Year in Review

volume 11, issue 4 - winter 2012
oncologistics | v o l u m e 1 1 , i s s u e 4 - w i n t e r 2 0 1 2
Year in Review
Millennium’s Mission in Oncology
Drug Update: Levo-leucovorin
New Payment Models in Healthcare Delivery

table of contents fall 2012
oncologistics volume 11, issue 4 - winter 2012
02
14
34
42
Industry Insight:
Millennium’s Mission in Oncology
By: Melissa Bradbury
Drug Update:
Levo-leucovorin in Colon Cancer
By: Sam E. Mikhail, M.D. and
John Marshall, M.D.
Reimbursement Watch:
New Payment Models in Healthcare Delivery
By: Sara Fernandez, PhD
The Physician-Payer Relationship: Using
Data to Drive the Future Of Oncology Care
By: Barry Fortner, PhD
editorial & design staff:
> Chris Vorce
Director, Marketing & Communications, ION Solutions
> Melissa Bradbury
Manager, Marketing & Communications, ION Solutions
> Amy Migliore
Graphic Designer, Marketing & Communications,
ION Solutions
article and advertising submissions:
Article submissions and suggestions, as well as
advertising inquiries, may be sent to:
Chris Vorce
Managing Editor, Oncologistics
c/o ION Solutions
3101 Gaylord Parkway
Frisco, TX 75034
or by e-mail: chris.vorce@iononline.com
Information presented in Oncologistics is not intended as a substitute
for the personalized advice given by a healthcare provider. The
opinions expressed on the pages of Oncologistics magazine are
those of the authors and do not necessarily reflect the views of
ION Solutions or AmerisourceBergen Specialty Group. Although
Oncologistics strives to present only current and accurate information,
readers should not consider it as professional advice or endorsement
of any position. Although great care has been taken in compiling and
checking the information given in this publication to ensure accuracy,
the authors, ION Solutions, and its employees or agents shall not
be responsible or in any way liable for the continued currency of
the information or for any errors, omissions, or inaccuracies in this
magazine, whether arising from negligence or otherwise or for any
consequence arising therefrom. The staff of Oncologistics provides
columns and other editorial support. In no way are they responsible
for the specific views presented in Oncologistics. Oncologistics
magazine is published by ION Solutions, an AmerisourceBergen
Specialty Group company.
All archived issues of Oncologistics are available online
at www.iononline.com.

industry insight
oncologistics industry insight
Millennium’s Mission
IN ONCOLOGy
By: Melissa Bradbury
Millennium Pharmaceuticals made headlines in 2003 with the launch of VELCADE ® for the treatment
of relapsed and refractory multiple myeloma (MM). As the first FDA-approved proteasome inhibitor,
Velcade represented the first treatment to be approved for MM patients in over a decade.
Acquired in 2008 by the Takeda Pharmaceutical Company, and positioned as Millennium: The
Takeda Oncology Company, the organization was equipped with the resources, leadership, and
direction needed to deliver extraordinary medicines to patients with cancer, worldwide. ION Solutions
recently had the opportunity to speak to Dr. Karen Ferrante, Chief Medical Officer, about Millennium’s
commitment to oncology, and how the company plans to support this critical market.
What differentiates Millennium in the
oncology marketplace What are your
primary objectives in this setting
Millennium’s singular focus in oncology and our unique
launches of TAK700 (orteronel) for treating prostate
cancer, MLN9708 (ixazomib citrate) for multiple
myeloma and MLN8237 (alisertib) for lymphoma.
business model as Takeda’s global center of excellence
for oncology R&D distinguishes the company within the
cancer marketplace. This distinctive positioning allows
us to focus on our ultimate aspiration: to cure cancer.
Can you talk about any patient
assistance you offer
The VELCADE Reimbursement Assistance Program
(VRAP) provides one-to-one case manager support
for patients, healthcare providers, and caregivers. The
oncologistics volume 11, issue 4 - winter 2012 2
What are Millennium’s long term goals
for its oncology business
It’s a very exciting time for Millennium and in the
next five years the company will transform from an
organization with only one marketed product, to one
that has commercialized five products that have the
potential to impact and improve the lives of cancer
patients on a global basis. Long-term, we will continue
to advance existing pipeline programs and bring
additional pre-clinical compounds into the clinic. The
company also looks forward to potential approvals/
program addresses reimbursement issues related to
the use of VELCADE ® for both patients and physicians.
VRAP offers assistance navigating the complex
reimbursement landscape and provides services
such as benefits investigation and patient referrals
to transportation and financial resources which can
facilitate timely access to treatment. Millennium also
offers the Patient Assistance Program through VRAP.
This program provides VELCADE for free to patients
who meet the eligibility criteria.
MILLENNIUM’s overall mission is, and wILL remain, to deliver
EXTRAORDINARy medicines to patients wITH cancer wORLDwIDE
THROUGH our science, innovation, and passion.
Dr. KAREN ferrante,
CHIEF MEDICAL officer
oncologistics 3

industry insight
What you’re looking for is
oncologistics volume 11, issue 4 - winter 2012 4
Can you tell us about your pipeline
We are quite enthusiastic about programs that build on
our recent addition of ADCETRIS, to our pipeline which
may potentially broaden our therapeutic approach to
include other ADCs (antibody drug conjugates) and
address a broader range of unmet medical needs in
both hematologic malignancies and solid tumors. In
2009, Millennium and Seattle Genetics entered into a
collaboration agreement to jointly develop ADCETRIS.
Under the terms of the collaboration agreement, Seattle
Genetics has U.S. and Canadian commercialization
rights and the Takeda Group has rights to commercialize
ADCETRIS in the rest of the world.
Additionally, we are placing a priority on targets/
molecules that are unique combination partners for
our internal pipeline; those that further our novel-novel
combination development strategy and allow us to apply
our translational medicine capabilities to advance our
patient-selection approaches in the clinic. We are also
interested in identifying innovative targets/molecules that
Millennium/Takeda can effectively develop by capitalizing
on our expertise in protein homeostasis, cell signaling
or growth/metabolism. We are particularly excited
about unique projects that have defined an important
new class of druggable targets in the protein
homeostasis field.
We have encouraging Phase II steroid-free dosing data
on TAK700 in non-metastatic prostate cancer that was
presented at ASCO this past June. Currently, there are
two ongoing, global Phase III multi-center trials with
TAK700 in metastatic castrate resistant prostate cancer.
MLN8237 is being studied in a global Phase III trial in
patients with relapsed peripheral T-cell Lymphoma,
as well as in Phase II trials in other hematologic
malignancies and solid tumors. MLN9708 is the next
product that will reinforce Millennium’s leadership in
protein homeostasis and builds on the success of
VELCADE. MLN9708 is the first oral proteasome inhibitor
to enter clinical trials and we have recently initiated
a Phase III global trial in relapsed/refractory multiple
myeloma, and another Phase III trial in amyloidosis.
How do you envision ION Solutions and
Millennium working together to improve
care What would you like ION Solutions’
members to know about Millennium’s
commitment to the oncology community
As a resource that interacts and influences a large
percentage of community-based oncologists throughout
the US, ION Solutions has the potential to help educate
and share Millennium’s mission and vision within
this important audience and, ultimately with their
patients. As Millennium continues to develop potentially
transformative new cancer treatments, we envision ION
Solutions being an important conduit of information
on our new products to oncologists. It is invaluable to
have oncologists become fully educated on the clinical
potential and medical benefits of our new cancer
medicines as they determine the most appropriate
treatment options for their patients.
Millennium’s overall mission is, and will remain, to
deliver extraordinary medicines to patients with cancer
worldwide through our science, innovation, and passion.
Our singular focus in oncology allows oncologists and
cancer patients to more clearly understand the potential
benefits our medicines may provide as well as the
commitment the company offers.
Ten years from now, what do you
hope to be able to say about
Millennium’s contribution to the
cancer care portfolio
In ten years we hope to have made good progress
against our bold vision to cure cancer. Each day our
team of passionate and dedicated scientists remain
focused on discovering and developing novel cancer
medicines directed at serving the needs of cancer
patients worldwide.
Melissa Bradbury is manager, marketing and
communication, ION Solutions.
right in front of you.
FUSILEV is a folate analog FDA-approved for:
Use in combination chemotherapy with 5-fluorouracil
in the palliative treatment of patients with advanced metastatic colorectal cancer.
Important Safety Information:
There is potential for dosing errors when interchanging leucovorin and levoleucovorin. FUSILEV is dosed at one-half the usual dose of the racemic form.
Due to Ca ++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute. Levoleucovorin enhances the
toxicity of fluorouracil. In addition, levoleucovorin may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the
frequency of seizures in susceptible patients. Allergic reactions were reported in patients receiving levoleucovorin. The most common adverse reactions
(>50%) in patients with advanced CRC were diarrhea, nausea, and stomatitis.
Please see Brief Summary on the adjacent pages. For full Prescribing Information visit FUSILEV.com.
Readily Available. Consistent Supply.
© 2012 Spectrum Pharmaceuticals, Inc. All Rights Reserved. May not be reproduced, altered, or distributed without express permission.
SPECTRUM PHARMACEUTICALS, INC. ® and FUSILEV ® are registered trademarks of Spectrum Pharmaceuticals, Inc. and its subsidiaries.
The Spectrum Pharmaceuticals logo and FUSILEV logo are trademarks owned by Spectrum Pharmaceuticals, Inc. and its subsidiaries.
0111-046600
FUSILEV has a
unique J-code for
reimbursement:
J0641 per 0.5 mg units
of FUSILEV
FUSILEV.com
Order FUSILEV today:
Call your wholesaler or specialty distributor
or 1-877-FUSILEV (1-877-387-4538)

FUSILEV ® (levoleucovorin) for Injection
FUSILEV ® (levoleucovorin) Injection
Rx only
BRIEF SUMMARY: Please see package insert for full
prescribing information.
1 INDICATIONS AND USAGE
• FUSILEV ® is a folate analog.
• FUSILEV rescue is indicated after high-dose methotrexate
therapy in osteosarcoma.
• FUSILEV is also indicated to diminish the toxicity and
counteract the effects of impaired methotrexate elimination
and of inadvertent overdosage of folic acid antagonists.
• FUSILEV is indicated for use in combination chemotherapy
with 5-fluorouracil in the palliative treatment of patients with
advanced metastatic colorectal cancer.
1.1 Limitations of Use
• FUSILEV is not approved for pernicious anemia and megaloblastic
anemias secondary to the lack of vitamin B 12. Improper
use may cause a hematologic remission while neurologic
manifestations continue to progress.
2 DOSAGE AND ADMINISTRATION
2.1 Administration Guidelines
FUSILEV is dosed at one-half the usual dose of the racemic form.
FUSILEV is indicated for intravenous administration only. Do not
administer intrathecally.
2.2 Co-administration of FUSILEV with other agents
Due to the risk of precipitation, do not co-administer FUSILEV with
other agents in the same admixture.
4 CONTRAINDICATIONS
FUSILEV is contraindicated for patients who have had previous
allergic reactions attributed to folic acid or folinic acid.
5 WARNINGS AND PRECAUTIONS
5.1 Rate of Administration
Because of the Ca ++ content of the FUSILEV solution, no more than
16 mL (160 mg of FUSILEV) should be injected intravenously per
minute.
5.2 Potential for Enhanced Toxicity with 5-Fluorouracil
FUSILEV enhances the toxicity of 5-fluorouracil. Deaths from severe
enterocolitis, diarrhea, and dehydration have been reported in
elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil.
When these drugs are administered concurrently in the palliative
treatment of advanced colorectal cancer, the dosage of 5-FU must
be lower than usually administered. Although the toxicities observed
in patients treated with the combination of FUSILEV and 5-FU are
qualitatively similar to those observed with 5-FU alone, gastrointestinal
toxicities (particularly stomatitis and diarrhea) are observed
more commonly and may be of greater severity and of prolonged
duration in patients treated with the combination.
In the first Mayo/NCCTG controlled trial, toxicity, primarily gastrointestinal,
resulted in 7% of patients requiring hospitalization when
treated with 5-FU alone or 5-FU in combination with 200 mg/m 2 of
d,l-leucovorin and 20% when treated with 5-FU in combination with
20 mg/m 2 of d,l-leucovorin. In the second Mayo/NCCTG trial,
hospitalizations related to treatment toxicity also appeared to occur
more often in patients treated with the low dose d,l-leucovorin/5-FU
combination than in patients treated with the high dose combination
– 11% versus 3%. Therapy with FUSILEV and 5-FU must not be
initiated or continued in patients who have symptoms of gastrointestinal
toxicity of any severity, until those symptoms have
completely resolved. Patients with diarrhea must be monitored with
particular care until the diarrhea has resolved, as rapid clinical
deterioration leading to death can occur. In an additional study
utilizing higher weekly doses of 5-FU and d,l-leucovorin, elderly
and/or debilitated patients were found to be at greater risk for severe
gastrointestinal toxicity.
Seizures and/or syncope have been reported rarely in cancer
patients receiving d,l-leucovorin, usually in association with
fluoropyrimidine administration, and most commonly in those with
CNS metastases or other predisposing factors. However, a causal
relationship has not been established.
5.3 Potential for interaction with trimethoprimsulfamethoxazole
The concomitant use of d,l-leucovorin with trimethoprimsulfamethoxazole
for the acute treatment of Pneumocystis carinii
pneumonia in patients with HIV infection was associated with
increased rates of treatment failure and morbidity in a placebocontrolled
study.
6 ADVERSE REACTIONS
6.1 Clinical Studies in High-Dose Methotrexate Therapy
Since 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 following table
presents the frequency of adverse reactions which occurred during
the administration of 58 courses of high dose methotrexate
12 grams/m 2 followed by FUSILEV rescue for osteosarcoma in
16 patients age 6-21. Most patients received FUSILEV 7.5 mg
every 6 hours for 60 hours or longer beginning 24 hours after
completion of methotrexate.
Table 1 Adverse Reactions with High-Dose Methotrexate Therapy
Body System/Adverse Reactions
Number (%) of Patients with
Number (%) of Courses with
Adverse Reactions
Adverse Reactions
(N =16) (N =58)
All Grade 3+ All Grade 3+
Gastrointestinal
Stomatitis
Vomiting
Nausea
Diarrhea
Dyspepsia
Typhlitis
Respiratory
Dyspnea
Skin and Appendages
Dermatitis
Other
Confusion
Neuropathy
Renal function abnormal
Taste perversion
6 (37.5)
6 (37.5)
3 (18.8)
1 (6.3)
1 (6.3)
1 (6.3)
1 (6.3)
1 (6.3)
1 (6.3)
1 (6.3)
1 (6.3)
1 (6.3)
1 (6.3)
0
0
0
0
1 (6.3)
0
0
0
0
0
0
10 (17.2)
14 (24.1)
3 (5.2)
1 (1.7)
1 (1.7)
1 (1.7)
1 (1.7)
1 (1.7)
1 (1.7)
1 (1.7)
3 (5.2)
1 (1.7)
1 (1.7)
0
0
0
0
1 (1.7)
0
0
0
0
0
0
Total number of patients
Total number of courses
9 (56.3)
25 (43.1)
2 (12.5)
2 (3.4)
The incidence of adverse reactions may be underestimated because
not all patients were fully evaluable for toxicity for all cycles in the
clinical trials. Leukopenia and thrombocytopenia were observed, but
could not be attributed to high dose methotrexate with FUSILEV
rescue because patients were receiving other myelosuppressive
chemotherapy.
6.2 Clinical Studies in Combination with 5-FU in Colorectal
Cancer
A randomized controlled trial conducted by the North Central Cancer
Treatment Group (NCCTG) in patients with advanced colorectal
6.3 Postmarketing Experience
Since adverse reactions from spontaneous reports are provided
voluntarily from a population of uncertain size, it is not always
possible to estimate reliably their frequency or establish a causal
relationship to drug exposure. Spontaneously reported adverse
reactions collected by the WHO Collaborating Center for International
Drug Monitoring in Uppsala Sweden have yielded seven
cases where FUSILEV was administered with a regimen of
methotrexate. The events were dyspnea, pruritus, rash, temperature
change and rigors. For 217 adverse reactions (108 reports) where
FUSILEV was a suspected or interacting medication, there were
40 occurrences of “possible allergic reaction”.
In an analysis where calcium levoleucovorin was reported as the
primary suspect drug and fluorouracil (FU) was reported as a
concomitant medication, possible allergic reactions were reported
among 47 cases (67 events).
7 DRUG INTERACTIONS
Folic acid in large amounts may counteract the antiepileptic effect of
phenobarbital, phenytoin and primidone, and increase the frequency
of seizures in susceptible children. It is not known whether folinic
acid has the same effects. However, both folic and folinic acids
share some common metabolic pathways. Caution should be taken
when taking folinic acid in combination with anticonvulsant drugs.
Preliminary human studies have shown that small quantities of
systemically administered leucovorin enter the CSF, primarily as its
major metabolite, 5-methyltetrahydrofolate (5-MTHFA). In humans,
the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower
than the usual methotrexate concentrations following intrathecal
administration.
FUSILEV increases the toxicity of 5-fluorouracil [see Warnings and
Precautions (5.2)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C. It is not known whether FUSILEV can
cause fetal harm when administered to a pregnant woman or if it can
affect reproduction capacity. Animal reproduction studies have not
been conducted with FUSILEV. FUSILEV should be given to a
pregnant woman only if clearly needed.
cancer failed to show superiority of a regimen of 5-FU + levoleucovorin
to 5-FU + d,l-leucovorin in overall survival. Patients were
randomized to 5-FU 370 mg/m 2 intravenously and levoleucovorin
100 mg/m 2 intravenously, both daily for 5 days, or with 5-FU
370 mg/m 2 intravenously and d,l-leucovorin 200 mg/m 2
intravenously, both daily for 5 days. Treatment was repeated week 4
and week 8, and then every 5 weeks until disease progression or
unacceptable toxicity. The following table presents the most frequent
adverse reactions which occurred in patients in the 2 treatment
arms.
Table 2 Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm
Adverse Reactions
Levoleucovorin/5FU
d,l-Leucovorin/5FU
n=318
n=307
Adverse Event N (%)
Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4
Gastrointestinal Disorders
Stomatitis
Diarrhea
Nausea
Vomiting
Abdominal Pain 1
General Disorders
Asthenia/Fatigue/Malaise
Metabolism and Nutrition
Anorexia/Decreased Appetite
Skin Disorders
Dermatitis
Alopecia
229 (72%)
222 (70%)
197 (62%)
128 (40%)
45 (14%)
91 (29%)
76 (24%)
91 (29%)
83 (26%)
37 (12%)
61 (19%)
25 (8%)
17 (5%)
10 (3%)
15 (5%)
13 (4%)
3 (1%)
1 (0.3%)
221 (72%)
201 (65%)
186 (61%)
114 (37%)
57 (19%)
99 (32%)
77 (25%)
86 (28%)
87 (28%)
44 (14%)
51 (17%)
26 (8%)
18 (6%)
10 (3%)
34 (11%)
5 (2%)
4 (1%)
3 (1%)
1
Includes abdominal pain, upper abdominal pain, lower pain, lower abdominal pain, and abdominal tenderness
8.3 Nursing Mothers
It is not known whether this drug 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
FUSILEV, 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
Please see Clinical Studies (14) in the Package Insert
8.5 Geriatric Use
Clinical studies of FUSILEV in the treatment of osteosarcoma did
not include subjects aged 65 and over to determine whether they
respond differently from younger subjects.
In the NCCTG clinical trial of FUSILEV in combination with 5-FU in
advanced colorectal cancer, adverse reactions were consistent with
5-FU related toxicity and were similar for patients age 65 and older
and for patients younger than age 65.
10 OVERDOSAGE
No data are available for overdosage with FUSILEV.
Manufactured for Spectrum Pharmaceuticals, Inc. Irvine, CA 92618
FUSILEV ® is a registered trademark of Spectrum Pharmaceuticals, Inc.
© 2011 Spectrum Pharmaceuticals, Inc. All rights reserved.
05 August 2011
0102-005901

INDICATIONS
THE FIRST AND ONLY
• Treatment of peripheral T-cell lymphoma (PTCL) in patients
DRUG APPROVED IN BOTH
who have received at least one prior therapy
PTCL AND CTCL
• Treatment of cutaneous T-cell lymphoma (CTCL) in patients
who have received at least one prior systemic therapy
These indications are based on response rate. Clinical benefit
such as improvement in overall survival has not been demonstrated.
RECHARGE THE POSSIBILITIES
www.istodax.com
Important Safety Information
WARNINGS AND PRECAUTIONS:
• Treatment with ISTODAX has been associated with
thrombocytopenia, leukopenia (neutropenia and
lymphopenia), and anemia; therefore, monitor these
hematological parameters during treatment with
ISTODAX and modify the dose as necessary
• Serious and sometimes fatal infections have been
reported during treatment and within 30 days after
treatment with ISTODAX and the risk of life threatening
infections may be higher in patients with a history of
extensive or intensive chemotherapy
• Electrocardiographic (ECG) changes have been observed
with ISTODAX
• In patients with congenital long QT syndrome, a history
of significant cardiovascular disease, and patients taking
anti-arrhythmic medicines or medicinal products that lead
to significant QT prolongation, appropriate cardiovascular
monitoring precautions should be considered, such
as monitoring electrolytes and ECGs at baseline and
periodically during treatment
• Ensure that potassium and magnesium are within the
normal range before administration of ISTODAX
• Tumor lysis syndrome has been reported during treatment
with ISTODAX. Patients with advanced stage disease
and/or high tumor burden should be closely monitored
and appropriate precautions taken, and treatment should
be instituted as appropriate
• ISTODAX may cause fetal harm when administered to
a pregnant woman. Advise women to avoid pregnancy
while receiving ISTODAX. 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 (Pregnancy Category D)
ADVERSE REACTIONS:
Peripheral T-Cell Lymphoma
The most common Grade 3/4 adverse reactions
(>5%) regardless of causality in Study 3 (n=131) were
thrombocytopenia (24%), neutropenia (20%), anemia
(11%), asthenia/fatigue (8%), and leukopenia (6%), and in
Study 4 (n=47) were neutropenia (47%), leukopenia (45%),
thrombocytopenia (36%), anemia (28%), asthenia/fatigue
(19%), pyrexia (17%), vomiting (9%), and nausea (6%).
Infections were the most common type of serious adverse
event reported in Study 3 (n=131) and Study 4 (n=47). 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.
The most common adverse reactions regardless of
causality in Study 3 (n=131) were nausea (59%),
asthenia/fatigue (55%), thrombocytopenia (41%), vomiting
(39%), diarrhea (36%), and pyrexia (35%), and in Study
4 (n=47) were asthenia/fatigue (77%), nausea (75%),
thrombocytopenia (72%), neutropenia (66%), anemia
(62%), leukopenia (55%), pyrexia (47%), anorexia (45%),
vomiting (40%), constipation (40%), and diarrhea (36%).
Cutaneous T-Cell Lymphoma
The most common Grade 3/4 adverse reactions (>5%)
regardless of causality in Study 1 (n=102) were infections
(11%) and asthenia/fatigue (8%), and in Study 2 (n=83)
were lymphopenia (37%), infections (33%), neutropenia
(27%), leukopenia (22%), anemia (16%), asthenia/fatigue
(14%), thrombocytopenia (14%), hypophosphatemia (10%),
vomiting (10%), dermatitis/exfoliative dermatitis (8%),
hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia
(6%), nausea (6%), and pruritus (6%).
Infections were the most common type of serious adverse
event reported in both Study 1 (n=102) and Study 2 (n=83)
with 8 patients (8%) in Study 1 and 26 patients (31%) in
Study 2 experiencing a serious infection.
The most common adverse reactions regardless of causality
in Study 1 (n=102) were nausea (56%), asthenia/fatigue
(53%), infections (46%), vomiting (34%), and anorexia (23%)
and in Study 2 (n=83) were nausea (86%), asthenia/fatigue
(77%), anemia (72%), thrombocytopenia (65%), ECG ST-T
wave changes (63%), neutropenia (57%), lymphopenia
(57%), infections (54%), anorexia (54%), vomiting
(52%), hypocalcemia (52%), hyperglycemia (51%),
hypoalbuminemia (48%), leukopenia (46%), dysgeusia
(40%), and constipation (39%).
DRUG INTERACTIONS:
• ISTODAX is metabolized by CYP3A4. Avoid concomitant
use with strong CYP3A4 inhibitors and potent CYP3A4
inducers if possible
• Caution should also be exercised with concomitant use of
moderate CYP3A4 inhibitors and P-glycoprotein (P-gp,
ABCB1) inhibitors
• Physicians should carefully monitor prothrombin time
(PT) and International Normalized Ratio (INR) in patients
concurrently administered ISTODAX and warfarin sodium
derivatives
USE IN SPECIFIC POPULATIONS:
• 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
• Patients with moderate and severe hepatic impairment
and/or patients with end-stage renal disease should be
treated with caution
Please see full Prescribing Information,
including WARNINGS AND PRECAUTIONS
and ADVERSE REACTIONS.
Please see Important Safety Information on adjacent page.
Please see Brief Summary of full Prescribing Information on following pages.
ISTODAX ® is a registered trademark of Celgene Corporation.
©2011 Celgene Corporation 10/11 IST11038

B:7”
B:7”
T:7”
T:7”
S:7”
S:7”
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:
• Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have
received at least one prior systemic therapy.
• Treatment of peripheral T-cell lymphoma (PTCL) in patients who have
received at least one prior therapy.
These indications are based on response rate. Clinical benefit such as
improvement in overall survival has not been demonstrated.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
The recommended dose of romidepsin is 14 mg/m 2 administered
intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle.
Cycles should be repeated every 28 days provided that the patient
continues to benefit from and tolerates the drug.
2.2 Dose Modification
Nonhematologic toxicities except alopecia
• Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed
until toxicity returns to ≤Grade 1 or baseline, then therapy may be
restarted at 14 mg/m 2 . If Grade 3 toxicity recurs, treatment with
romidepsin should be delayed until toxicity returns to ≤Grade 1 or
baseline and the dose should be permanently reduced to 10 mg/m 2 .
• Grade 4 toxicity: Treatment with romidepsin should be delayed until
toxicity returns to ≤Grade 1 or baseline, then the dose should be
permanently reduced to 10 mg/m 2 .
• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after
dose reduction.
Hematologic toxicities
• Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with
romidepsin should be delayed until the specific cytopenia returns to
ANC ≥1.5×10 9 /L and/or platelet count ≥75×10 9 /L or baseline, then
therapy may be restarted at 14 mg/m 2 .
• Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that
requires platelet transfusion: Treatment with romidepsin should be
delayed until the specific cytopenia returns to ≤Grade 1 or baseline,
and then the dose should be permanently reduced to 10 mg/m 2 .
2.3 Instructions for Preparation and Intravenous Administration
ISTODAX should be handled in a manner consistent with recommended
safe procedures for handling cytotoxic drugs.
5 WARNINGS AND PRECAUTIONS
5.1 Hematologic
Treatment with ISTODAX can cause thrombocytopenia, leukopenia
(neutropenia and lymphopenia), and anemia; therefore, these hematological
parameters should be monitored during treatment with ISTODAX, and the
dose should be modified, as necessary [See Dosage and Administration
(2.2) and Adverse Reactions (6)].
5.2 Infection
Serious and sometimes fatal infections, including pneumonia and sepsis,
have been reported in clinical trials with ISTODAX. These can occur
during treatment and within 30 days after treatment, and the risk of life
threatening infections may be higher in patients with a history of extensive
or intensive chemotherapy [See Adverse Reactions (6)].
5.3 Electrocardiographic Changes
Several treatment-emergent morphological changes in ECGs (including T-wave
and ST-segment changes) have been reported in clinical studies. The clinical
significance of these changes is unknown [See Adverse Reactions (6)].
In patients with congenital long QT syndrome, patients with a history of
significant cardiovascular disease, and patients taking anti-arrhythmic
medicines or medicinal products that lead to significant QT prolongation,
appropriate cardiovascular monitoring precautions should be considered,
such as the monitoring of electrolytes and ECGs at baseline and periodically
during treatment.
Potassium and magnesium should be within the normal range before
administration of ISTODAX [See Adverse Reactions (6)].
5.4 Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients
with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients
Only
with advanced stage disease and/or high tumor burden should be closely
monitored, appropriate precautions should be taken, and treatment should
be instituted as appropriate.
5.5 Use in Pregnancy
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 of 14 mg/m 2 /week. 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 [See Use in Specific Populations (8.1)].
6 ADVERSE REACTIONS
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.
Cutaneous T-Cell Lymphoma
The safety of ISTODAX was evaluated in 185 patients with CTCL in
2 single arm clinical studies in which patients received a starting dose of
14 mg/m 2 . The mean duration of treatment in these studies was
5.6 months (range: 20%)
regardless of causality using the National Cancer Institute-Common
Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due
to methodological differences between the studies, the AE data are
presented separately for Study 1 and Study 2. Adverse reactions are
ranked by their incidence in Study 1. Laboratory abnormalities commonly
reported (> 20%) as adverse reactions are included in Table 1.
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
Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82)
Nausea 57 (56) 3 (3) 71 (86) 5 (6)
Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14)
Infections 47 (46) 11 (11) 45 (54) 27 (33)
Vomiting 35 (34) 1 (

B:7”
T:7”
S:7”
(AUC) ≥0.2% of the human exposure at the recommended dose of
14 mg/m 2 /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/m 2 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/m 2 /dose) following the clinical dosing schedule. This dose resulted
in AUC 0-inf. values that were approximately 2% the exposure level in patients
receiving the recommended dose of 14 mg/m 2 /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/m 2 /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/m 2 /dose) following the clinical dosing schedule. This dose
resulted in AUC 0-inf. values that were 0.3% of those in patients receiving
the recommended dose of 14 mg/m 2 /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/m 2 /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 published 1-4 [See
References (15)].
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling.
17.1 Instructions
• Nausea and Vomiting
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)].
• Low Blood Counts
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)].
• Infections
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)].
• Tumor Lysis Syndrome
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)].
• Use in Pregnancy
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)].
• Patients should be instructed to read the patient insert carefully.
Manufactured for:
Celgene Corporation
Summit, NJ 07901
Manufactured by:
Ben Venue Laboratories, Inc.
Bedford, OH 44146
ISTODAX ® is a registered trademark of Celgene Corporation
U.S. Patents: 4,977,138; 7,608,280; 7,611,724
ISTBVPI.003/PPI.003 09/11
S:9.875”
T:9.875”
B:9.875”
MORE PATIENTS. MORE PRESCRIPTIONS.
A MORE COMPlETE CONTINuuM Of CARE
wIThIN yOuR PRACTICE.
The SpecialTy OncOlOgy neTwOrk frOm iOn SOluTiOnS.
establishing your own in-practice dispensing service through iOn Solutions
not only allows your patients more convenient access to medication, but
it also enhances your control and oversight of their therapy. The Specialty
Oncology network (SOn) exists to help community oncology practices
successfully optimize in-practice dispensing services — in fact, 90% of
all dispensing oncology practices are part of SOn. with the largest and
longest-tenured pharmacy program in the market, and eight gpO contracts
currently in place, iOn Solutions harnesses the collective power of community
oncology to accelerate practice growth and improve patient care.
For additional information, please visit iononline.com or email
SON@iononline.com.
Cosmos Communications 718.482.1800
22847a_pi 08.08.12 133
1 Q1 Q2
js
9

drug update
oncologistics drug update
LEVO-LEUCOVORIN in
COLON CANCER
By: Sam E. Mikhail, M.D. and John L. Marshall M.D.
Fluorouracil (5-FU) remains an essential component of many chemotherapy regimens. Modulation of 5-FU
by folinic acid (leucovorin[LV]) has been shown to double the response rate and improve overall survival in
patients with advanced colon cancer. 1 LV enhances the inhibitory action of 5-FU on thymidylate synthase (TS),
the rate-limiting enzyme in thymidine synthesis. 2,3 LV is a racemic mixture of levo (l), or 6S leucovorin, and
dextro (d) leucovorin. 4 The (d) isomer has been shown to be biologically inactive in preclinical studies, while
the (l) isomer is the active isomer. 4-7 After absorption, l-LV is metabolized to 5, 10-methylenetetrahydrofolate. 3
Adding LV to 5-FU results in an interaction between TS, 5-fluoro-2’-deoxyuridine monophosphate, and 5,
10-methylenetetrahydrofolate, which leads to the formation of a stable ternary complex which results in TS
inactivation. 2,3 Studies have suggested that d-LV is not inert. 6 Investigators have shown that it may compete
with l-LV for uptake by cells. 6 Moreover, it has been reported that d-LV is an inhibitor for folypolyglutamate
synthase, an enzyme involved in the folate-induced modulation of 5-FU. 8 An analysis of tumor biopsies
It is reasonable to believe that
obtained 30 minutes after intravenous (IV) administration of racemic LV at a dose of 200 mg/m 2 demonstrated
THE efficacy and safety results
that d-LV may partially inhibit tissue distribution of l-LV. 5,9 It is worth noting, however, that preclinical studies
OF regimens investigated in
have showed that such effects occur only with the use of extremely high LV. 9 Nevertheless, these reasons have
THOSE studies, wAS derived
prompted investigators to evaluate the use of l-LV “without d-LV” for 5-FU modulation.
MOSTLy from the cyTOTOXIC
CHEMOTHERAPEUTIC agents
oncologistics volume 11, issue 4 - winter 2012 14
Pharmacological data
A phase I/II trial was conducted to examine the efficacy
and toxicity of 5-FU and l-LV and also to evaluate
the pharmacokinetics (PK) of l-LV. 10 After IV bolus
administration of l-LV 100 mg/m 2 , the and half-lives were
7.2 and 126 minutes, respectively. The concentration of
l-LV was maintained above 10 µmol for 75 minutes. Large
amounts of folate appeared rapidly after injection and
consisted mostly of methylenetetrahydrofolate.
Meropol el al 11 also conducted a phase II trial to evaluate
the PK, activity and toxicity of l-LV in patients with
metastatic colorectal cancer. The study also attempted
to define the effect of adding 6R -leucovorin on the PK
of l-LV. Eligible patients received 4 weekly doses of 5-FU
and l-LV with one week of rest in a 35-day cycle. The LV
regimen consisted of 250 mg/m 2 over two hours with
750 mg/m 2 of 5-FU given as a bolus dose in the middle
of each infusion. Of note, study protocol was amended
twice secondary to gastrointestinal toxicity and the dose
of 5-FU was reduced to 600 mg/m 2 . Thirty patients
THEMSELVES and that I-LV can
SUCCESSFULLy replace racemic
LV. Moreover, several studies
IN JAPAN have demonstrated
THAT I-LV can replace racemic LV
AS a 5-FU modulating agent in
JAPANESE patients.
oncologistics 15

drug update
oncologistics drug update
were included in the study and twenty of them were used
in the PK analysis. The PK phase of the study randomized
patients to receive racemic LV at a dose of 500 mg/m 2 or
l-LV at a dose of 250 mg/m 2 on days -2 and -1, respectively.
There was no difference in the plasma concentration, peak
plasma level, area under the curve, half-life and clearance of
both types of LV. The overall response rate (ORR) was 40%
(95% CI 23%-60%). The dose limiting grade 3 and 4 toxicities
included diarrhea, dermatitis and oral mucositis. The PK
parameters, response and toxicity of 5-FU/l-LV were similar to
those described with other 5-FU/racemic LV regimens. These
results suggest that there both compounds are comparable
and that there was no clinical benefit to one versus the other.
Additionally, Devito et al 12 conducted two bioequivalence
prompted further exploration of l-LV as a viable option for
5-FU modulation. Similarly, Valone et al 13 conducted a phase
I clinical trial of 5-FU and l-LV in patients with advanced
gastrointestinal malignancies. Patients received a 5-day
continuous infusion of l-LV and daily IVB of 5-FU at 370 mg/
m2 for 5 days in a 28-day treatment cycle. The four dose
levels of l-LV were 200 mg/m 2 /day, 400 mg/m 2 /day, 700
mg/m 2 /day and 1000 mg/m 2 /day. Seventeen patients were
enrolled in the trial. The maximum tolerated dose (MTD)
was 700 mg/m 2 . The most common severe toxicities were
diarrhea, mucositis, nausea/vomiting and abdominal/rectal
pain. Out of the 12 patients evaluable for response, there
was one complete response (CR), one partial response
(PR) and one minor response. All three responses occurred
Table 1: Phase III trials comparing Levo-leucovorin and racemic leucovorin
Goldberg et al
Scheithauer et al
Design
5-FU 370 mg/m 2 IVB daily for
5 days +
A) l-LV 100mg/m 2 IVB
B) Oral d,l LV 125 mg/m 2
given 0, 1, 2 and 3 hrs prior to
5-FU;
5-FU 400 mg/m 2 IV over 2 hrs +
racemic LV 100 mg/m 2 IVB or
l-LV 100 mg/m 2 IVB.
Both regimens are administered daily
for 5 days and repeated every 28 days
for 6 months
C) IV d,l LV 200 mg/m 2
N 926 248
Response rate (p-value) A) 32%; B) 28% C) 34%
(adjusted p=0.36)
25% versus 32%
(p=0.25)
studies to compare oral and IV racemic LV and l-LV. They
randomized 35 subjects to receive five 2.5-mg l-LV tablets,
five 5-mg racemic LV tablets, one 12.5-mg l-LV tablet or one
25-mg racemic LV tablet, in study 1. In study 2, 33 subjects
received a 15-mg l-LV injection, two 7.5-mg l-LV tablets, 30-
mg LV injection, or two 15-mg LV tablets. Pharmacokinetic
among the nine patients who had colorectal cancer. These
results sparked optimism about the potential role of l-LV in
modulation of 5-FU and prompted the development of further
clinical trials to explore its effectiveness and tolerability.
Median duration of response NR 7.2 versus 8.0 months
(p =0.65)
Median time to progression NR 6.25 versus 8.0 months (p=0.0505)
Median survival NR 14.5 versus 15.0 months (p=0.28)
Grade 4 Neutropenia A) 1.1% B) 2.2% C) 1.8% 2% vesus 0%
values were calculated for N-5-methyltetrahydrofolate, the
primary metabolite and circulating form of reduced folate after
LV administration, and total tetrahydrofolate. Their analysis
showed that 12.5-mg oral dose and 15-mg intravenous
Phase III trials comparing Levo-leucovorin
vesus racemic leucovorin
In an attempt to compare the effectiveness of l-LV and
Grade 3/4 diarrhea A) 18.9% B) 15.6% C) 17.6% 10% versus 7%
Grade 3/4 stomatitis A) 18.6% B) 11.2% C) 14.2% 6 versus 6%
Grade 3/4 Nausea/vomiting A) 18.2% B) 14.7% C) 15% 1% versus 3%
dose of l-LV are bioequivalent to 25-mg oral dose and
racemic LV, Goldberg et al 14 conducted a large phase III
30-mg intravenous dose of racemic LV, respectively. The
randomized clinical trial between 1990 and 1995 (Table 1).
oncologistics volume 11, issue 4 - winter 2012 16
bioavailability of l-LV (74%) was not significantly different from
that of racemic LV (65%). A study by Schuller et al, 9 however,
showed that l-LV exhibited better tissue uptake in liver
metastases from gastrointestinal tumors.
Phase I trials of Levo-leucovorin
Based on the encouraging data regarding the use of l-LV,
Machover et al 10 conducted a phase I/II trial to evaluate the
combination of l-LV with 5-FU in patients with advanced
colorectal cancer. The trial included 25 patients and
administered l-LV 100 mg/m 2 as an IV bolus (IVB) injection
and 5-FU 350-550mg/m 2 IV over 2 hours. The response
rate (RR) was 52%, median time to progression (TTP) was
9.2 months and the estimated probability of survival at one
year was 73%. Dose-limiting toxicity (DLT) included grade 3
diarrhea, dermatitis and oral mucositis. No grade 4 toxicities
were encountered. These results were encouraging and
The trial included three arms combining bolus 5-FU with A)
Levo-leucovorin as an IVB at a dose of 100 mg/m 2 . B) Oral
(d,l) LV at a maximum dose of 500 mg/m 2 given in four doses
of 125 m/m 2 at 0, 1, 2 and 3 hours prior to chemotherapy.
C) Intravenous (d,l) LV at a dose of 200 mg/m 2 (control arm).
5-FU was administered as an IVB at a dose of 370 mg/m 2
immediately following IV LV and one hour (hour 4) after the
last dose of oral LV. The three regimens were administered
daily for 5 days and were repeated at 4 weeks and 8 weeks.
Subsequent doses were given every 4 weeks. The trial
enrolled 926 patients and was open for 5 ½ years. At the
end of the follow up period, 824 patients (89%) in all three
arms had progressed; 86% in the l-LV arm, 90% in the oral
racemic LV arm and 91%in the IV racemic LV arm. There was
no statistically significant difference in TTP between the three
treatment arms [adjusted P=0.70; 756 patients died during
the study; 81% in the l-LV arm, 83% in the oral LV arm and
81% in the IV racemic LV arm. There was again no statistically
significant difference in overall survival (OS) between the three
groups (adjusted P=0.37). The RR was 32%, 28% and 34%
in arms A, B and C, respectively. There was no statistically
significant difference between the three arms (adjusted
P=0.36) in RR. There was also no difference in toxicity,
both hematological and nonhematological, between the
three groups. Moreover, rates of grade 3/4 toxicity, severity
and pattern of toxicity for patients older than 72 years were
similar. This study demonstrated that l-LV can potentially
substitute racemic LV with similar efficacy and toxicity.
Scheithauer et al 15 also published a randomized phase
III clinical trial to compare racemic -and l-LV. The study
randomized 248 patients with metastatic/recurrent colorectal
cancer to 5-FU 400 mg/m 2 /day IV over two hours and
racemic LV 100 mg/m 2 /day as an IVB or l-LV 100 mg/m 2
in combination with the same 5-FU schedule. It is worth
noting that the authors elected to use an identical dose of
l-LV to evaluate the utility of using a higher than therapeutic
dose of LV. Patients received each regimen daily for 5
days every 28 days for a total of 6 months or until disease
progression. The median follow up was 23 months (range
17-48 months). During the study, 184 patients (76.3%) had
died. The ORR was 25% and 32% in the 5-FU/racemic LV
and 5-FU/l-LV arms, respectively. This difference was not
statistically significant (P=0.25). The median time to response
and median duration of response were also not statistically
different. Of note, the TTP was 6.25 months (95% CI 5.0-8.0)
in the 5-FU/racemic LV and 8.0 months (95 % CI 7.0-9.0) in
the 5-FU/ l-LV arm. This difference approached statistical
significance (P= 0.0505). The median OS was 14.5 months
(95% CI 12-17.0) and 15.0 months (95% CI 12.5-18.5) for
patients who received 5-FU/racemic LV and 5-FU/ l-LV,
respectively. This difference was not statistically significant.
Similarly, the one- and two year-survival rates were also not
statistically significant. Chemotherapy was not completed
for the planned 6 months in 34% of patients. There was no
statistically significant difference between the two groups in
oncologistics 17

drug update
oncologistics drug update
the number of patients who discontinued chemotherapy
prematurely (P=0.28). The overall incidence of at least
one adverse effect and at least one severe adverse effect
was similar between the two groups (P=0.23 and P=0.29,
respectively). However, there was a higher incidence of
leucopenia (41% versus 25%) and granulocytopenia (39%
versus 21%) in the 5-FU/racemic LV arm versus the 5-FU/
l-LV arms, respectively. These differences were statistically
significant (P=0.01 and P=0.03, respectively). The authors
have, however, noted that there were no cytopenia-related
complications in the study. This study, therefore, provided
additional evidence that l-LV and racemic LV are equivalent
in terms of efficacy and toxicity.
Phase II trials of Levo-leucovorin as a
modulator for 5-fu monotherapy:
Several studies used l-LV for modulation of 5-FU
administered as a single agent (Table 2). Sugano et al 16
conducted a multicenter randomized phase II trial that
compared high dose 5-FU (600 mg/m 2 ) given IV with high
dose l-LV (250mg/m 2 ) administered over 2 hours versus
lower dose 5-FU (370 mg/m 2 ) given with high dose l-LV
(100 mg/m 2 ) versus lower dose 5-FU (370 mg/m 2 ) given
with low dose l-LV (10mg/m 2 ) in 122 patients with advanced
colorectal cancer. A higher RR was observed in the two
high dose l-LV arms as compared with the low dose l-LV
arms. Additionally, higher rates of diarrhea and leucopenia
were also observed in the high dose l-LV + higher dose
5-FU arms. The p-value was not available in the abstract,
thus it is unclear if these observations were statistically
significant. Similarly, Sasaki et al 17 conducted a randomized
three-arm phase II study in patients with gastric cancer.
Their study used the same regimens evaluated by Sugano
et al. 16 The results were also consistent with the results of
the study by Sugano et al 16 in showing a better response
in the high dose l-LV arm. Moreover, patients on the high
dose l-LV arm had better median OS, numerically. Again,
the p-values were not included in the abstract, which raises
questions about the validity of those results. Andre et al 18,19
used l-LV and racemic LV interchangeably. Their study,
however, did not report a comparison between the efficacy
and toxicity of the two forms of LV.
Levo-leucovorin in combination
chemotherapeutic regimens
Several trials have included l-LV as a modulator of 5-FU in
combination with other chemotherapeutic agents in several
different cancer types (Table 3).
Colon cancer
Labianca et al conducted a phase III trial to compare
intermittent versus continuous chemotherapy in first line
treatment of patients with metastatic colorectal cancer 20 .
The study enrolled 337 patients who were randomized
between l-LV, 100/mg/m 2 IV, 5-FU; 400 mg/m 2 IVB + 5-FU;
600 mg/m 2 22-h continuous infusion, days 1 and
2 + irinotecan 180 mg/m 2 day 1, administered every
two weeks 2 months on and 2 months off (arm A) or
continuously (arm B) until disease progression. OS was
comparable in both arms (18 months in arm A and 17
Hasewaga et al
(34)
Konishi et al
(35)
Nobile et al
(36)
Sasaki et al
(17)
Advanced colorectal
cancer; N=54
Advanced colorectal
cancer; N=66
Advanced colorectal
cancer; N=70
Gastric cancer;
N=75
Randomized
phase II trial
comparing
monthly
(A) versus
bimonthly
(B)regimens
Phase II trial to
evaluate efficacy
and toxicity of
5-FU/l-LV
Phase II trial to
evaluate high
dose 5-FU given
over 24 hours
+l-LV
Randomized
phase II trial to
evaluate efficacy
and toxicity of
5-FU/l-LV
5-FU 500 or 750/body and l-LV
A: weekly x 3 wks→1 wks rest
B: weekly x 6 wks → 2 wks rest
l-LV 250 mg/m 2 over 2 hrs→5-
FU 600 mg/m 2 over 1 hr
weekly for 6 wks →2 wks rest
L-LV 100 mg/m 2 over 4 hrs→5-
FU 2600 mg/m 2 over 24 hrs
+ fixed dose oral l-LV 50 mg
every 4 hrs
A: L-LV 250mg/m 2 + 5-FU
600mg/m 2 weekly
B: L-LV 100mg/m 2 + 370 mg/
m 2 for 5 days
C: L-LV 10 mg/m 2 + 370 mg/
m 2 for 5
ORR 23.5 % arm B; 0%
arm A.
Diarrhea: 33.3% arm B;
6.5 % arm A
Median OS:12.8m;
Toxicity: N/
V=56%,Diarrhea 48%,
leucopenia 54%
ORR :35.3%, CR: 7 pts,
PR: 11 pts
Grade III/IV toxicities:
Diarrhea=27%, HFS=
5%, mucositis=4%.
PR: Arm A,B and C
35.7, 25% and 0%,
respectively
Median survival: 9.6m, 8
m, and 5.9 m for arms A,
B and C, respectively.
Note: p-values not
reported in abstract
RR: Regimens A,B and
C= 32.4 %, 20%, 11.1%,
respectively.
Toxicity: A: Diarrhea
53.8%, leucopenia
53.8%
Note: p-values not
reported in abstract
oncologistics volume 11, issue 4 - winter 2012 18
Table 2: Phase II trials of Levo-leucovorin for modulation of 5-FU monotherapy
Study
Andre et al
(18,19)
Cancer type, Number
of patients (N)
Stage II and III colon
cancer; N=905
Study design Chemotherapy schedule Results
Randomized
phase III trial
comparing
monthly versus
bimonthly 5-FU/
LV
Bimonthly: d-l-LV 200mg/
m 2 or l-LV 100 mg/m 2 over 2
hrs→5-FU 400 mg/m 2 bolus
and 5-FU 600 mg/m 2 over 22
hours.
Monthly: 5 days of d-l-LV or
l-LV over 15 min →5-FU 400
mg/m 2 over 15 min
Toxicities (neutropenia,
diarrhea and mucositis)
lower in bimonthly
regimen (p

drug update
oncologistics drug update
Table 3: Levo-leucovorin in combination chemotherapeutic regimens
Study
Labianca et al
(20)
Cancer type, Number
of patients (N)
mCRC; phase III;
N=337
Chemotherapy schedule
A)l-LV, 100/mg/m 2 IV, 5-FU; 400
mg/m 2 IV bolus + 5-FU; 600 mg/
m 2 22-h infusion, days 1 and 2 +
irinotecan; 180 mg/m 2 day 1 for 2
months with a 2 months break
B) Same regimen continuously
Baba et al (23) mCRC;Phase II; N=29 Weekly irinotecan and bolus 5-FU/lleucovorin
for 3 weeks every 28
days
Kato et al
(24)
2nd line therapy in
mCRC; Phase II; N=49
Oxaliplatin 100 mg/m 2 and l-LV
(200 mg/m 2 IV over 2 hours →5-FU
bolus 400 mg/m 2 IV and 46-h infusion
of 2400 mg/m 2 .
Irinotecan 165 mg/m 2 day 1, oxaliplatin
85 mg/m 2 day 1, l-LV 200
mg/m 2 day 1 and 5-FU 3200 mg/m 2
as a 48-h continuous
Results
OS: Arm A 18 m Arm B 17 m (HR
0.88) PFS 6 m in both groups (HR
1.03)
G 3/4 toxicity: similar in both
groups
Drug holiday 3.5 m
PFS: 17.3 m; PR 11 pts; SD 16 pts
Toxicity: leukopenia 22.6%;neutropenia
45.2%.
RR 14.3%; CR 1 pts; PR 6 pts; PFS
5.3 m; OS 11.4 m
G3/4 neutropenia 43.2%
Watanabe et al
(29)
Kornek et al
(30)
Bascioni et al
(31)
Locally advanced H &
N induction therapy;
Phase II; N=35
Metastatic breast
cancer (1st and 2nd
line);
Phase II; N=53 pts
Metastatic BC; Phase
II; N=46
28-day cycles of docetaxel 48 mg/
m 2 over 1 hr on D1 → cisplatin 24
mg/m 2 /day and 5-FU, 560 mg/m 2 /
day with l-LV, 125 mg/body/day D
1-4 by continuous IV infusion.
VNB 40 mg/m 2 D 1, 14 , l-LV 100
mg/m 2 IVB and 5-FU 400 mg/m 2
over 2 hrs, both D 1-5 q 4 wks. G-
CSF 5 mcg/kg/day D 6-10
5-FU 370 mg/m 2 and l-LV 100 mg/
m 2 D 1-3 versus D1-5 with mitoxantrone
12 mg/m 2 D1
ORR 88.2%; CR 58.8%; PR 29.4%; 2
yrs OS 92.8 2 yrs PFS 75.3%;
grade 3/4 neutropenia 18.7% of
cycles
1st line: ORR 19%; SD 9 pts; PD 4
pts; TTP 10.5 m
2nd line: TTP 7 m
G 3/4 neutropenia 36% (19 pts); G
3 anemia 8%; G3 ↓ PLTs 6 pts; G3
stomatitis 6%
ORR 32.6% (95% CI 19-46%) 3 day
regimen: CR 2 and PR 6 pts; 5 day
regimen: PR 7. G 3/4 leukopenia
5 pts; PLT 3 pts; stomatitis 4 pts;
diarrhea 5 pts
Masi et al
(21)
mCRC; Phase II; N=32
OS 28.4 m, PFS 10.8 ORR 72%
(95% CI 53-86%) CR 4 pts, PR 19,
SD 7 pts PD 2 pts.G 4 neutropenia
34%, G 3 diarrhea 16%, G 3
stomatitis 6%and G 2-3 peripheral
neurotoxicity 37%
OS 63 weeks (95% CI,54-71);TTF)
27 weeks; CR 5 pts; PR 25 pts;
ORR 31% (95% CI 22-41%). G 3/4
leukopenia 8%, Grade 3 diarrhea
5%; G3 mucositis 4%.
OS (HR of death = 0.90; 95% CI
0.64-1.26); DFS HR of recurrence
= 0.92; 95% CI 0.66-1.27; G 3/4
toxicity: Vomiting 21%, leucopenia
20%, mucositis 8%, and
diarrhea12%.
Mostly myelosuppression
oncologistics volume 11, issue 4 - winter 2012 20
Comella et al
(22)
Di Constanzo et
al (25)
Adamo et al
(26)
Mastsubara et
al (27)
mCRC, phase II,
N=100
Resected GC, Phase III
adjuvant; N=258
Metastatic gastic
cancer; Phase II;
N=33
Advanced GC, Phase
II; N=35
MTX 750 mg/m 2 IV over 2-h D1,
and l-LV 250 mg/m 2 over 2 hrs →
5-FU 800 mg/m IV bolus on day 2,
every two weeks.
Obversvation versus
cisplatin 40 mg/m 2 , D1,5 epirubicin
30 mg/m 2 , D 1,5, L-LV 100 mg/
m 2 ,D 1-4, and 5-FU 300 mg/m 2 ,
days 1-4 q 3 wks
l-LV150 mg/m2 over 10 min → etoposide
120 mg/m 2 over 50 minute
→5-FU 500 mg/m 2 as over 10 D1-3
every 22 days
Paclitaxel 80 mg/m 2 over 1 hr →
5-FU 600 mg/m 2 bolus and l-LV 250
mg/m 2 as over 2 hrs days 1, 8 and
15 on a 28 day cycle
RR: 43%; SD 46%; PFS 6.8 m; OS
16.2 m.
Toxicity: neutropenia 54%, febrile
neutropenia 3%, diarrhea 6% and
sensory neuropathy 11%.
LEVO-LEUCOVORIN appears to be a viable alternative in
CASE of shortage of racemic LV. UNDERSTANDING the
IDIOSyNCRASIES of reimbursement is essential, howEVER,
PRIOR to substituting I-LV for racemic LV. THE price
TAG for I-LV is higher than racemic LV. It is important
TO note, howEVER, that I-LV is reimbursable by most
INSURANCE carriers wHICH makes it a feasible choice in
CASE of racemic LV shortage.
oncologistics 21

drug update
oncologistics drug update
oncologistics volume 11, issue 4 - winter 2012 22
months in arm B [hazard ratio (HR), 0.88]. Also PFS was 6
months in both arms, with a HR of 1.03. Interestingly, grade
3-4 toxicity (mainly myelosuppression, fever and diarrhea) was
similar. The median chemotherapy-free period (drug holiday) in
arm A was 3.5 months.
Masi et al published a phase II trial to evaluate the safety and
efficacy of irinotecan, oxaliplatin, and 5-FU in first line treatment
of patients with metastatic colorectal cancer. 21 Thirty two
patients received biweekly irinotecan 165 mg/m 2 on day 1,
oxaliplatin 85 mg/m 2 on day 1, l-LV 200 mg/m 2 day 1 and 5-FU
3200 mg/m 2 as a 48-hour continuous infusion starting on day
1. The reported toxicity included grade 4 neutropenia (34%),
grade 3 diarrhea (16%), grade 3 stomatitis (6%) and grade
2-3 peripheral neurotoxicity (37%). Delivered dose intensity
was 88% of that planned, and no toxic deaths occurred. The
intention-to-treat analysis for activity showed an ORR of 72%
(95% CI 53-86%) with four CR, 19 PR, seven SD and two
progressive disease. Eight (25%) patients with residual liver or
lung metastases were radically resected after chemotherapy.
The median PFS was 10.8 months and median OS was
28.4 months.
Comella et al 22 conducted several trials that utilized l-LV for
modulation of 5-FU in combination with oxaliplatin, irinotecan,
raltitrexed and methotrexate. Their group conducted a phase
II trial to assess the activity and toxicity of double modulation
of 5-FU with methotrexate (MTX) and l-LV and 5-FU in patients
with colorectal cancer. One hundred patients were enrolled
and received MTX 750 mg/m 2 IV as a 2-hour infusion on day 1,
and l-LV 250 mg/m 2 IV as a 2-hour infusion followed by 5-FU
800 mg/m 2 IVB on day 2, every two weeks for a maximum
of 16 cycles. Patients had 5 CR and 25 PR, translating into
an ORR of 31% (95% CI 22-41%). Median OS was 63 weeks
(95% CI 54-71) and median time to treatment failure (TTF)
was 27 weeks. The 2- and 3-year probability of survival was
34% and 12%, respectively. Grade 3 to 4 leukopenia affected
8% of patients, whereas grade 3 diarrhea and mucositis
were encountered in 5% and 4%, respectively. The same
group also conducted a trial combining 5-FU, l-LV in addition
to either irinotecan (CPT) or ralitrexed (Ral) in patients with
metastatic colon cancer. The study also included a third arm
to draw a preliminary comparison between both arms and a
methotrexate (MTX) containing arm. One hundred and fifty
nine patients were randomized to one of three arms: Arm A:
CPT, 200 mg/m 2 IV on day 1, followed by l-LV 250 mg/m 2 IV
infusion and 5-FU 850 mg/m 2 IVB on day 2; Arm B: Ral 3 mg/
m 2 IV on day 1, followed by l-LV 250 mg/m 2 IV infusion and
5-FU 1050 mg/m 2 IVB on day 2; Arm C: MTX 750 mg/m 2 IV on
day 1, followed by l-LV 250 mg/m 2 IV infusion and 5-FU, 800
mg/m 2 IVB on day 2. The RR for arms A, B and C were 34%,
24% and 24%, respectively. The median TTP was 38, 25 and
27 weeks, in the three arms, respectively. The irinotecan/l-LV/5-
FU arm compared favorably with other combination arms in
terms of toxicity and activity.
Levo-leucovorin also appeared to be associated with
similar efficacy and toxicity as racemic leucovorin in Asian
patients. Baba et al conducted a phase II trial of modified
Salz chemotherapy regimen (weekly irinotecan and bolus
5-FU/l-LV for 3 weeks every 28 days) in Japanese patients with
metastatic colon cancer. 23 Twenty nine patients were included
in the trial. Disease control rate was 93.1% with 11 PR, SD in
16 patients, and progressive disease in two patients. Median
PFS was 17.3 months. The main hematologic toxicities were
leukopenia (22.6%) and neutropenia (45.2%). No treatmentrelated
deaths occurred. The study concluded that the
modified Salz regimen with l-LV was had manageable toxicity
with reasonable efficacy.
Kato et al also conducted a multicenter phase II trial to evaluate
the safety and efficacy of FOLFOX6 as second line therapy in
Japanese patients with metastatic colon cancer. 24 Forty nine
patients were included and received oxaliplatin 100 mg/m 2 and
l-LV (200 mg/m 2 IV over 2 hours followed by 5-FU bolus 400
mg/m 2 IV and 46-h infusion of 2400 mg/m 2 . RR was 14.3 %
(95% CI: 5.9-27.2%) with one CR and 6 PR. Median PFS was
5.3 months and OS was 11.4 months. The incidence of grade
2/3 peripheral neuropathy was 41.2%, whereas the overall
incidence of grade 3/4 neutropenia was 43.2%.
Gastric cancer
Di Constanzo conducted a randomized phase III trial
to evaluate the benefit of platinum containing adjuvant
chemotherapy in patients with resected gastric cancer 25 . Two
hundred fifty eight patients were randomized to observation
or chemotherapy with four 21-day cycles of PELF (cisplatin [40
mg/m 2 , on days 1 and 5], epirubicin [30 mg/m 2 , days 1 and 5],
L- l-LV [100 mg/m 2 , days 1-4], and 5-FU [300 mg/m2, days 1-4].
Grade 3/4 toxicity including vomiting, mucositis, and diarrhea
occurred in 21.1%, 8.4%, and 11.8% patients, respectively.
Grade 3/4 leucopenia, anemia, and thrombocytopenia
occurred in 20.3%, 3.3%, and 4.2% patients, respectively.
Adjuvant chemotherapy did not increase disease-free survival
(HR of recurrence = 0.92; 95% CI [CI] = 0.66 to 1.27) or OS (HR
of death = 0.90; 95% CI = 0.64 to 1.26).
Similarly, Adamo et al conducted a phase II trial to evaluate
the effect of etoposide, l-LV and 5-FU (ELF) in patients with
metastatic gastric cancer. 26 Thirty three patients received l-LV
150 mg/m 2 as a 10 minute bolus followed by etoposide 120 mg/
m 2 50 minute IV followed by 5-FU 500 mg/m 2 as a 10 minute
bolus on days 1-3, every 22 days. Two patients (6%) achieved
a CR, 10 patients (30%) had a PR, 9 patients (27%) had SD and
12 patients had disease progression. The median OS for all
patients was 6 months (range, 1 to 40+). The main toxicity was
myelosuppression but, overall, ELF was well tolerated.
Matsubara et al 27 conducted a phase II study to evaluate
efficacy and safety of bolus 5-fluorouracil (5-FU) and l l-LV
combined with weekly paclitaxel (FLTAX) in advanced gastric
cancer (GC) patients. Thirty-five patients were included in the
study and received paclitaxel 80 mg/m 2 as a 1-hour infusion,
followed by 5-FU 600 mg/m 2 as a bolus infusion and l-LV 250
mg/m s as a 2-hour infusion on days 1, 8 and 15. Treatment
cycles were repeated every 28 days. RR was 43% (95% CI
26-61). SD was observed in 16 (46%) patients. Median PFS
was 6.8 months (95% CI 5.8-7.4) and OS was 16.2 months
(95% CI 10.0-22.8. Grade 3-4 adverse events included
neutropenia (54%), febrile neutropenia (3%), diarrhea (6%) and
sensory neuropathy (11%). These results were encouraging
and led to the initiation of a randomized trial to further explore
this regimen.
Pancreatic cancer
Colleoni et al conduted a phase II trial in patients with untreated
metastatic pancreatic cancer. 28 Nine patients received threeweekly
carboplatin infusions (300 mg/m 2 on day 1), Oral l-LV 5
mg/m 2 twice a day on days 1-5, and 5-FU 1,000 mg/m 2 as a
120-hr infusion on days 1-5. Three patients had SD, and 6 had
disease progression. None of the patients achieved complete
or partial remission. Median TTP was 2 months (range, 2-8),
and median OS was 4 months (range, 3-12). Toxicity consisted
of mucositis, diarrhea and neutropenia. This regimen did not
prove to be clinically beneficial in patients with metastatic
pancreatic cancer.
Head and neck cancers
Levo-leucovorin has been also used in regimens developed for
patients with head and neck cancer. Watanabe et al designed
a clinical trial to investigate the efficacy and safety of a modified
TPF regimen (docetaxel, cisplatin and 5-FU/l-LV) as induction
chemotherapy in Japanese patients with locally advanced
squamous cell cancers of the head and neck. 29 Thirty-four
patients received 28-day cycles of docetaxel 48 mg/m 2 as a
1-hour IV infusion on day 1 followed by cisplatin 24 mg/m 2 /
day and 5-FU, 560 mg/m 2 /day with l-LV 125 mg/m 2 /day were
delivered on days 1-4 by continuous IV infusion. This regimen
was administered every 28 days. Toxicities included grade
III/IV neutropenia, in 18.7% of cycles. The most common
oncologistics 23

drug update
oncologistics drug update
oncologistics volume 11, issue 4 - winter 2012 24
nonhematologic toxicities included anorexia, stomatitis and
alopecia. The clinical ORR was 88.2%, with 58.8% CRs and
29.4% PR. After definitive locoregional therapy, 25 of 34
patients were disease-free with preserved primary tumor
site anatomy. OS and PFS at the 2-years were 92.8 and
75.3%, respectively.
Breast cancer
The use of l-LV has extended to several regimens in patients
with breast cancer. Kornek et al 30 conducted a phase II trial to
investigate the efficacy and safety of vinorelbine (VNB), 5-FU,
l-LV and recombinant human granulocyte colony-stimulating
factor (G-CSF) in advanced breast cancer. Fifty-three patients
received VNB 40 mg/m 2 on days 1 and 14 and l-LV 100 mg
m 2 as an IVB and 5-FU 400 mg m 2 as a 2 hour infusion, both
given on days 1-5 every 4 weeks. G-CSF was administered at
a dose of 5 mcg/kg/day on days 6-10 during each cycle. In the
first line setting, the ORR was 59% (95% CI 42-75%), including
five CR (13%) and 17 PR (46%); Ten patients (27%) had SD and
only five (14%) progressed. In the second line setting the ORR
was 19% (3/16), but nine patients had SD and four had PD.
The median TTP was 10.5 months (range 2-23) in previously
untreated patients and 7.0 months (range 2-19) in those who
had failed prior chemotherapy. Grade 3/4 neutropenia was
encountered in 15 (28%) and four patients (8%) respectively.
Two of those patients developed septicemia. Grade 3 anemia
and thrombocytopenia were noted in four (8%) and three (6%)
patients, respectively. Grade 3 stomatitis and nausea/vomiting
occurred in 6% and 2% of patients, respectively.
In an effort to develop a regimen that is active in patients with
metastatic breast cancer that had already progressed on
anthracycline-containing regimens, Bascioni et al conducted a
phase II trial to evaluate 2 mitoxantrone-containing regimens. 31
Both regimens contained l-LV. The first regimen consisted of
mitoxantrone 12 mg/m 2 administered on day 1; 5-FU 370
mg/m 2 and l-LV 100 mg/m 2 given on days 1-3 every three
weeks. The second regimen was similar to the three-day
regimen, but 5-FU was infused over 5 days. Twenty-three
patients were enrolled in each treatment arm. Two CR and
6 PR were observed with the three-day regimen. The 5-day
regimen was associated with 7 PR. The ORR was 32.6% (95%
CI: 19-46%). The median response duration was 9 months
(range 3-16). Grade 3/4 leucopenia and thrombocytopenia
occurred in 5 and 3 patients respectively. Grade 3/4 stomatitis
and diarrhea were observed in 4 and 5 patients, respectively,
all of which had received 5 days of 5-FU. Based on the
efficacy and toxicity profiles of both regimens, the authors
concluded that the 3-day regimen was equally efficacious and
better tolerated than the 5 day regimen.
A similar regimen was investigated in a phase II trial by Colloza
et al in patients with metastatic breast cancer. 32 Twenty-six
patients received mitoxantrone 9-12 mg/m 2 on day 1, l-LV 150
mg IV as a 1-hour infusion before 5-FU 350 mg/m 2 IVB days
1- 3. This regimen was repeated every 3 weeks. This regimen
was thought to be efficacious and well tolerated. The ORR was
27% (95% CI: 10-44%) with 2 CR, 5 PR and a median duration
of response of 38 weeks (range 23-68). Myelosuppression,
the most frequent toxicity, was mild in the majority of patients.
Nine episodes of neutropenic fever occurred in six patients,
but none of these episodes were fatal. Overall, the above 2
regimens were well tolerated. The substitution of racemic LV
with l-LV appeared to be associated with similar toxicity
and efficacy.
Conclusion
The literature suggests that l-LV can be used as an alternative
to racemic LV but does not offer significant benefit in efficacy
or toxicity over racemic LV. Phase III trials that compared 5-FU
modulation with racemic versus l-LV demonstrated that they
were comparable in terms of antitumor activity and toxicity
profile. Additionally, several studies used l-LV as a substitute
for racemic LV. It is reasonable to believe that the efficacy and
safety results of regimens investigated in those studies, was
derived mostly from the cytotoxic chemotherapeutic agents
themselves and that l-LV can successfully replace racemic LV.
Moreover, several studies in Japan have demonstrated that
l-LV can replace racemic LV as a 5-FU modulating agent in
Japanese patients.
Most oncologists, to our knowledge, continue to use racemic
LV. Based on published reports, some centers in Europe,
however, appear to use l-LV instead of racemic LV. Japanese
investigators appear to have adopted the use of l-LV more
exclusively, compared to other parts of the world.
Levo-leucovorin appears to be a viable alternative in case of
shortage of racemic LV. Understanding the idiosyncrasies of
reimbursement is essential, however, prior to substituting l-LV
for racemic LV. The price tag for l-LV is higher than racemic
LV. It is important to note, however, that l-LV is reimbursable
by most insurance carriers which makes it a feasible choice in
case of racemic LV shortage.
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28. Colleoni M, Nelli P, Vicario G, Pancheri F, Sgarbossa G, Manente
P. Phase II study of oral L-leucovorin, 120-hour fluorouracil
infusion and carboplatin in advanced pancreatic cancer. Tumori
1996 Nov-Dec;82(6):573-575.
29. watanabe A, Taniguchi M, Sasaki S. Induction chemotherapy
with docetaxel, cisplatin, fluorouracil and l-leucovorin for locally
advanced head and neck cancers: a modified regimen for
Japanese patients. Anticancer Drugs 2003 Nov;14(10):801-807.
30. Kornek GV, Haider K, Kwasny W, Lang F, Krauss G, Hejna
M, et al. Effective treatment of advanced breast cancer
with vinorelbine, 5-fluorouracil and l-leucovorin plus human
granulocyte colony-stimulating factor. Br J Cancer 1998
Sep;78(5):673-678.
31. Bascioni R, Giorgi F, Silva RR, Acito L, Giustini L, De Signoribus
G, et al. Mitoxantrone, fluorouracil, and L-folinic acid in
anthracycline-pretreated metastatic breast cancer patients.
Breast Cancer Res Treat 1997 Sep;45(3):205-210.
32. Colozza M, Gori S, Mosconi AM, Anastasi P, Basurto C, Ludovini
V, et al. Salvage chemotherapy in metastatic breast cancer: an
experience with the combination of mitoxantrone, 5-fluorouracil,
and L-leucovorin. Breast Cancer Res Treat 1996;38(3):277-282.
33. Goldberg P. The Cancer Letter. 2009; Available at: http://www.
bcm.edu/cancercenter/PMID=10432. Accessed October 2,
2012.
34. Hasegawa S, Akaike M, Yamamoto Y, Shiraishi R, Ozawa Y,
Suzuki H, et al. An institution-randomized trial of 5-fluorouracil
and l-leucovorin therapy given monthly versus every two months
to patients with advanced colorectal carcinoma. Gan To Kagaku
Ryoho 2004 May;31(5):729-733.
35. Konishi K, Yabushita K, Taguchi T, Ota J, Takashima S, Abe
T, et al. A late phase II trial of l-leucovorin and 5-fluorouracil
in advanced colorectal cancer. l-Leucovorin and 5-FU Study
Group (Japan Western Group). Gan To Kagaku Ryoho 1995
Jun;22(7):925-932.
36. Nobile MT, Barzacch MC, Sanguineti O, Chiara S, Gozza A,
Vincenti M, et al. Activity of high dose 24 hour 5-fluorouracil
infusion plus L-leucovorin in advanced colorectal cancer.
Anticancer Res 1998 Jan-Feb;18(1B):517-521.
37. Takeda S, Taguchi T, Ohta J, Kurihara M, Abe T, Ohtani T, et al. A
cooperative late phase II trial of l-leucovorin and 5-fluorouracil in
the treatment of advanced gastric cancer. l-Leucovorin and 5-FU
Study Group (Japan Western Group). Gan To Kagaku Ryoho
1995 Jun;22(7):903-910.
38. Yoshino M, Ota K, Kurihara M, Akazawa S, Tominaga T,
Sasaki T, et al. Late phase II trial of high-dose l-leucovorin and
5-fluorouracil in advanced colorectal carcinoma. l-Leucovorin
and 5-FU Study Group (Japan Eastern Group). Gan To Kagaku
Ryoho 1995 May;22(6):785-792.
Sam Mikhail, MD is a Chief Fellow in the Division of
Hematology/Oncology, Lombardi Comprehensive Cancer
Center, Medstar Georgetown University Hospital.
John L. Marshall, MD is Chief of Hematology and
Oncology, Lombardi Comprehensive Cancer Center,
Medstar Georgetown University Hospital.
A Perspective on Adjuvant Therapy
Significant effect on
relapse-free survival
Based on 696 relapse-free survival (RFS) events, determined by the Independent Review Committee,
median RFS was 34.8 months (95% CI, 26.1–47.4) and 25.5 months (95% CI, 19.6–30.8) in the group
treated with SYLATRON (peginterferon alfa-2b) and the observation group, respectively. The estimated
hazard ratio for RFS was 0.82 (95% CI, 0.71–0.96; unstratified log-rank P=0.011) in favor of SYLATRON.
SYLATRON is indicated for the adjuvant treatment of melanoma with microscopic or gross nodal
involvement within 84 days of definitive surgical resection including complete lymphadenectomy.
SELECT IMPORTANT SAFETY INFORMATION
WARNING: Depression and other Neuropsychiatric Disorders
The risk of serious depression, with suicidal ideation and completed suicides, and other
serious neuropsychiatric disorders are increased with alpha interferons, including SYLATRON.
Permanently discontinue SYLATRON in patients with persistently severe or worsening signs
or symptoms of depression, psychosis, or encephalopathy. These disorders may not resolve
after stopping SYLATRON.
SYLATRON is contraindicated in patients with a history of anaphylaxis to peginterferon alfa-2b or
interferon alfa-2b, in patients with autoimmune hepatitis, and in patients with hepatic decompensation
(Child-Pugh score >6 [Class B and C]).
Please see the adjacent Brief Summary of the Prescribing Information.
oncologistics 27

SELECT IMPORTANT SAFETY INFORMATION
• Peginterferon alfa-2b can cause life-threatening or fatal neuropsychiatric reactions. These
include suicide, suicidal and homicidal ideation, depression, and an increased risk of relapse
of recovering drug addicts. Depression occurred in 59% of patients treated with SYLATRON
(peginterferon alfa-2b) and 24% of patients in the observation group. Depression was severe
or life-threatening in 7% of patients treated with SYLATRON compared with

SYLATRON (peginterferon alfa-2b) is indicated for the adjuvant treatment of melanoma
with microscopic or gross nodal involvement within 84 days of definitive surgical resection
including complete lymphadenectomy.
A Perspective on Adjuvant Therapy
Significant effect on
relapse-free survival
• In the pivotal study, the dose of SYLATRON was adjusted to maintain an ECOG Performance Status of 0 or 1.
• Median duration of therapy:
– 6-mcg/kg/wk dose: median 8.0 weeks
– 3-mcg/kg/wk dose: median 14.3 months
• Patients achieved a significant improvement in relapse-free survival.
– Based on 696 RFS events, determined by the Independent Review Committee.
– Median RFS was 34.8 months (95% CI, 26.1–47.4) and 25.5 months (95% CI, 19.6–30.8) in the group
treated with SYLATRON and the observation group, respectively.
– The estimated hazard ratio for RFS was 0.82 (95% CI, 0.71–0.96; unstratified log-rank P=0.011)
in favor of SYLATRON.
SELECT IMPORTANT SAFETY INFORMATION
• There are no adequate and well-controlled studies of SYLATRON in pregnant women. Use SYLATRON
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• It is not known whether the components of SYLATRON are excreted in human milk. Because of the
potential for adverse reactions from the drug in nursing infants, a decision must be made whether to
discontinue nursing or discontinue treatment with SYLATRON.
• Safety and effectiveness in patients below the age of 18 years have not been established.
• Increase frequency of monitoring for SYLATRON toxicity in patients with moderate and severe renal impairment.
For more detailed information, please see the adjacent
Brief Summary and read the Prescribing Information.
Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved. ONCO-1039467-0000
Brief Summary of the Prescribing Information
WARNING: DEPRESSION AND OTHER NEUROPSYCHIATRIC DISORDERS
The risk of serious depression, with suicidal ideation and completed suicides,
and other serious neuropsychiatric disorders are increased with alpha interferons,
including SYLATRON. Permanently discontinue SYLATRON in patients with
persistently severe or worsening signs or symptoms of depression, psychosis, or
encephalopathy. These disorders may not resolve after stopping SYLATRON
[see Warnings and Precautions and Adverse Reactions].
INDICATIONS AND USAGE
SYLATRON is an alpha interferon indicated for the adjuvant treatment of melanoma with
microscopic or gross nodal involvement within 84 days of definitive surgical resection including
complete lymphadenectomy.
CONTRAINDICATIONS
SYLATRON is contraindicated in patients with a history of anaphylaxis to peginterferon alfa-2b
or interferon alfa-2b, autoimmune hepatitis, or hepatic decompensation (Child-Pugh score >6 [class
B and C]).
WARNINGS AND PRECAUTIONS
Depression and Other Serious Neuropsychiatric Adverse Reactions
Peginterferon alfa-2b can cause life-threatening or fatal neuropsychiatric reactions. These include
suicide, suicidal and homicidal ideation, depression, and an increased risk of relapse of recovering
drug addicts. In the clinical trial, depression occurred in 59% of SYLATRON-treated patients and
24% of patients in the observation group. Depression was severe or life threatening in 7% of
SYLATRON-treated patients compared with

Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The incidence of antibodies
to peginterferon alfa-2b has not been studied in patients with melanoma. In clinical studies
conducted in patients with chronic hepatitis C, the incidence of binding antibodies to peginterferon
alfa-2b was approximately 10% (174/1,759). Among the patients tested positive for binding
antibodies, 18% (32/174) developed neutralizing antibodies.
The incidence of antibody formation is highly dependent on the sensitivity and specificity of the
assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity
in an assay may be influenced by several factors, including assay methodology, sample handling,
timing of sample collection, concomitant medications, and underlying disease. For these reasons,
comparison of the incidence of antibodies to SYLATRON (peginterferon alfa-2b) with the
incidence of antibodies to other products may be misleading.
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of peginterferon
alfa-2b as monotherapy and in combination with ribavirin in chronic hepatitis C (CHC) patients.
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.
Blood and Lymphatic System Disorders: pure red cell aplasia, thrombotic thrombocytopenic
purpura
Ear and Labyrinth Disorders: hearing loss, vertigo, hearing impairment
Endocrine Disorders: diabetic ketoacidosis
Eye Disorders: Vogt-Koyanagi-Harada syndrome
Gastrointestinal Disorders: aphthous stomatitis, pancreatitis, colitis
Infusion reactions: angioedema, urticaria, bronchoconstriction
Immune System Disorders: systemic lupus erythematosus, erythema multiforme, thyroiditis,
thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, rheumatoid arthritis,
interstitial nephritis, and systemic lupus erythematosus
Infections: sepsis
Metabolism and Nutrition Disorders: hypertriglyceridemia
Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, myositis
Nervous System Disorders: seizures, memory loss, peripheral neuropathy, paraesthesia,
migraine headache
Respiratory, Thoracic, and Mediastinal Disorders: dyspnea, pulmonary infiltrates, pneumonia,
bronchiolitis obliterans, interstitial pneumonitis, sarcoidosis, and pulmonary hypertension
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic epidermal
necrolysis, psoriasis
Vascular Disorders: hypertension, hypotension, stroke
DRUG INTERACTIONS
In healthy subjects who were administered peginterferon alfa-2b subcutaneously at 1 mcg/kg once
weekly for four weeks with probe drugs of metabolic enzymes administered before the first dose
and after the fourth dose, a measure of CYP2C9 activity increased to 125% of baseline, whereas a
measure of CYP2D6 activity decreased to 51% of baseline.
When administering SYLATRON with medications metabolized by CYP2C9 or CYP2D6, the
therapeutic effect of these drugs may be altered.
The effects of pegylated interferon alfa-2b on the pharmacokinetics of drugs metabolized by
cytochrome P-450 enzymes have not been studied at the higher clinical doses for patients with
melanoma (3 mcg/kg/week and 6 mcg/kg/week).
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C:
There are no adequate and well-controlled studies of SYLATRON in pregnant women.
Nonpegylated interferon alfa-2b was an abortifacient in Macaca mulatta (rhesus monkeys) at
15 and 30 million international units (IU)/kg (estimated human equivalent of 5 and 10 million IU/kg,
based on body surface area adjustment for a 60-kg adult). The estimated INTRON ® A (interferon
alfa-2b) human equivalent dose of 5 to 10 million IU/kg daily is approximately equal to a human
equivalent dose of 79 to 158 mcg/kg/week of SYLATRON. Use SYLATRON during pregnancy only
if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether the components of SYLATRON are excreted in human milk. Studies in
mice have shown that mouse interferons are excreted in breast milk. Because of the potential
for adverse reactions from the drug in nursing infants, a decision must be made whether to
discontinue nursing or discontinue the SYLATRON treatment, taking into account the importance of
the therapy to the mother.
Pediatric Use
Safety and effectiveness in patients below the age of 18 years have not been established.
Geriatric Use
Clinical studies of SYLATRON did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects.
Hepatic Impairment
SYLATRON has not been studied in patients with severe hepatic impairment. Peginterferon alfa-2b
treatment is contraindicated in patients with viral hepatitis who have moderate or severe hepatic
impairment (Child-Pugh scores >6). Discontinue SYLATRON if hepatic decompensation (Child-Pugh
scores >6) occurs during treatment. [See Contraindications and Warnings and Precautions.]
Renal Impairment
The mean area under the concentration-time curve (AUC last
) following a single dose of
peginterferon alfa-2b at 1 mcg/kg increased by 1.3-, 1.7- and 1.9-fold in subjects with mild
(creatinine clearance 50–79 mL/min), moderate (creatinine clearance 30–50 mL/min), and severe
(creatinine clearance 10–29 mL/min) renal impairment, respectively. After multiple doses, the
mean AUC tau
increased by 1.3-fold in moderate and 2.1-fold in severe renal impairment. No
clinically meaningful amounts of peginterferon alfa-2b were removed during hemodialysis.
Dose reductions of 25% and 50% are recommended in patients with moderate and severe renal
impairment, respectively, receiving alpha interferons for chronic hepatitis C.
The effect of varying degrees of renal impairment on the pharmacokinetics of peginterferon
alfa-2b at the recommended doses of 3 mcg/kg or 6 mcg/kg for patients with melanoma has not
been studied.
OVERDOSAGE
The experience with overdose of SYLATRON is limited. Patients who were over dosed
experienced the following adverse reactions: severe fatigue, headache, mylagia, neutropenia, and
thrombocytopenia. The highest single dose administered was 14 mcg/kg.
For more detailed information, please read the Prescribing Information.
Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved. ONCO-1039467-0000
2013 Meeting Schedule
Meeting Date Meeting Name Location Venue
January 25-27, 2013 ASH Review Orlando, FL Hyatt Grand Cypress
February 8-10, 2013 Rescheduled 2012 San Diego, CA Westin San Diego
ION National Meeting
March 8-10, 2013 Targeted Therapies Meeting Dallas, TX Gaylord Texan
April 19-21, 2013 LPP National Meeting Washington, DC Renaissance
May 17-19, 2013 Business of Oncology Washington, DC Renaissance
Sept 20-22, 2013 National Healthcare Nashville, TN Loews Vanderbilt
Practitioners Meeting
Sept 27-29, 2013 LPP Select Meeting Dallas, TX Fairmont Dallas
Oct 25-27, 2013 LPP Excel Meeting Dallas, TX Dallas Marriott City
Center
November 8-10, 2013 ION National Meeting TBD TBD
*Meeting dates subject to change*

eimbursement watch
NEW PAYMENT MODELS
IN HEALTHCARE DELIVERY
By: Sara Fernandez, PhD
You’ve likely recently heard a great deal about how escalating costs call for improvement in the
quality of care are driving the creation of new payment models in the US healthcare delivery
system. The Patient Protection and Affordable Care Act (ACA) of 2010 introduced several new
programs to incentivize stakeholders to work toward cutting costs and increasing quality. Similarly,
private payers are also exploring new payment models and incentives for providers.
oncologistics reimbursement watch
WITH THE ONGOING
IMPLEMENTATION OF
HEALTHCARE REFORM,
ESPECIALLY GIVEN THE
SUPREME COURT’S RULING,
ONCOLOGY PATIENTS MAY
HAVE GREATER ACCESS TO
COORDINATED, QUALITY,
AND AFFORDABLE COVERAGE
TO CARE.
Yet you may wonder how new payment models are relevant to oncology practices and what you
will need to do to prepare for changes associated with a more value-focused healthcare system.
Oncology is an area of special interest to payers. This is largely due to rising costs caused by
improved detection and treatment processes, which are leading to more patients being diagnosed
with cancer and increasing survival rates. 1 There are also more available treatments, many of which
are highly specific and, therefore, more costly, than previous chemotherapy agents.
Below we describe some of these new payment models and how some oncology practices
are responding.
ACCOUNTABLE CARE ORGANIZATIONS (ACOS)
it difficult for oncology providers to demonstrate
increased quality and/or value under the program, and
oncologistics volume 11, issue 4 - winter 2012 34
A Medicare defines ACOs as groups of doctors,
hospitals, and other healthcare providers who come
together voluntarily to deliver coordinated, high-quality
care to Medicare patients. 2 Although all specialties
can participate in ACOs, the Medicare Shared Savings
Program (MSSP) is oriented toward primary and chronic
care, with beneficiaries linked to ACOs primarily on the
basis of services provided by primary care physicians
(PCPs). 3 Currently, no oncology-focused quality metrics
are being tracked within Medicare ACOs. This makes
poses barriers to oncologists who want to capitalize on
opportunities for enhanced reimbursement. 4 According to
the Community Oncology Alliance (COA), without quality
metrics, oncology practices participating in an ACO may
be pressured by ACO governance to focus on reducing
costs rather than also addressing ways to improve quality.
A focus only on cutting costs could be perceived as
rationing care.
However, more flexibility exists in the private payer world.
In one recent example, health plan Florida Blue, Florida’s
oncologistics 35

eimbursement watch
oncologistics reimbursement watch
SOME stakeholders believe that oncology-FOCUSED
ACOs can help reduce variation in treatment by
PROMOTING adherence to clinical guidelines that
DRIVE most cancer care decisions today.
oncologistics volume 11, issue 4 - winter 2012 36
Blue Cross and Blue Shield company, partnered with
Baptist Health South Florida and Advanced Medical
Specialties to create the first oncology-focused ACO. 5
Since cancer cases represent 16% of all medical costs
for this payer, it was no surprise that oncology was
targeted as an area of opportunity to explore new
approaches to cutting costs and improving care. This
initial oncology-focused ACO program is centered on
6 cancer types representing more than 80% of the
payer’s cancer cases. The main focus has been around
evidence-based treatment regimens, advanced care
planning, and avoiding of unnecessary emergency room
(ER) visits and hospital admissions.
Some stakeholders believe that oncology-focused
ACOs can help reduce variation in treatment by
promoting adherence to clinical guidelines that drive
most cancer care decisions today.
patient-centered MEDICAL HOMES (pcMHs)
The PCMH model emerged as a way to improve
coordination, efficiency, and communication while
maintaining focus on patient needs. It involves a teambased
approach to delivering healthcare services,
led by a healthcare professional who provides
comprehensive, continuous medical care to patients
in order to maximize health outcomes. The Centers for
Medicare & Medicaid Services (CMS) started a 3-year
demonstration program in May 2012 to evaluate
the effectiveness of this advanced primary care
practice model.*
It remains to be seen whether the PCMH model will
deliver the hoped-for savings and quality on a wide
scale. However, one of the first oncology-specific
PCMHs was established in May 2012 when the Center
for Medicare and Medicaid Innovation (CMMI) 6 granted
1 of 81 Health Care Innovation Awards**, to an oncology
group. Innovative Oncology Business Solutions, Inc.,
implemented and is testing a medical home model of
care for breast, lung, or colorectal cancer patients. 7
The goal of this oncology medical home is to improve
cancer care, reduce duplication of tests, and decrease
hospitalizations by offering comprehensive outpatient
cancer care, including patient education and inpatient
care coordination.
Success under this approach has been demonstrated
by one of the earliest adopters of the oncology medical
home model. Consultants in Medical Oncology and
Hematology (CMOH), a practice in southeastern
Pennsylvania, has been recognized as a Level 3
PCMH—the highest level of quality recognition
for PCMHs—by the National Coalition for Quality
Assurance (NCQA). The practice decreased ER visits
(-65% from 2006 to 2011), hospital admissions (-51%
from 2007 to 2011), and length of hospital stays (-21%
from 2008 to 2011) among their chemotherapy patients
after adopting the PCMH model. 8
(* The official name of the program is Federally Qualified Health Center
Advance Primary Practice Demonstration. The demonstration project
officially started in November 2011. http://innovations.cms.gov/
initiatives/FQHCs/FQHC-Fact-Sheet.html.
** The Health Care Innovation Awards are funding up to $1 billion in
grants to applicants who will implement the most compelling new
ideas to deliver improved care and lower costs to individuals
enrolled in Medicare, Medicaid, and the Children’s Health Insurance
Program (CHIP).)
oncologistics 37

eimbursement watch
oncologistics reimbursement watch
References
oncologistics volume 11, issue 4 - winter 2012 38
BUNDLED PAYMENTS
United Healthcare (UHC) launched its own episodeof-care
payment pilot program in 2010 with 5 medical
oncology groups around the country. 9 The program
focuses on determining best treatment practices and
improving health outcomes for patients with breast, colon,
or lung cancers. The initial payment covers the standard
treatment period (typically 6 to 12 months) with incentives
to physicians who improve their results. Those providers
who increase patient survival time or decrease the total
cost of care from one year to the next will trigger UHC
to increase the episode payment. 10 A study found that
the pilot participants have been able to achieve costeffective
patient outcomes with on-pathway treatments,
such as lower outpatient costs (35% reduction) for those
treated on-pathway, lower chemotherapy costs (37%
reduction), and lower non-chemotherapy drug costs (39%
reduction). 11
coMMON ELEMents TO THE NEW MODELS
OF CARE
Most of these new payment programs (ACOs, PCMHs,
and bundled payments) share a few common threads:
adoption of electronic health records, coordination of
care, and adherence to clinical guidelines.
Adoption of electronic health records (ehr):
Adoption of EHR systems is seen as one of the first steps
in improving care. EHR systems may lead to bettercoordinated
patient care and lower healthcare costs by:
> Enhancing communication among providers about
patient care, therefore reducing medical errors
> Providing access to clinical decision-making tools
through evidence-based protocols
> Reducing paperwork
> Eliminating unnecessary or duplicate screenings
and tests 12
In 2011, CMS launched the Medicare and Medicaid
EHR Incentive Programs to spur eligible professionals to
adopt and meaningfully use certified EHR technology.
Incentives to adopt EHR are available until 2016, although
some penalties start in 2015. 14 According to an industry
report, about 63% of surveyed oncologists used EHR
technology in 2010. 15
Coordination of care:
Both the ACO and medical home programs emphasize
coordinated care by PCPs and specialists. Care for
the patient is seen as a synchronized effort to avoid
duplication of services and to ensure aligned care by
different providers. Oncologists, who have historically
coordinated care for their patients without any type of
payment for these efforts, could potentially benefit by
receiving reimbursement for coordination-related services.
Seamless coordination of care relies heavily on EHR
technology at all levels.
Adherence to clinical guidelines:
Clinical pathways are detailed, evidence-based
processes for delivering cancer care for specific patient
presentations, including the state and stage of disease. 16
Various large payers have introduced clinical pathways
programs specific to oncology through partnerships with
companies such as Via Oncology, Innovent Oncology,
and P4 Healthcare. Some oncologists have embraced
these programs, saying they promote consistent quality
care and offer enhanced reimbursement for following
approved guidelines.
Oncology lives covered by clinical pathways are
expected to increase from an estimated 15% in 2010 to
approximately 25% in 2015. 17 However, the complexity
of cancer diagnoses and available therapies make
standardization a challenge. Many times, payers start by
targeting the most common and expensive cancers (eg,
breast, lung, colon) and align reimbursement or financial
incentives to adherence to these clinical guidelines. Many
of the more successful programs have incorporated
clinical guidelines developed by independent, third-party
organizations such as the American Society of Clinical
Oncology (ASCO) or the National Comprehensive Cancer
Network (NCCN)
recoMMENDATIONS TO PRACTICES
Increasing costs, demands for higher quality care, and health
information technology (HIT) are pushing payers toward valuebased
reimbursement. Considering this new value-based
healthcare world, oncology practices may benefit from the
following strategies:
> Ensuring that HIT systems allow for timely and accurate
communication and coordination with other providers
> Evaluating new technologies and processes to improve
coordination; these tools may also present opportunities
to improve operational processes, which can allow
more time to focus on patient care instead of
administrative tasks
> Exploring the implementation of clinical pathways and the
potential implications that pathways would have on
practice relationships with payers
> Working with other oncologists and/or specialty societies
to engage payers proactively to ensure clinicians have
input into the creation of appropriate clinical pathways
> Considering the benefits of joining or forming oncology
ACOs or PCMHs
> Evaluating the time, human resource, and financial
investment involved with participating in new
collaborations (eg, negotiating new contracts,
reporting quality measures for payers, establishing
infrastructure such as HIT systems, etc.)
> Staying informed of developing payment models and
timelines, as they may impact cancer care
The healthcare system in the US is shifting toward valuebased
models. Oncology practices will need to continue
adapting and identifying new opportunities to thrive in this
changing marketplace.
Sara Fernandez, PhD, is associate director,
Xcenda Reimbursement Strategy & Trends.
1. http://www.cancer.gov/newscenter/newsfromnci/2011/
CostCancer2020 Accessed November 13, 2012.
2. CMS. Accountable Care Organizations. http://www.cms.
gov/Medicare/Medicare-Fee-for-Service-Payment/ACO/
index.htmlredirect=/ACO/ Accessed November 13, 2012.
3. CMS. Medicare Program; Medicare Shared Savings
Program: Accountable Care Organizations Final Rule.
http://www.gpo.gov/fdsys/pkg/FR-2011-11-02/pdf/2011-
27461.pdf. Accessed November 13, 2012.
4. COA. ACO Proposed Rule Comment Letter. http://
communityoncology.org/UserFiles/files/87f3205e-ee73-
4b03-85fb-094870cc430d/COA_ACO_Comment_Letter.
pdf. Accessed November 13, 2012.
5. AIS Health. Florida Blue Teams With Hospital System,
Oncologists to Form Cancer-Focused ACO. http://
aishealth.com/archive/nspn0612-02. Accessed
November 13, 2012.
6. http://www.innovations.cms.gov/ Accessed November
13, 2012.
7. CMS. Health Care Innovation Award Profiles. http://
innovation.cms.gov/Files/x/HCIA-Project-Profiles.pdf
Accessed November 13, 2012.
8. Oncology Times. Inside Look: First Oncology Medical
Home. http://journals.lww.com/oncology-times/
Fulltext/2012/04250/Inside_Look___First_Oncology_
Medical_Home.3.aspx Accessed November 13, 2012.
9. http://www.prweb.com/releases/OncologyMedicalHome/
MichiganAugust2012/prweb9795555.htm Accessed
November 13, 2012.
10. United Healthcare Report Recommends Adopting New
Cancer Care Payment Model to Reward Physicians
for Health Outcomes. http://www.uhc.com/news_
room/2012_news_release_archive/new_cancer_care_
payment_model.htm Accessed November 13, 2012.
11. http://www.clinicaloncology.com/ViewArticle.
aspxd=Policy+and+Management&d_
id=151&i=December+2010&i_id=685&a_id=16263.
Accessed November 13, 2012.
12. Accenture. Making the Case for Connected Health. http://
www.accenture.com/us-en/Pages/insight-making-caseconnected-health.aspx
Accessed November 13, 2012.
13. HHS. News Release. http://www.hhs.gov/news/
press/2012pres/06/20120619a.html Accessed November
13, 2012.
14. http://www.cms.gov/EHRIncentivePrograms/35_Basics.
asp#TopOfPage Accessed November 13, 2012.
15. Genentech . The 2010-2011 Genentech Oncology Trend
Report. December 2010.
16. http://jop.ascopubs.org/content/7/1/54.full Accessed
November 13, 2012.
17. http://www.mckinsey.com/~/media/mckinsey/dotcom/
client_service/Pharma%20and%20Medical%20Products/
PMP%20NEW/PDFs/786594_Strategies_in_Oncology.
ashx Accessed November 13, 2012.
oncologistics 39

All lung cancers are tough
to treat.
Why are some even
tougher
We ask why.
Although outcomes in certain subtypes of lung cancer have
improved, many patients have complex pathology and progress
rapidly. We at Celgene believe there should be more options
for these patients—and we are working to find them.
©2012 ©2011 Celgene Corporation 04/12 01/11 US-CELG120019 ABR10015
For more information on our research and development, visit celgene.com

oncologistics
THE PhySICIAN-PayER RELATIONSHIP:
USING DATA to DRIVE
THE FUTURE of
ONCOLOGy CARE
BESIDES cutting costs, the most
SIGNIFICANT move that community
ONCOLOGISTS can make to remain
in business is to maximize their revenue.
New payMENT models are emerging in the
wAKE of ASP that value the oncologist
BEING more accountable for qUALITy and
COST of care.
By: Barry Fortner, PhD
The Rising Cost of Cancer Care
The relationship between providers and payers in oncology has changed—due, at least in part, to
the unintended consequences of the ASP model for reimbursement.
By moving to ASP plus 6 percent in 2005, Medicare sought to level off the exponential rise in the income
that physicians made from specialty oncolytics. Unfortunately, this has led to a much broader and
significant impact on the marketplace, including:
oncologistics volume 11, issue 4 - winter 2012 42
The increase in the usage of high-price drugs.
Physicians rely on the drug margin revenue to cover
the cost of value-added services. With ASP plus 6%,
physicians can make more from the higher priced
drugs, so they are encouraged to use these instead of
generics, which leads to the next paradoxical change.
Downward trends in generic pricing.
The price of generics has dropped to the point where
many manufacturers have exited the business,
exacerbating the likelihood of drug shortages.
In fact, in a recent survey, nearly 50 percent of
oncologists suggested that they have seen patients
who have had poor responses that were directly
attributed to drug shortages.
Termination of patient value-add services.
Many of the additional services that community
oncologists offer their patients—like weekend clinics or
24/7 call centers—are funded from operating capital
generated from drug margins. As these margins
declined, so too have the services.
Practices closing satellite offices and shifting
to hospitals.
Oncology practices are now being consumed by hospital
systems, or they are shifting their services to hospitals.
Many have contended that this only increases the cost to
the patient and the overall health delivery process.
oncologistics 43

oncologistics
oncologistics volume 11, issue 4 - winter 2012 44
In light of these effects, what are practices doing today
Besides cutting costs, the most significant move that
community oncologists can make to remain in business
is to maximize their revenue. New payment models are
emerging in the wake of ASP that value the oncologist
being more accountable for quality and cost of care.
Pilot models are being launched where oncologists get
paid for services that are of great value to the payer, like
ensuring that care is coordinated across specialties while
the patient is receiving cancer treatment. These models
allow payers to experience some relative savings while
incentivizing the practice by sharing some of those
savings back to them through bonuses or payment for
services required to produce the savings. These models
also allow payers to achieve some accountability on
drug choices and have some assurance about how those
drug choices compare to national guidelines.
Pay for performance, medical home, episode of care
and pathway models are not new to medicine, but they
are relatively new to oncology. Payers and practices
are turning to these models to try to create equitable
reimbursement to keep practices viable while stemming
the exponential year over year increases in the cost of
oncology drugs and services.
Technology: Managing Data to Reclaim
Revenue
While there are some inherent conflicts between the
various stakeholders, everyone agrees that value is the
goal. To achieve the highest value, new technologies
will be amplifiers in making new physician-payer
models affordable and feasible. Technology is crucial
in managing data and improving processes that can
reclaim revenue, manage costs and make an impact on
the bottom line. Oncology practices are starting to use
technology solutions to:
Determine total care cost
Oncologists can now look at the payer’s plan, by
drug and by regimen. They can also look at this
data over a period of time to determine how much
a treatment approach contributes to the practice’s
operating capital considering the drug costs and
administrative costs, overhead and other expenses
that are included in the total cost of a particular
treatment option.
Manage inventory
Technology can enable more effective inventory
management through all phases of a product’s time
in a practice. For example, better inventory reporting
can help a practice reduce its carrying costs without
impacting patient care. At the same time, inventory
solutions can ensure that all dispensed products are
accurately tracked to ensure proper billing. Failing
to bill for a delivered drug just half a percent of
the time has a differentially negative impact on the
practice bottom line and easily goes undetected
because of the complexity of combining inventory
management with drug/dose specific billing.
Identify denial patterns
For denials, practices need to look at patterns,
particular drugs and regimens, to see where the
office needs to make changes in how it works with
a particular payer. First time denials are the primary
target. Once a charge is denied, the effort that is
required to reverse the denial for many charges has
diminishing return because of the human resource
cost required to track the denial. The goal is to
eliminate the denials in the first place.
Analyze remittance leads
By the very nature of buy and bill, practices float
the cost of the drug from the time they purchase
it to the time that they are actually paid for
it. Practices may utilize a line of credit to float
these substantial drug purchases which results
ongoing interest charges. In some cases, the cost
of money incurred through a 2 – 4 percent line of
credit represents the difference of whether or not a
regimen remains viable. The faster a practice can get
payment, the lower the amount of time they have to
float the drug cost. Good human resource processes
combined with technology solutions help get
payment time down to seven, twelve or fourteen
days and analyze remittance trends so that processes
can be continually monitored and improved.
Clean billing
New tools help facilitate proper documentation for
auditing purposes and clean billing so practices don’t
start off at a disadvantage. Practices frequently do
not bill for the series for which they are eligible or do
not bill the service they rendered at the proper rate.
Technology can make the process of determining the
proper billing more efficient and more accurate.
Perhaps the area where technology plays the most
exciting role is in managing the data and communication
required by emerging care models, like pathways,
medical home and episodes of care. All of these models
require clinical and financial data to support decisions
that create mutual benefit for oncologists, payers and
patients. Without data, these models simply cannot
exist. The latest technology helps practices produce this
oncologistics 45

oncologistics volume 11, issue 4 - winter 2012 46
data to document clinical decisions, cost savings and
outcomes—reinforcing the value of cancer care in the
community setting.
IMPACT ON THE FUTURE OF ONCOLOGY CARE
Data visibility is not a standard practice in medicine
right now, the way it is for other industries. However,
this will be changing. Technology—and more
specifically—data visibility is driving this change.
Companies like ION Solutions and community oncology
practices are proactively working to develop a data
infrastructure and analytic processes that embrace the
patients, oncologists and payers.
Another significant change on the horizon is the way
information is obtained from and delivered to patients.
Right now, patient information is collected through
paper, pencil and interviews and patients remain fairly
blind to the contents of their medical records. Patients
don’t have access to instantaneous information on their
mobile phones the way they have come to expect in
basically every other area of their lives. This, too, will
change as technology allows for easier and more secure
information exchange between complex systems.
Currently, physicians don’t have the resources to
aggregate data and facilitate this change. Payers face
barriers as well. Due to the very complicated nature of
oncology, payers are just now beginning to look at new
models of remuneration based on more sophisticated
ways of looking at treatment selection and management
of multi-dimensional care. They see specialty drugs
growing year over year at a rate that exceeds medical
costs and other prescription drug categories. Recent
technology solutions are just now allowing them to look
at data and consider other models of care.
As new technologies are being developed that help
with this data exchange, it’s important for physicians to
cooperate in pilot programs and for payers to embrace
new models that can be implemented in ways that
protects both the cost of care and quality of care.
Cancer care is at a crossroads of change and
opportunity. As new technologies drive this forward,
physicians and payers must embrace change and share
a vision of future oncology that values the quality of
care with the cost of care.
Barry Fortner is senior vice president, payer strategy,
ION Solutions.
Brief Summary of the Prescribing Information for INDICATIONS AND USAGE
EMEND ® (fosaprepitant (aprepitant) capsules dimeglumine) for Injection
Prevention regimen of of aprepitant Chemotherapy-Induced and on Days 4, 8, Nausea and 15: and intravenous midazolam AUC h 25% on Day 4, AUC i 19% on were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic
Vomiting Day 8, and (CINV): AUC i EMEND, 4% on Day in combination 15 with other General disorders and general administration site conditions: exposure fatigue: 15.4, of about 15.6; 2.8 asthenia: to 3.6 times 4.7, 4.6 the human exposure at the recommended dose. Treatment with aprepitant
antiemetic agents, is indicated for prevention of acute
Oral aprepitant 125 mg, intravenous midazolam 2 mg given In 1 a hour combined after aprepitant: analysis of these intravenous 2 studies, midazolam isolated cases of serious produced adverse skin fibrosarcomas experiences were at 125 similar and in 500 the mg/kg/day 2 doses in male mice. Carcinogenicity studies were not
and delayed nausea and vomiting associated with
AUC h 1.5-fold
treatment groups.
conducted with fosaprepitant.
initial and repeat courses of highly emetogenic cancer
A difference of less than 2-fold increase of midazolam AUC
Highly
was not
and
considered
Moderately
clinically
Emetogenic
important.
Chemotherapy: The following Aprepitant additional and clinical fosaprepitant adverse were experiences not genotoxic (incidence
the Ames test, the human lymphoblastoid cell (TK6)
CAPSULES
chemotherapy (HEC), including high-dose cisplatin; and
>0.5% and greater than standard therapy), regardless of causality, mutagenesis were reported test, the in rat patients hepatocyte treated DNA with strand the
for The prevention potential of effects nausea of and increased vomiting plasma associated concentrations with
break test, the Chinese hamster ovary (CHO) cell chromosome
of aprepitant midazolam regimen or other in benzodiazepines either HEC or MEC metabolized studies:
initial and repeat courses of moderately emetogenic cancer chemotherapy via CYP3A4 (alprazolam, (MEC).
aberration test and the mouse micronucleus test.
triazolam) should be considered when coadministering these agents with fosaprepitant
Infections and infestations: candidiasis, herpes simplex, lower
or aprepitant.
Fosaprepitant, respiratory infection, when administered oral candidiasis, intravenously, pharyngitis,
Prevention of Postoperative Nausea and Vomiting (PONV): EMEND is indicated for prevention of postoperative
is rapidly converted to aprepitant. In the fertility studies
septic shock, upper respiratory infection, urinary tract infection
nausea and vomiting.
conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained
CYP2C9 Substrates (Warfarin, Tolbutamide): Warfarin: A single
Neoplasms
125-mg
benign,
dose of
malignant,
oral aprepitant
and unspecified
was administered
(including cysts following and polyps): oral administration malignant neoplasm, of aprepitant. non–small-cell Oral aprepitant did not affect the fertility or general reproductive
Limitations of Use: EMEND has not been studied for treatment on Day of established 1 and 80 mg/day nausea and on Days vomiting. 2 and 3 to healthy subjects
lung
who
carcinoma
were stabilized on chronic warfarin therapy.
performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily
Chronic continuous administration is not recommended. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(–) warfarin determined on Day
Blood and lymphatic system disorders: anemia, febrile neutropenia, (providing thrombocytopenia
exposure in male rats lower than the exposure at the recommended human dose and exposure in
CONTRAINDICATIONS
3, there was a 34% decrease in S(–) warfarin trough concentration accompanied by a 14% decrease in the
prothrombin time (reported as INR) 5 days after completion Metabolism of dosing with and oral nutrition aprepitant. disorders: In patients appetite on decreased, chronic diabetes female mellitus, rats at hypokalemia about 1.6 times the human exposure).
EMEND is contraindicated in patients who are hypersensitive to any component of the product.
warfarin therapy, the prothrombin time (INR) should be closely Psychiatric monitored disorders: in the 2-week anxiety disorder, period, particularly confusion, depression at 7 PATIENT COUNSELING INFORMATION
EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme to 10 days, 3A4 following (CYP3A4). initiation EMEND of should fosaprepitant not be used with each chemotherapy Nervous system: cycle. peripheral neuropathy, sensory neuropathy, [See taste FDA-Approved disturbance, tremor Patient Labeling]: Physicians should instruct their patients to read the patient package
concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in
Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day Days 2 and 3, decreased the insert before starting therapy with EMEND for Injection and to reread it each time the prescription is renewed.
elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug
Eye disorders: conjunctivitis
Interactions].
AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% Cardiac on Day disorders: 15, when myocardial a single infarction, dose of tolbutamide palpitations, tachycardia Patients should follow the physician’s instructions for the regimen of EMEND for Injection.
500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days
WARNINGS AND PRECAUTIONS
Vascular disorders: deep venous thrombosis, flushing, hot flush, Allergic hypertension, reactions, hypotension which may be sudden and/or serious, and may include hives, rash, itching, redness of the
4, 8, and 15.
face/skin, and may cause difficulty in breathing or swallowing, have been reported. Physicians should instruct
CYP3A4 Interactions: EMEND, a dose-dependent inhibitor of CYP3A4, should be used with caution in patients Respiratory, thoracic, and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain,
Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4;
their patients to stop using EMEND and call their doctor right away if they experience an allergic reaction. In
receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance
by aprepitant, 125-mg/80-mg regimen, could result in elevated
therefore,
plasma
coadministration
concentrations of
of
these
fosaprepitant
concomitant
or aprepitant with drugs that inhibit CYP3A4 activity may result addition, severe skin reactions may occur rarely.
Gastrointestinal disorders: abdominal pain upper, acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia,
medications.
in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant
eructation, flatulence, obstipation, salivation increased Patients who develop an infusion-site reaction such as erythema, edema, pain, or thrombophlebitis should be
or aprepitant with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin,
Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations
clarithromycin, ritonavir, nelfinavir) should be approached with
Skin
caution.
and subcutaneous
Because moderate
tissue disorders:
CYP3A4
acne,
inhibitors
diaphoresis, pruritus,
instructed
rash
on how to care for the local reaction and when to seek further evaluation.
of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree.
(eg, diltiazem) result in a 2-fold increase in plasma concentrations Musculoskeletal of aprepitant, and connective concomitant tissue administration disorders: arthralgia, back EMEND pain, for muscular Injection weakness, may interact musculoskeletal with some drugs, pain, including chemotherapy; therefore, patients should
When aprepitant is used concomitantly with another CYP3A4 should inhibitor, also aprepitant be approached plasma with concentrations caution. could be myalgia
be advised to report to their doctor the use of any other prescription or nonprescription medication or
elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma
herbal products.
Aprepitant is a substrate for CYP3A4; therefore, coadministration Renal and of fosaprepitant urinary disorders: aprepitant dysuria, renal with insufficiency drugs
concentrations could be reduced and this may result in decreased efficacy of EMEND [see Drug Interactions].
that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, Reproductive phenytoin) system may and result breast in disorders: reduced pelvic plasma pain
Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the
Chemotherapy agents that are known to be metabolized by CYP3A4
concentrations
include docetaxel,
and decreased
paclitaxel,
efficacy.
etoposide,
2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle.
General disorders and administrative site conditions: edema, malaise, pain, rigors
irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND (125-mg/80-mg
Administration of EMEND for Injection may reduce the efficacy of hormonal contraceptives. Patients should be
regimen) was administered commonly with etoposide, vinorelbine, Ketoconazole: or paclitaxel. When The a doses single of 125-mg these agents dose of were oral not aprepitant Investigations: was administered weight on loss Day 5 of a 10-day regimen
advised to use alternative or backup methods of contraception during treatment with and for 1 month following
adjusted to account for potential drug interactions. of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the Stevens-Johnson AUC of aprepitant syndrome increased was reported approximately as a serious 5-fold adverse the experience last dose of in fosaprepitant a patient receiving or aprepitant. aprepitant with
and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of
In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics cancer chemotherapy in another CINV study.
fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously.
was observed when EMEND (125-mg/80-mg regimen) was coadministered.
Laboratory Adverse Experiences: Following are the percentage For of detailed patients information, receiving highly please emetogenic read the chemotherapy Prescribing Information.
Due to the small number of patients in clinical studies who received
Rifampin:
the
When
CYP3A4
a single
substrates
375-mg
vinblastine,
dose of
vincristine,
oral aprepitant was in Cycle administered 1 with laboratory on Day 9 adverse of a 14-day experiences regimen reported of 600 at an Rx incidence only of ≥3% for the aprepitant regimen (n=544)
or ifosfamide, particular caution and careful monitoring are advised mg/day in of patients rifampin, receiving a strong these CYP3A4 agents inducer, or other the AUC of aprepitant and standard decreased therapy approximately (n=550), respectively: 11-fold and the
chemotherapy agents metabolized primarily by CYP3A4 that were mean not terminal studied half-life [see Drug decreased Interactions]. approximately 3-fold. Proteinuria: 6.8, 5.3
Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of of EMEND fosaprepitant with warfarin or aprepitant may result with drugs that ALT induce increased: CYP3A4 6.0, 4.3 activity may result in reduced
in a clinically significant decrease in international normalized plasma ratio (INR) concentrations of prothrombin and time. decreased In patients efficacy. on chronic Blood urea nitrogen increased: 4.7, 3.5
warfarin therapy, the INR should be closely monitored in the 2-week Additional period, Interactions: particularly Diltiazem: at 7 to 10 days, In a study following
10 patients Serum with creatinine mild to moderate increased: hypertension, 3.7, 4.3 intravenous
initiation of the 3-day regimen of EMEND with each chemotherapy infusion cycle, of 100 or following mg of fosaprepitant administration with of a diltiazem single 120 mg 3 times daily resulted in a 1.5-fold increase of
AST increased: 3.0, 1.3
Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
40-mg dose of EMEND for prevention of postoperative nausea aprepitant and vomiting AUC [see and Drug a 1.4-fold Interactions]. increase in diltiazem AUC. It also resulted in a small but clinically meaningful
All rights reserved. ONCO-1029338-0022 10/12
further maximum decrease in diastolic blood pressure (mean
The
[SD]
following
of 24.3
additional
[±10.2]
laboratory
mmHg with
adverse
fosaprepitant
experiences
vs
(incidence >0.5% and greater than standard therapy),
Coadministration With Hormonal Contraceptives: Upon coadministration with EMEND, the efficacy of hormonal
15.6 [±4.1] mmHg without fosaprepitant) and resulted in a
regardless
small further
of causality,
maximum
were
decrease
reported
in systolic
in patients
blood
treated with the aprepitant regimen: alkaline phosphatase
contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or backup
increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia.
methods of contraception should be used during treatment with pressure EMEND (mean and for [SD] 1 month of 29.5 following [±7.9] mmHg the last with dose fosaprepitant of vs 23.8 [±4.8] mmHg without fosaprepitant),
EMEND [see Drug Interactions].
which may be clinically meaningful, but did not result in a clinically The adverse-experience meaningful further profiles change in the in Multiple-Cycle heart rate or extensions of HEC and MEC studies for up to 6 cycles of
PR interval beyond those changes induced by diltiazem alone. chemotherapy were generally similar to that observed in Cycle 1.
Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe
hepatic impairment (Child-Pugh score >9). Therefore, caution In should the same be exercised study, administration when EMEND of is aprepitant administered once daily as
Postoperative
a tablet formulation
Nausea and
comparable
Vomiting:
to
In
230
well-controlled
mg of the
clinical studies in patients receiving general anesthesia, 564
in these patients.
capsule formulation, with diltiazem 120 mg 3 times daily for
patients
5 days,
were
resulted
administered
in a 2-fold
40-mg
increase
aprepitant
of aprepitant
orally and 538 patients were administered 4-mg ondansetron IV.
Chronic Continuous Use: Chronic continuous use of EMEND AUC for prevention and a simultaneous of nausea 1.7-fold and vomiting increase is not of diltiazem AUC. Clinical These adverse pharmacokinetic experiences effects were did reported not result in approximately in 60% of patients treated with 40-mg aprepitant
recommended because it has not been studied and because clinically the drug interaction meaningful profile changes may in change ECG, heart during rate, or blood pressure compared beyond with approximately those changes 64% induced of patients by diltiazem treated with 4-mg ondansetron IV. Following are the percentage
chronic continuous use.
alone.
of patients receiving general anesthesia with clinical adverse experiences reported at an incidence of ≥3% in the
combined studies for aprepitant 40 mg (n=564) and ondansetron (n=538), respectively:
ADVERSE REACTIONS
Paroxetine: Coadministration of once-daily doses of aprepitant as a tablet formulation comparable to 85 mg
or 170 mg of the capsule formulation, with paroxetine 20 mg
Infections
once daily,
and
resulted
infestations:
in a
urinary
decrease
tract
in
infection:
AUC by approximately
25% and C max by approximately 20% of both aprepitant Blood and and lymphatic paroxetine. system disorders: anemia: 3.0, 4.3
2.3, 3.2
The overall safety of aprepitant was evaluated in approximately 5300 individuals.
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 USE IN trials SPECIFIC of another POPULATIONS drug and may not reflect the rates Psychiatric disorders: insomnia: 2.1, 3.3
observed in clinical practice.
Pregnancy: Teratogenic effects: Pregnancy Category B: In the Nervous reproduction system disorders: studies conducted headache: with 5.0, 6.5
Clinical Trials Experience: Chemotherapy-Induced Nausea and fosaprepitant Vomiting: Highly and aprepitant, Emetogenic the Chemotherapy: highest systemic In 2 exposures Cardiac to aprepitant disorders: were bradycardia: obtained 4.4, following 3.9 oral
well-controlled clinical trials in patients receiving highly emetogenic administration cancer chemotherapy, of aprepitant. 544 Reproduction patients were studies treated performed Vascular in rats disorders: at oral doses hypotension: of aprepitant 5.7, 4.6; of up hypertension: to 2.1, 3.2
with aprepitant during Cycle 1 of chemotherapy and 413 of these 1000 patients mg/kg continued twice daily into (plasma the Multiple-Cycle AUC 0–24hr of extension 31.3 mcg•hr/mL, Gastrointestinal about 1.6 times disorders: the human nausea: exposure 8.5, 8.6; at constipation: the 8.5, 7.6; flatulence: 4.1, 5.8; vomiting 2.5, 3.9
for up to 6 cycles of chemotherapy. EMEND was given in combination recommended with ondansetron dose) and and in rabbits dexamethasone. at oral doses of up to 25 mg/kg/day (plasma AUC 0–24hr of 26.9 mcg•hr/mL,
Skin and subcutaneous tissue disorders: pruritus: 7.6, 8.4
In Cycle 1, clinical adverse experiences were reported in approximately about 1.4 69% times of the patients human treated exposure with at the the aprepitant recommended dose) revealed no evidence of impaired fertility
regimen compared with approximately 68% of patients treated or with harm standard to the fetus therapy. due Following to aprepitant. are the There percentage are, however,
General
no adequate
disorders
and
and
well-controlled
general administration
studies in
site conditions: pyrexia: 5.9, 10.6
of patients receiving highly emetogenic chemotherapy in Cycle pregnant 1 with clinical women. adverse Because experiences animal reproduction reported at an studies are The not following always predictive additional of clinical human adverse response, experiences this drug (incidence >0.5% and greater than ondansetron), regardless
incidence of ≥3% for the aprepitant regimen (n=544) and standard should therapy be used (n=550), during pregnancy respectively: only if clearly needed. of causality, were reported in patients treated with aprepitant:
Body as a whole/Site unspecified: asthenia/fatigue: 17.8, 11.8; Nursing dizziness: Mothers: 6.6, 4.4; Aprepitant dehydration: is excreted 5.9, 5.1; in abdominal the milk of rats. Infections It is not known and infestations: whether this postoperative drug is excreted infection in
pain: 4.6, 3.3; fever: 2.9, 3.5; mucous membrane disorder: 2.6, human 3.1 milk. Because many drugs are excreted in human milk Metabolism and because and nutrition of the potential disorders: for hypokalemia, possible serious hypovolemia
Digestive system: nausea: 12.7, 11.8; constipation: 10.3, 12.2; adverse diarrhea: reactions 10.3, 7.5; in nursing vomiting: infants 7.5, 7.6; from heartburn: aprepitant and because Nervous of system the potential disorders: for dizziness, tumorigenicity hypoesthesia, shown for syncope
5.3, 4.9; gastritis: 4.2, 3.1; epigastric discomfort: 4.0, 3.1 aprepitant in rodent carcinogenicity studies, a decision should Vascular be made disorders: whether hematoma
discontinue nursing or to
Eyes, ears, nose, and throat: tinnitus: 3.7, 3.8
discontinue the drug, taking into account the importance of
Respiratory,
the drug to
thoracic,
the mother.
and mediastinal disorders: dyspnea, hypoxia, respiratory depression
Hemic and lymphatic system: neutropenia: 3.1, 2.9 Pediatric Use: Safety and effectiveness of EMEND for Injection
Gastrointestinal
in pediatric
disorders:
patients have
abdominal
not been
pain,
established.
abdominal pain upper, dry mouth, dyspepsia
Metabolism and nutrition: anorexia: 10.1, 9.5
Geriatric Use: In 2 well-controlled CINV clinical studies, of Skin the total and number subcutaneous of patients tissue (N=544) disorders: treated urticaria
Nervous system: headache: 8.5, 8.7; insomnia: 2.9, 3.1 with oral aprepitant, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or
General disorders and administrative site conditions: hypothermia, pain
Respiratory system: hiccups: 10.8, 5.6
effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older
individuals cannot be ruled out. Dosage adjustment in the elderly
Investigations:
is not necessary.
blood pressure decreased
In addition, isolated cases of serious adverse experiences, regardless of causality, of bradycardia, disorientation, Injury, poisoning, and procedural complications: operative hemorrhage, wound dehiscence
and perforating duodenal ulcer were reported in highly emetogenic Patients CINV With clinical Severe studies. Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with
severe hepatic impairment (Child-Pugh score >9). Therefore, Other caution adverse should experiences be exercised (incidence when ≤0.5%) fosaprepitant reported in patients treated with aprepitant 40 mg for postoperative
Moderately Emetogenic Chemotherapy: During Cycle 1 of 2 moderately emetogenic chemotherapy studies, 868
or aprepitant is administered in these patients. nausea and vomiting included:
patients were treated with the aprepitant regimen and 686 of these patients continued into extensions for up to 4
cycles of chemotherapy. In the combined analysis of Cycle 1 data OVERDOSAGE
Nervous system disorders: dysarthria, sensory disturbance
for these 2 studies, adverse experiences were
reported in approximately 69% of patients treated with the aprepitant There is regimen no specific compared information with approximately on the treatment 72% of overdosage
Eye disorders:
with fosaprepitant
miosis, visual
or aprepitant.
acuity reduced
of patients treated with standard therapy.
Respiratory, thoracic, and mediastinal disorders: wheezing
In the event of overdose, fosaprepitant and/or oral aprepitant should be discontinued and general supportive
In the combined analysis of Cycle 1 data for these 2 studies, the treatment adverse-experience and monitoring profile should in both be provided. moderately Because of the Gastrointestinal antiemetic activity disorders: of aprepitant, bowel sounds drug-induced abnormal, stomach discomfort
emetogenic chemotherapy studies was generally comparable emesis to the highly may not emetogenic be effective. chemotherapy Aprepitant studies. cannot be removed There by hemodialysis. were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical
Following are the percentage of patients receiving moderately emetogenic chemotherapy in Cycle 1 with clinical
Thirteen patients in the randomized controlled trial of EMEND
studies
for Injection
in patients
received
taking
both
40-mg
fosaprepitant
aprepitant.
150 mg
adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=868) and standard therapy
(n=846), respectively:
and at least one dose of oral aprepitant, 125 mg or 80 mg. Laboratory Three patients Adverse reported Experiences: adverse One reactions laboratory that adverse were experience, hemoglobin decreased (40-mg aprepitant
similar to those experienced by the total study population. 3.8%, ondansetron 4.2%), was reported at an incidence ≥3% in a patient receiving general anesthesia.
Blood and lymphatic system disorders: neutropenia: 5.8, 5.6
NONCLINICAL TOXICOLOGY
The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron),
Metabolism and nutrition disorders: anorexia: 6.2, 7.2
regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased,
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in
Psychiatric disorders: insomnia: 2.6, 3.7
blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present.
Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated
Nervous system disorders: headache: 13.2, 14.3; dizziness: 2.8,
with
3.4
The adverse experience of increased ALT occurred with similar incidence in patients treated with aprepitant 40 mg
oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure
Gastrointestinal disorders: constipation: 10.3, 15.5; diarrhea: to 7.6, aprepitant 8.7; dyspepsia: (plasma 5.8, AUC3.8; 0–24hr) nausea: of 0.7 5.8, to 1.65.1;
(1.1%) as in patients treated with ondansetron 4 mg (1.0%).
times the human exposure (AUC 0–24hr=19.6 mcg•hr/mL) at the
stomatitis: 3.1, 2.7
recommended dose of 125 mg/day. Treatment with aprepitant Other at Studies: doses of In 5 addition, to 1000 2 mg/kg serious twice adverse daily experiences caused were reported in postoperative nausea and vomiting
Skin and subcutaneous tissue disorders: alopecia: 12.4, 11.9 an increase in the incidences of thyroid follicular cell adenomas (PONV) and clinical carcinomas studies in in male patients rats. taking In female a higher rats, dose it of aprepitant: 1 case of constipation, and 1 case of subileus.
produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid
follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals

For appropriate patients receiving highly emetogenic chemotherapy who are at risk of chemotherapy-induced nausea and vomiting (CINV)
PREVENTION BEGINS WHERE
TRIPLE THERAPY STARTS
On Cycle 1, Day 1, start with Triple Therapy—EMEND ®
(fosaprepitant dimeglumine) for Injection, a 5-HT 3 antagonist,
and a corticosteroid—for first-line prevention of CINV.
EMEND for Injection, in combination with other antiemetic agents,
is indicated in adults for prevention of acute and delayed nausea
and vomiting associated with initial and repeat courses of highly
emetogenic cancer chemotherapy, including high-dose cisplatin.
EMEND for Injection has not been studied for treatment of
established nausea and vomiting. Chronic continuous administration
of EMEND for Injection is not recommended.
Selected Important Safety Information
• EMEND for Injection is contraindicated in patients who are
hypersensitive to EMEND for Injection, aprepitant, polysorbate 80,
or any other components of the product. Known hypersensitivity
reactions include flushing, erythema, dyspnea, and anaphylactic
reactions.
• Aprepitant, when administered orally, is a moderate cytochrome
P450 isoenzyme 3A4 (CYP3A4) inhibitor. Because fosaprepitant
is rapidly converted to aprepitant, neither drug should be used
concurrently with pimozide or cisapride. Inhibition of CYP3A4 by
aprepitant could result in elevated plasma concentrations of these
drugs, potentially causing serious or life-threatening reactions.
• EMEND for Injection should be used with caution in patients
receiving concomitant medications, including chemotherapy
agents, that are primarily metabolized through CYP3A4. Inhibition
of CYP3A4 by EMEND for Injection could result in elevated plasma
concentrations of these concomitant medications. Conversely,
when EMEND for Injection is used concomitantly with another
CYP3A4 inhibitor, aprepitant plasma concentrations could be
elevated. When EMEND for Injection is used concomitantly with
medications that induce CYP3A4 activity, aprepitant plasma
concentrations could be reduced, and this may result in decreased
efficacy of aprepitant.
• Chemotherapy agents that are known to be metabolized by
CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan,
ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine.
In clinical studies, EMEND ® (aprepitant) was administered
commonly with etoposide, vinorelbine, or paclitaxel. The doses
of these agents were not adjusted to account for potential drug
interactions. In separate pharmacokinetic studies, EMEND did not
influence the pharmacokinetics of docetaxel or vinorelbine.
• Because a small number of patients in clinical studies received the
CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular
caution and careful monitoring are advised in patients receiving
these agents or other chemotherapy agents metabolized primarily
by CYP3A4 that were not studied.
Selected Important Safety Information
(continued)
• There have been isolated reports of immediate hypersensitivity
reactions including flushing, erythema, dyspnea, and anaphylaxis
during infusion of fosaprepitant. These hypersensitivity reactions
have generally responded to discontinuation of the infusion and
administration of appropriate therapy. It is not recommended to
reinitiate the infusion in patients who have experienced these
symptoms during first-time use.
• Coadministration of EMEND for Injection with warfarin (a
CYP2C9 substrate) may result in a clinically significant decrease
in international normalized ratio (INR) of prothrombin time.
In patients on chronic warfarin therapy, the INR should be
closely monitored in the 2-week period, particularly at 7 to
10 days, following initiation of EMEND for Injection with each
chemotherapy cycle.
• The efficacy of hormonal contraceptives may be reduced
during coadministration with and for 28 days after the last
dose of EMEND for Injection. Alternative or backup methods
of contraception should be used during treatment with and
for 1 month after the last dose of EMEND for Injection.
• Chronic continuous use of EMEND for Injection for prevention
of nausea and vomiting is not recommended because it has
not been studied and because the drug interaction profile
may change during chronic continuous use.
• In clinical trials of EMEND ® (aprepitant) in patients receiving
highly emetogenic chemotherapy, the most common adverse
events reported at a frequency greater than with standard
therapy, and at an incidence of 1% or greater were hiccups
(4.6% EMEND vs 2.9% standard therapy), asthenia/fatigue
(2.9% vs 1.6%), increased ALT (2.8% vs 1.5%), increased AST
(1.1% vs 0.9%), constipation (2.2% vs 2.0%), dyspepsia (1.5%
vs 0.7%), diarrhea (1.1% vs 0.9%), headache (2.2% vs 1.8%),
and anorexia (2.0% vs 0.5%).
• In a clinical trial evaluating safety of the 1-day regimen of
EMEND for Injection 150 mg compared with the 3-day regimen
of EMEND, the safety profile was generally similar to that seen
in prior highly emetogenic chemotherapy studies with aprepitant.
However, infusion-site reactions occurred at a higher incidence
in patients who received fosaprepitant (3.0%) than in those who
received aprepitant (0.5%). Those infusion-site reactions included
infusion-site erythema, infusion-site pruritus, infusion-site pain,
infusion-site induration, and infusion-site thrombophlebitis.
Please see the adjacent Brief Summary of the Prescribing
Information.
An antiemetic regimen including
Merck Oncology
Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved. ONCO-1029338-0022 10/12
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