ASH Clinical News May 2016 | Page 70

CMS Expands Coverage

Another obstacle to acquiring data about
alloHCT in these diseases is their rarity. For instance,
myelofibrosis has an incidence rate ranging from 0.1
per 100,000 per year to 1 per 100,000 per year.2
As Ms. Farnia mentioned, though, the science
has advanced, and studies have demonstrated
the efficacy of alloHCT for myelofibrosis in older
patients, including a retrospective registry analysis
of 289 patients (age range = 18-73 years) that found
a long-term relapse-free survival in one-third of
patients who received a transplant.3,4

Dr. Michaelis was part of a group that facilitated some changes to the NCD when it was still
in the planning stages. In an early version of the
NCD, there was a requirement that Medicareeligible patients with myelofibrosis undergoing
“As a result, fewer transplants have been performed
alloHCT be matched to non-transplant control
in this Medicare population for these disease
patients.
states,” Ms. Farnia said. “But that changed over
“As myelofibrosis specialists, we had some contime; the science has come along to support
cerns about that. [CMS] wanted a scenario where
allogeneic transplant in this patient population,
patients would be transplanted and non-transplantand that’s taken some time to work through the
ed simultaneously,” Dr. Michaelis said. “So, a group
CMS [NCD] process.”
of us who specialize in myelofibrosis
– 22 in total – sent a letter to the
CMS Coverage and Analysis Group
asking that they not require concurrent non-transplant controls. We felt
that patients seeking transplant were
seeking any and all curative options
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
for their illness; it was unlikely that
numerically two times more frequent than in the placebo group. The overall incidence of
BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR
they would be willing to move into a
bone
pain
in
Cycle
1
of
treatment
was
3.4%
(3.4%
GRANIX,
1.4%
placebo,
7.5%
non-USGRANIX® (tbo-filgrastim) injection, for subcutaneous use
approved filgrastim product).
non-transplant control group.”
SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
Leukocytosis
Additionally, people who are in6
1
INDICATIONS AND USAGE
In clinical studies, leukocytosis (WBC counts > 100,000 x 10 /L) was observed in less than
GRANIX is indicated to reduce the duration of severe neutropenia in patients with noneligible for alloHCT are “inherently
1% patients with non-myeloid malignancies receiving GRANIX. No complications attributmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a able to leukocytosis were reported in clinical studies.
poor controls and wouldn’t serve as
clinically significant incidence of febrile neutropenia.
Additional Adverse Reactions
a good comparative group,” she said.
4
CONTRAINDICATIONS
Other adverse reactions known to occur following administration of human granulocyte
None.
colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute
In the final NCD, controls are still
febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia.
5
WARNINGS AND PRECAUTIONS
required in the form of data on non6.2
Immunogenicity
5.1
Splenic Rupture
As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of
transplant myelofibrosis patients, but
Splenic rupture, including fatal cases, can occur following administration of human granantibody development in patients receiving GRANIX has not been adequately determined.
ulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder
the information does not have to be
pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or 7
DRUG INTERACTIONS
gathered concurrently.
splenic rupture.
No formal drug interaction studies between GRANIX and other drugs have been per5.2
Acute Respiratory Distress Syndrome (ARDS)
formed.
This is one example of how the
Acute respiratory distress syndrome (ARDS) can occur in patients receiving human gran- Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used
transplant community and advocacy
ulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates with caution.
or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients
Increased hematopoietic activity of the bone marrow in response to growth factor therapy
groups are working with CMS to
with ARDS.
has been associated with transient positive bone imaging changes. This should be considfine-tune the NCD – and an example
5.3
Allergic Reactions
ered when interpreting bone-imaging results.
of how those groups will continue to
Serious allergic reactions including anaphylaxis can occur in patients receiving human 8
USE IN SPECIFIC POPULATIONS
granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The
8.1
Pregnancy
collaborate.
administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may
Pregnancy Category C
“We are very confident that we
reduce the severity of the reactions. Permanently discontinue GRANIX in patients with Risk Summary
serious allergic reactions. Do not administer GRANIX to patients with a history of serious There are no adequate and well-controlled studies of GRANIX in pregnant women. In
will be able to work with CMS and
allergic reactions to filgrastim or pegfilgrastim.
animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in
address their concerns,” said Linda
5.4
Use in Patients with Sickle Cell Disease
increased spontaneous abortion and fetal malformations at systemic exposures substanSevere and sometimes fatal sickle cell crises can occur in patients with sickle cell disease tially higher than the human exposure. GRANIX should be used during pregnancy only if
Burns, MD, vice president and
receiving human granulocyte colony-stimulating factors. Consider the potential risks and ben- the potential benefit justifies the potential risk to the fetus.
medical director of Health Services
efits prior to the administration of human granulocyte colony-stimulating factors in patients Animal Data
Research at NMDP/Be The Match.
with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.
In an embryofetal developmental study, pregnant rabbits were administered subcutaneous
5.5
Capillary Leak Syndrome
doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day.
To that end, the Center for InterCapillary leak syndrome (CLS) can occur in patients receiving human granulocyte colony- Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day.
national Blood and Marrow Transstimulating factors and is characterized by hypotension, hypoalbuminemia, edema and This dose was maternally toxic as demonstrated by reduced body weight. Other embryhemoconcentration. Episodes vary in frequency, severity and may be life-threatening if
ofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean
plant Research (CIBMTR), on whose
treatment is delayed. Patients who develop symptoms of capillary leak syndrome should
live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and
executive committee Dr. Burns also
be closely monitored and receive standard symptomatic treatment, which may include a
cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of
need for intensive care.
serves, has designated a faculty to
approximately 50-90 times the exposures observed in patients treated with the clinical
5.6
Potential for Tumor Growth Stimulatory Effects on Malignant Cells
tbo-filgrastim dose of 5 mcg/kg/day.
develop the protocols to “get these
The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts 8.3
Nursing Mothers
trials up and running as soon as
has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for
It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs
any tumor type, including myeloid malignancies and myelodysplasia, diseases for which are excreted in human milk, caution should be exercised when GRANIX is administered to
possible, certainly in less than a year.
GRANIX is not approved, cannot be excluded.
a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk
We recognize that we need to do this
6
ADVERSE REACTIONS
and G-CSF is not orally absorbed by neonates.
The following potential serious adverse reactions are discussed in greater detail in other 8.4
Pediatric Use
quickly, but also appropriately.”
sections of the labeling:
The safety and effectiveness of GRANIX in pediatric patients have not been established.
Dr. Horowitz noted that w hen
• Splenic Rupture [see Warnings and Precautions (5.1)]
8.5
Geriatric Use
the MDS study launched in 2010, the
• Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)]
Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients
• Serious Allergic Reactions [see Warnings and Precautions (5.3)]
were 65 years of age and older. No overall differences in safety or effectiveness were
expectation was that the study would
• Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)]
observed between patients age 65 and older and younger patients.
take time just for patient accrual, but
• Capillary Leak Syndrome [see Warnings and Precautions (5.5)]
8.6
Renal Impairment
• Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and
The safety and efficacy of GRANIX have not been studied in patients with moderate or
that wasn’t the case. Now, more than
Precautions (5.6)]
severe renal impairment. No dose adjustment is recommended for patients with mild
1,200 patients have been enrolled.
The most common treatment-emergent adverse reaction that occurred at an incidence of
renal impairment.
at least 1% or greater in patients treated with GRANIX at the recommended dose and was 8.7
Hepatic Impairment
“Clearly, there was an undernumerically two times more frequent than in the placebo group was bone pain.
The safety and efficacy of GRANIX have not been studied in patients with hepatic impairserved
population for allogenic
6.1
Clinical Trials Experience
ment.
transplant,” she said, suggesting that
Because clinical trials are conducted under widely varying conditions, adverse reaction
10
OVERDOSAGE
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
No case of overdose has been reported.
the same kind of rapid enrollment is
clinical trials of another drug and may not reflect the rates observed in clinical practice.
possible with the current CED.
GRANIX clinical trials safety data are based upon the results of three randomized clinical
• Assess what treatment facility characteristics
predicts meaningful clinical improvement in
outcomes.

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.

©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.

The CED Paradigm

However challenging the CED
may seem, organizations such as
the CIBMTR already prospectively
collect data on all alloHCT recipients in the United States, and the
existing data collection and analysis

May 2016