ASH Clinical News February 2016 | Page 40

Written in Blood

• rs1998081 on chromosome
20 (OR=2.28; 95% CI 1.6-3.1;
p=5.17x10-7)
• rs62322307 on chromosome
4 (OR=2.79; 95% CI 1.8-4.3;
p=2.25x10-7)
“These risk alleles were found either
almost exclusively or in higher frequency
among populations of African descent,”
wrote Dr. Hernandez and co-authors.

The subsequent replication study
confirmed a significant association with
increased risk of VTE for rs2144940 and
rs1998081, while rs2144940 and rs1998081
reached genome-wide significance.
These risk variants were found in higher
frequency among populations of African
descent (>20%) compared with other
ethnic groups (<10%). “Together, these
data support the association of rs2144940,
rs2567617, and rs1998081 with increased

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR
GRANIX® (tbo-filgrastim) injection, for subcutaneous use
SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a
clinically significant incidence of febrile neutropenia.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Splenic Rupture
Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder
pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or
splenic rupture.
5.2
Acute Respiratory Distress Syndrome (ARDS)
Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates
or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients
with ARDS.
5.3
Allergic Reactions
Serious allergic reactions including anaphylaxis can occur in patients receiving human
granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The
administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may
reduce the severity of the reactions. Permanently discontinue GRANIX in patients with
serious allergic reactions. Do not administer GRANIX to patients with a history of serious
allergic reactions to filgrastim or pegfilgrastim.
5.4
Use in Patients with Sickle Cell Disease
Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease
receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients
with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.
5.5
Capillary Leak Syndrome
Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and
hemoconcent ration. Episodes vary in frequency, severity and may be life-threatening if
treatment is delayed. Patients who develop symptoms of capillary leak syndrome should
be closely monitored and receive standard symptomatic treatment, which may include a
need for intensive care.
5.6
Potential for Tumor Growth Stimulatory Effects on Malignant Cells
The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts
has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for
any tumor type, including myeloid malignancies and myelodysplasia, diseases for which
GRANIX is not approved, cannot be excluded.
6
ADVERSE REACTIONS
The following potential serious adverse reactions are discussed in greater detail in other
sections of the labeling:
• Splenic Rupture [see Warnings and Precautions (5.1)]
• Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)]
• Serious Allergic Reactions [see Warnings and Precautions (5.3)]
• Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)]
• Capillary Leak Syndrome [see Warnings and Precautions (5.5)]
• Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and
Precautions (5.6)]
The most common treatment-emergent adverse reaction that occurred at an incidence of
at least 1% or greater in patients treated with GRANIX at the recommended dose and was
numerically two times more frequent than in the placebo group was bone pain.
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 clinical practice.
GRANIX clinical trials safety data are based upon the results of three randomized clinical
trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung
cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of
patients were female, the median age was 50 years, and 86% of patients were Caucasian.
In the lung cancer study, 80% of patients were male, the median age was 58 years, and
95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients
were male, the median age was 55 years, and 88% of patients were Caucasian. In all three
studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim
product were administered at 5 mcg/kg subcutaneously once daily beginning one day
after chemotherapy for at least five days and continued to a maximum of 14 days or until
an ANC of ≥10,000 x 106/L after nadir was reached.

risk of VTE among African Americans,”
the authors concluded.
“Our newly discovered SNPs are common in African Americans, with one in
three carrying at least one copy, and African Americans who carry this mutation
have double the risk of VTE,” Dr. Perera
told ASH Clinical News.
“We able to find a strong genetic
predictor, and we were able to assign a
function that makes biologic sense,” she

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at
least 1% or greater in patients treated with GRANIX at the recommended dose and was
numerically two times more frequent than in the placebo group. The overall incidence of
bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product).
Leukocytosis
In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than
1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.
Additional Adverse Reactions
Other adverse reactions known to occur following administration of human granulocyte
colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute
febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia.
6.2
Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of
antibody development in patients receiving GRANIX has not been adequately determined.
7
DRUG INTERACTIONS
No formal drug interaction studies between GRANIX and other drugs have been performed.
Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used
with caution.
Increased hematopoietic activity of the bone marrow in response to growth factor therapy
has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies of GRANIX in pregnant women. In
animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in
increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
Animal Data
In an embryofetal developmental study, pregnant rabbits were administered subcutaneous
doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day.
Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day.
This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean
live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and
cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of
approximately 50-90 times the exposures observed in patients treated with the clinical
tbo-filgrastim dose of 5 mcg/kg/day.
8.3
Nursing Mothers
It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when GRAN IX is administered to
a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk
and G-CSF is not orally absorbed by neonates.
8.4
Pediatric Use
The safety and effectiveness of GRANIX in pediatric patients have not been established.
8.5
Geriatric Use
Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients
were 65 years of age and older. No overall differences in safety or effectiveness were
observed between patients age 65 and older and younger patients.
8.6
Renal Impairment
The safety and efficacy of GRANIX have not been studied in patients with moderate or
severe renal impairment. No dose adjustment is recommended for patients with mild
renal impairment.
8.7
Hepatic Impairment
The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.
10
OVERDOSAGE
No case of overdose has been reported.
©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd.
All rights reserved.
GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd.
Manufactured by:
Distributed by:
Sicor Biotech UAB
Teva Pharmaceuticals USA, Inc.
Vilnius, Lithuania
North Wales, PA 19454
U.S. License No. 1803
Product of Israel
GRX-40580 January 2015
This brief summary is based on TBO-004 GRANIX full Prescribing Information.

added. Using bioinformatics analysis,
Dr. Perera and colleagues found that
these SNPs are associated with decreased
thrombomodulin (THBD) gene expression – a regulator of the coagulation
pathway in humans that inhibits clot
formation – suggesting a mechanistic
link between these genetic variants and
increased VTE risk.
Though the study is limited by its
small sample size, Dr. Perera noted that
these results “have implications for
personalized medicine. We need
more discovery research in African
Americans if they are to benefit from
personalized medicine, as well.”
“This is the first study of its
kind, so we need to follow up this
work with a study to see if using
this genotype can improve outcomes,” she added. ●
REFERENCE
Hernandez W, Gamazon ER, Smithberger E, et al. Novel
genetic predictors of venous thromboembolism risk in African
Americans. Blood. 2016. [Epub ahead of print]

E-Consultations:

What Is the Value in
Hematologic Care?

Electronic consultation (e-Consult),
in which a consultant provides medical recommendations by reviewing
a patient’s electronic medical record
(EMR), offers an alternative to
face-to-face health care – potentially
improving the timeliness of care,
decreasing costs, preventing unnecessary medical visits, and addressing
a shortage of specialists. Though
e-Consult has been implemented in
the radiology and pathology settings
and is being used more broadly in
internal medicine, no data have been
published regarding the effectiveness
of e-Consults in hematology.
In a recent letter to the editor
published in Blood, Michael Cecchini, MD, from the Department of
Medical Oncology at Yale School of
Medicine, and colleagues reported
on the use of a hematology e-Consult
program in the Veterans Affairs
(VA) Connecticut Healthcare System
(VACT).
The VACT initiated hematology eConsults in 2011 as part of a national
initiative to improve access to care; in
the program, referring providers are
given the choice between an e-Consult
and a face-to-face clinic visit.
Dr. Cecchini and colleagues
analyzed data from patient EMRs
collected from 2009 through 2013.
“The majority of referrals to our
service come from primary-care

February 2016