOTYN Dose Modiﬁcations for All Other
Treatment-related Toxicities
a
Toxicity Gradea on Day
of Treatment
Action
Dose upon Recovery to
bGrade 2
Grade 3
Omit dose
20 mg/m2
Grade 4
Stop therapy
Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI
CTCAE, Version 3.0)
Manufactured for:
Allos Therapeutics, Inc.
Westminster, CO 80020
1-888-ALLOS88 (1-888-255-6788)
FOLOTYN is a registered trademark of Allos Therapeutics, Inc.
U.S. Patent: 6,028,071 and 7,622,470
Rev.2: May 2010
© 2010 Allos Therapeutics, Inc. All rights reserved.
2012 PROGRAM
NOW ACCEPTING APPLICATIONS
Translational Research Training in Hematology (TRTH)
is a year-long training and mentoring program for
early-career scientists interested in translational research in
hematology. TRTH provides training to postdoctoral medical
and biomedical and pharmaceutical translational scientists in pathogenesis,
diagnostics and experimental treatments of hematological disorders.
About TRTH
TRTH is a joint effort of the European Hematology Association (EHA) and the American Society of Hematology
(ASH) in response to the demand for translational research in Europe and the United States. The program
hosts 20 promising young scientists for an intensive training course and two follow-up meetings over the span
of one year.
Translational Research
Laboratory-based translational research is the focus of TRTH. Training in biostatistics and biomarkers, genetics
and molecular biology, ethics, and phase I clinical design is offered, along with practical advice on
professional networking to help trainees build their careers in hematological translational research.
How to Apply
Applicant research projects must be hypothesis-driven and directly connected to some aspect of human
biology. Applicants must be members of either EHA or ASH.
• Step 1: A letter of intent (LOI), curriculum vitae (CV) and research project abstract must be submitted by
May 1, 2011. A template LOI is available on the EHA website. Those who are eligible will be
invited to proceed to step 2 and submit a full application.
• Step 2: Eligible candidates invited to submit a full application must submit a comprehensive
hematological translational research project proposal and other required documents by
September 1, 2011.
Important dates
Letter Of Intent due:
May 1, 2011
Full application due:
September 1, 2011
For more information
Contact the EHA Executive Office at
[email protected] or +31 (0)70 3020 099
TRTH is being made possible by a generous
unrestrictededucational grant from the Wallace
H. Coulter Foundation.
TRANSLATIONAL RESEARCH TRAINING IN HEMATOLOGY
Dysregulated JAK signaling—
a common link among MF, PV and ET
MPL may be
mutated and
constitutively
active
JAK2 may be
mutated and
constitutively
active
JAK2
STATs
Excess cytokines
may continuously
activate receptors
JAK1
Excess JAK
activity leads
to overactivation
of STATs
Increased JAK1
signaling
References: 1. Pesu M et al. Immunol Rev. 2008;223:132-142. 2. Levine RL et al. Nat Rev Cancer. 2007;7:673-683. 3. Verstovsek S et al. N Engl J Med. 2010;363:1117-1127. 4. Verstovsek S. Hematology Am
Soc Hematol Educ Program. 2009:636-642. 5. Holle N et al. Neth J Med. 2010;68:293-298. 6. Panteli KE et al. Br J Haematol. 2005;130:709-715. 7. Cervantes F et al. Haematologica. 2009;94:1484-1488.
8. Hsieh P-P et al. Mod Pathol. 2007;20:929-935. 9. Quintás-Cardama A et al. Blood. 2010;115:3109-3117. 10. Pikman Y et al. PLoS Med. 2006;3:1140-1151. 11. Plo I et al. Clin Lymphoma Myeloma. 2009;9(Suppl
3):S329-S339. 12. Delhommeau F et al. Int J Hematol. 2010;91:165-173.
©2010 Incyte Corporation.
All rights reserved.
10/10.
INCY-00435A.
Multiple abnormalities can lead to dysregulated
JAK signaling
Janus kinase (JAK) pathway signaling is essential for normal hematopoiesis and immune function.1 JAK pathway
dysregulation, however, leads to the development of 3 Philadelphia chromosome–negative myeloproliferative
neoplasms (MPNs): myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET).2
Excessive JAK1 and JAK2 signaling overstimulates signal transducers and activators of transcription (STATs),
which activate cell proliferation, survival of malignant cells and increased cytokine production. Manifestations
of overactive signaling in MPNs include splenomegaly and constitutional symptoms.3-8
Multiple abnormalities may cause JAK pathway dysregulation, including4:
tJAK2 mutations — leading to constitutive activation of JAK2 and increased cell proliferation
and survival of malignant cells4
–JAK2 V617F is the most common mutation and results in a constitutively active form of the JAK2 protein4
tI ncreased JAK1 signaling — associated with increased cell proliferation and constitutional symptoms9
tExcess cytokines — leading to overactivation of the JAK signaling pathway and constitutional symptoms4-6
tMPL mutations — leading to constitutive JAK2 signaling and increased megakaryocyte production10
JAK dysregulation is thought to occur in most MPN patients, independent of JAK2V617F mutational status.11
In fact, many MF and ET patients do not have a known mutation.9,11 MF patients also have elevated levels of
activated JAK1, which suggests that dysregulated JAK1 and JAK2 signaling is central to the pathogenesis of
MF.2,9,12 Regardless of the mechanism of JAK dysregulation, further research on JAK1 and JAK2 mechanisms is
providing new insight into their role in MPNs.
Visit www.MPNConnect.org/JAKs
To learn more about the dysregulated JAK pathway, visit MPNConnect.org/JAKs today and download the
JAK Signaling in MPNs video. Other benefits include free educational resources such as an MPN presentation
and brochure.
Excess myeloid and
erythroid cell proliferation
as a result of dysregulated
JAK-STAT signaling
Nucleus
DNA
Excess STAT activation leads
to transcription of genes
related to proliferation, cell
survival and differentiation
DILUENT
XYNTHA
For illustration of size only. Please see full Prescribing
Information for reconstitution instructions.
Indication for XYNTHA
Xyntha® Antihemophilic Factor (Recombinant),
Plasma/Albumin-Free is indicated for the control and
prevention of bleeding episodes in patients with
hemophilia A (congenital factor VIII deficiency or
classic hemophilia) and for surgical prophylaxis in
patients with hemophilia A.
XYNTHA does not contain von Willebrand factor and,
therefore, is not indicated in von Willebrand’s disease.
Important Safety Information for XYNTHA
• Anaphylaxis and severe hypersensitivity reactions are
possible. Should such reactions occur, treatment with
the product should be discontinued, and appropriate
treatment should be administered.
• Patients using coagulation factor VIII products
should be monitored for inhibitors, which have been
detected in patients receiving factor VIII-containing
products, including XYNTHA.
• The most common adverse reaction in study 1 (safety
and efficacy study) is headache (24% of subjects)
and in study 2 (surgery study) is fever (41% of
subjects). The most common adverse reactions
(≥5% of subjects) in clinical studies were headache,
fever, nausea, diarrhea, vomiting, and weakness.
• Patients may develop hypersensitivity to hamster
protein, which is present in trace amounts in XYNTHA.
• XYNTHA is an injectable medicine administered by
intravenous (IV) infusion.
Please see brief summary of Prescribing Information.
Available Now in 3000 IU.
Additional dosing options in 2011.
Visit PfizerHemophilia.com to learn more.
New for your hemophilia A patients
The only one
that’s all-in-one
Next-generation purification now in an innovative
reconstitution-ready device.1,2
Zero transfer step. More convenience. For the first time ever, factor VIII
and diluent come preloaded in a single device for your patients.3
References: 1. Xyntha™ Antihemophilic Factor (Recombinant),
Plasma/Albumin-Free Prescribing Information, Wyeth
Pharmaceuticals Inc. 2. Kelley B, Jankowski M, Booth J. An improved
manufacturing process for Xyntha/ReFacto AF. Haemophilia. 2009.
doi:10.1111/j.1365-2516.2009.02160.x. 3. Xyntha™ Antihemophilic
Factor (Recombinant), Plasma/Albumin-Free Prescribing
Information, Wyeth Pharmaceuticals Inc. August 2010.
Manufactured by Wyeth Pharmaceuticals Inc.
271246-01 Copyright © 2010 Pfizer Inc. All rights reserved.
Marketed by Pfizer Inc.
December 2010
Brief Summary
See package insert for full Prescribing Information. For further product information
and current package insert, please visit XYNTHA.com or call Wyeth Pharmaceuticals
toll-free at 1-800-934-5556.
INDICATIONS AND USAGE
Control and Prevention of Bleeding Episodes in Hemophilia A
XYNTHA Antihemophilic Factor (Recombinant), Plasma/Albumin-Free is indicated
for the control and prevention of bleeding episodes in patients with hemophilia A
(congenital factor VIII deficiency or classic hemophilia). XYNTHA does not contain
von Willebrand factor, and therefore is not indicated in patients with von Willebrand’s
disease.
Surgical Prophylaxis in Patients with Hemophilia A
XYNTHA Antihemophilic Factor (Recombinant), Plasma/Albumin-Free is indicated for
surgical prophylaxis in patients with hemophilia A.
Study 2 (surgery) is an open-label, single-arm study of at least 25 evaluable PTPs with
severe or moderately severe hemophilia A (factor VIII activity in plasma [FVIII:C] ≤ 2%)
who required elective major surgery and were planned to receive XYNTHA
replacement therapy for at least 6 days post-surgery. Twenty-two subjects received at
least one dose of XYNTHA, resulting in 766 infusions [see Clinical Studies in full
Prescribing Information]. In Study 2, the most frequently reported treatmentemergent adverse reaction was pyrexia (41% of subjects). Other adverse reactions
reported in ≥ 5% of subjects were: headache (9%), nausea (9%), diarrhea (5%),
vomiting (5%) and asthenia (5%). The adverse reactions reported in either study were
considered mild or moderate in severity.
Immunogenicity
In Study 1, the incidence of FVIII inhibitors to XYNTHA was the primary safety
endpoint. Two subjects with inhibitors were observed in 89 subjects (2.2%) who
completed ≥ 50 exposure days. These results were consistent with the pre-specified
endpoint that no more than 2 inhibitors may be observed in at least 81 subjects.
CONTRAINDICATIONS—None.
In a Bayesian statistical analysis, results from this study were used to update PTP
results from a prior supporting study using XYNTHA manufactured at the initial
facility, where one de novo and two recurrent inhibitors were observed in 110
subjects, and the experience with predecessor product (1 inhibitor in 113 subjects).
This Bayesian analysis indicates that the population (true) inhibitor rate for XYNTHA,
the estimate of the 95% upper limit of the true inhibitor rate, was 4.17%.
WARNINGS AND PRECAUTIONS
DRUG INTERACTIONS—None known.
DOSAGE FORMS AND STRENGTHS
XYNTHA is supplied as a white to off-white freeze-dried powder in the following
dosages: 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU.
Anaphylaxis and Severe Hypersensitivity Reactions—Allergic type
hypersensitivity reactions are possible. Patients should be informed of the early
signs or symptoms of hypersensitivity reactions [including hives (rash with itching),
generalized urticaria, tightness of the chest, wheezing, and hypotension] and
anaphylaxis. Patients should be advised to discontinue use of the product and
contact their physicians if these symptoms occur.
Neutralizing Antibodies—The occurrence of neutralizing antibodies (inhibitors) is
well known in the treatment of patients with hemophilia A. Inhibitors have been
detected in patients receiving factor VIII-containing products. Inhibitors are common
in previously untreated patients and have been observed in previously treated
patients on factor VIII products. Patients using coagulation factor VIII products,
including XYNTHA, should be monitored for the development of factor VIII inhibitors.
If expected factor VIII activity plasma levels are not attained, or if bleeding is not
controlled with an appropriate dose, an assay should be performed to determine if
a factor VIII inhibitor is present. If detected, inhibitors should be titered in Bethesda
Units (BU).
Formation of Antibodies to Hamster Protein—XYNTHA contains trace amounts of
hamster proteins. Patients treated with this product could develop hypersensitivity to
these non-human mammalian proteins.
Monitoring: Laboratory Tests—Monitor plasma factor VIII activity levels by the
one-stage clotting assay to confirm that adequate factor VIII levels have been
achieved and are maintained, when clinically indicated [see Dosage and
Administration in full Prescribing Information].
It is recommended that individual factor VIII values for recovery and, if clinically
indicated, other pharmacokinetic characteristics be used to guide dosing and
administration.
Monitor for development of factor VIII inhibitors. Perform assay to determine if factor
VIII inhibitor is present when expected factor VIII activity plasma levels are not
attained, or when bleeding is not controlled with the expected dose of XYNTHA.
Use Bethesda Units (BU) to titer inhibitors.
ADVERSE REACTIONS
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.
Study 1 is a pivotal phase 3 (safety and efficacy) study in which previously treated
patients (PTPs) with hemophilia A received XYNTHA for routine prophylaxis and
on-demand treatment, 94 subjects received at least one dose of XYNTHA, resulting
in a total of 6,775 infusions [see Clinical Studies in full Prescribing Information]. In
Study 1, the most frequently reported treatment-emergent adverse reaction was
headache (24% of subjects). Other adverse reactions reported in ≥ 5% of subjects
were: nausea (6%), diarrhea (5%), asthenia (5%) and pyrexia (5%). No subject
developed anti-CHO or anti-TN8.2 antibodies.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C - Animal reproduction studies have not been conducted with
XYNTHA Antihemophilic Factor (Recombinant), Plasma/Albumin-Free. It is also not
known whether XYNTHA can cause fetal harm when administered to a pregnant
woman or can affect reproduction capacity. XYNTHA should be given to a pregnant
woman only if clinically indicated.
Labor and Delivery—There is no information available on the effect of factor VIII
replacement therapy on labor and delivery. XYNTHA should be used only if clinically
indicated.
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
XYNTHA is administered to nursing mothers. XYNTHA should be given to nursing
mothers only if clinically indicated.
Pediatric Use—Pharmacokinetics of XYNTHA was studied in 7 previously treated
patients 12-16 years of age. Pharmacokinetic parameters in these patients were
similar to those obtained for adults after a dose of 50 IU/kg. For these 7 patients, the
mean (± SD) Cmax and AUC∞ were 1.09 ± 0.21 IU/mL and 11.5 ± 5.2 IU·h/mL,
respectively. The mean clearance and plasma half-life values were 5.23 ± 2.36 mL/h/
kg and 8.03 ± 2.44 hours (range 3.52 – 10.6 hours), respectively. The mean K-value
and in vivo recoveries were 2.18 ± 0.41 IU/dL per IU/kg and 112 ± 23%, respectively.
Geriatric Use—Clinical studies of XYNTHA did not include subjects aged 65 and
over. In general, dose selection for an elderly patient should be individualized.
STORAGE AND HANDLING
Product as Packaged for Sale - Store XYNTHA under refrigeration at a temperature of
2° to 8°C (36° to 46°F) for up to 36 months from the date of manufacture until the
expiration date stated on the label. XYNTHA may also be stored at room temperature
not to exceed 25°C (77°F) for up to 3 months. The starting date at room temperature
storage should be clearly recorded in the space provided on the outer carton. At the
end of the 3-month period, the product must not be put back into the refrigerator, but
must be used immediately or discarded. Do not use XYNTHA after the expiration
date stated on the label or after 3 months when stored at room temperature,
whichever is earlier. Do not freeze, to prevent damage to the XYNTHA prefilled
syringe. During storage, avoid prolonged exposure of XYNTHA to light.
Product After Reconstitution - Administer XYNTHA within 3 hours after reconstitution
or after removal of the grey rubber tip cap from the XYNTHA prefilled syringe. The
reconstituted solution may be stored at room temperature prior to administration.
This brief summary is based on the Xyntha® [Antihemophilic Factor (Recombinant),
Plasma/Albumin-Free] Prescribing Information W10528C004, revised 04/08, and
W10547C002, revised 08/10.
Manufactured by Wyeth Pharmaceuticals Inc.
270327-01 Copyright © 2010 Pfizer Inc.
Marketed by Pfizer Inc.
All rights reserved.
September 2010
SAVE THE DATE
2011 ASH State-of-the-Art Symposium
3%04%-"%2s#()#!'/),s0!,-%2(/53%(),4/.
2011 ASPIRE Hemophilia Research Awards
Pfizer is proud to announce the Advancing Science through Pfizer – Investigator Research Exchange (ASPIRE)
2011 Investigator Awards in Hemophilia Research, a competitive, peer-reviewed grants program sponsored by
Pfizer for investigators in the United States.
Mission
• To support basic science, translational and clinical research through a competitive grants program that advances medical
knowledge in the pathogenesis and treatment of hemophilia.
• To support academic research as well as the career development of promising young and established scientists.
Area of Research Focus
Pfizer will support competitive grant programs which address one of the following areas in Hemophilia A and/or Hemophilia B.
•
•
•
•
•
•
Epidemiology / burden of disease / Outcomes Research
Patient adherence to prescribed regimen
Routine prophylaxis and preventative treatment
Surgical prophylaxis, dosing
On Demand dosing
Treatment of inhibitors: Immune Tolerance Therapy,
inhibitor bypass therapy
•
•
•
•
•
•
Switching experience
Management of adolescent Hemophilia patients & quality of life
Management of the aging hemophilia population
Basic science: Point of differentiation study
Clinical monitoring of hemophilia treatment
Recovery experience (hemophilia B patients)
Application & Selection Process
Application is open to US investigators. Selection of research proposals will be performed by an independent, external expert
panel comprised of nationally known academic clinicians. Project duration should be 1-3 years and should be approximately
$100,000/year, inclusive of overhead costs (capped at 28%).
For more information please visit www.aspireresearch.org
How do you get
double the exposure
for the same price?
Your classified advertisement in Blood gives you more exposure than you
think. When you place a print advertisement, you will also receive a free
30-day* posting on the American Society of Hematology’s online Job
Bank. This employment resource is located at www.hematology.org and
is free for all job seekers. For more information on submitting a classified
ad in Blood, contact Valerie Marvin at [email protected] or at
201-767-4170.
*Your 30-day online posting will start when your print advertisement first appears in Blood.
"NFSJDBO4PDJFUZ of )FNBUPMPHZ
Scholar Awards
ASH Announces the 2011 Application Cycle
ASH Scholar Awards are designed to support hematologists who have dedicated their
careers to research by providing ﬁnancial support during the critical period between
completion of training and achievement of independent investigator
status. The Scholar Awards support both basic and clinical/
translational research, and ASH encourages fellows and
junior faculty to apply.
Interested applicants must submit a letter of intent by
April 29, 2011, in order to be eligible to apply in June.
Support and Beneﬁts:
UÊÊf£ää]äääÊvÀÊviÜÊÃV>ÀÃÊ>`Êf£xä]äääÊvÀÊ
junior faculty scholars over a two- to three-year
period
UÊ
«iÌ>ÀÞÊ-ÊiLiÀÃ«
UÊÊÊÃÕLÃVÀ«ÌÊÌÊBlood, the Journal of the
American Society of Hematology
UÊÊ
«iÌ>ÀÞÊ-Ê>Õ>ÊiiÌ}ÊÀi}ÃÌÀ>ÌÊ
and covered travel, lodging, and meal expenses
Eligibility Criteria:
At the time of application, applicants in the
Junior Faculty* category must:
UÊÊiÊÜÌÊÌiÊwÀÃÌÊÌÀiiÊÞi>ÀÃÊvÊÌiÀÊÌ>Ê
faculty appointment
UÊ7ÀÊÊ>Ê1°-°ÊÀÊ
>>`>ÊÃÌÌÕÌÊÊ
*Instructors, lecturers, and assistant professors are only
eligible to apply in the junior faculty category.
At the time of application, applicants in the
Fellow category must:
UÊÊ>ÛiÊÀiÊÌ>ÊÌÜ]ÊLÕÌÊiÃÃÊÌ>ÊwÛi]ÊÞi>ÀÃ
of postdoctoral research training
UÊÊ>ÛiÊV«iÌi`ÊÌiÀÊ
ÊVV>ÊÞi>ÀÊ«ÕÃÊÌÜÊvÕ]
but no more than ﬁve, years of postdoctoral research
UÊ7ÀÊÊ>Ê1°-°ÊÀÊ
>>`>ÊÃÌÌÕÌ
Visit www.hematology.org/awards for detailed timeline,
eligibility, and application requirements.
Now enrolling
Investigating INCB018424, an oral JAK1
and JAK2 inhibitor, in polycythemia vera
RESPONSE
Randomized Study of Efficacy and Safety in POlycythemia Vera
with JAK INhibitor INCB018424 VerSus BEst Available Care
Patients with PV
(N=300)
RANDOMIZE 1:1
RESPONSE is a global, randomized, open-label, multicenter, phase III study of INC424
in polycythemia vera (PV) subjects who are resistant to or intolerant of hydroxyurea
Treatment duration=80 weeks
*Physician’s choice: HU, IFN, pipobroman,
anagrelide, IMiDs, or observation.
†
Patients randomized to Best Available Therapy
may be eligible to cross over to INC424 at
Week 32.
INC424 10 mg bid
Best Available Therapy*†
Primary Endpoint
Composite endpoint of spleen reduction and phlebotomy independence
Secondary Endpoints
Proportion of patients who maintain the primary response endpoint for ≥48 weeks
Proportion of patients who achieve complete hematologic remission at 32 weeks
Eligibility Criteria
Age ≥18 years
Resistant to or intolerant of HU
Phlebotomy requirement due to inadequate hematocrit control at least once every 3 months
Palpable splenomegaly ≥5 cm below the costal margin
Elevated white blood cell and/or platelet counts
For more information or to enroll a patient outside the United States
in RESPONSE, please contact your local Novartis Medical Science
Liaison or visit www.clinicaltrials.gov.
RESPONSE is sponsored by Novartis Oncology and Incyte Corporation.
Abbreviations: HU, hydroxyurea; IFN, interferon; IMiD, immunomodulator.
This is an investigational study; efficacy and safety have not been established for this use. There is no guarantee that INC424
will become commercially available for this indication.
RESPONSE
Randomized Study of Efficacy and Safety in POlycythemia Vera
with JAK INhibitor INCB018424 VerSus BEst Available Care
Novartis Pharma AG
CH-4002 Basel, Switzerlan
©Novartis 2010
11/10
GCT8697
ash -sap
®
American Society of Hematology Self-Assessment Program
Fourth Edition
Did You Know You Can Purchase
ASH-SAP Fourth Edition at
This Year’s Annual Meeting?
Hematologists and others working in
hematology-related fields need to stay
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The American Society of Hematology Self-Assessment
Program (ASH-SAP) is the only complete,
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that fulfills this need, while also providing board
and recertification preparation, as well as AMA PRA
Category 1 Credits™.
21 PM
7/26/10 10:20:
The ASH-SAP website contains the full contents of the
book, presented in a searchable format with interactive
multiple-choice questions. Access to the electronic
version is included with the purchase price of the print
version.
Price Details
Print Copy with
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