1. No category

VOL. 9 NO. 5 MAY 2015
Microbiome may
drive the course of
diabetes, obesity
I N S I D E
Bacterial balance may afect metabolism.
News from the AGA
BY MICHELE G.
Fairbanks s chool
oF
Public h ealth
at
iuPu
®
Dr. Hongmei Nan and colleagues found that aspirin/NSAIDs’
protection against colon cancer is based on 3 polymorphisms.
NSAIDs’ ca protection
tied to gene variations
BY MARY ANN MOON
Frontline Medical News
T
he well-documented
protective efect that
aspirin and nonsteroidal
anti-infammatory drugs exert against colon cancer has
been linked to three genetic
variations at chromosome 12
and 15, according to a report
published online in JAMA.
In a genome-wide investigation of the interrelationship between genetic
markers and the regular use
of aspirin/NSAIDs, researchers found that the drugs
were diferentially associated
with colorectal cancer risk
according to variations at
single-nucleotide polymor-
phisms (SNPs) on chromosome 12p12.3 (rs2965667 and
rs10505806) and chromosome 15q25.2 (rs16973225).
These fndings “can help
to identify population subgroups defned by genetic
background that may preferentially beneft from chemopreventive use of these
agents and ofer novel insights into underlying mechanisms of carcinogenesis,”
said Dr. Hongmei Nan of
the department of epidemiology at Indiana University
and the Bren Simon Cancer
Center, both in Indianapolis,
and her associates.
To obtain a large population for the genome-wide
See Colon cancer · page 24
SULLIVAN
Frontline Medical News
E
merging research suggests that the complex
microbial gut communities – which interact
fuidly not only with their
human host, but also with
each other – play important
roles in health and disease.
They appear to confer both
protection from and risk for
many chronic illnesses, from
asthma and allergies to obesity and diabetes.
And what we don’t know
about them dwarfs what we
do know, said Dr. Robert Ratner, the chief medical ofcer
of the American Diabetes
Association, at the annual advanced postgraduate course
held by the ADA.
The microbiome is as individual as every person who
carries it. The diferences are
myriad, in the amount and
variety of species, and in the
sheer numbers of microbes
that make up each community. Each region of the
gut, from mouth to rectum,
hosts a completely diferent
population.
Two main phyla populate the gut: Bacteroidetes, which are involved in
protein and carbohydrate
breakdown, and Firmicutes, which promote the
absorption of fat. The ratios
See Microbiome · page 30
News
Stage 3
meaningful use
CMS says all should be
ready by 2018. • 4
Strategic Plan
2015-2020
Dr. John I. Allen outlines
a vision for AGA’s
future. • 17
Liver Diseases
Are the new HCV
drugs cost
effective?
Two complex studies
examine the issue. • 18
IBD and Intestinal
Disorders
Stem cells for
Crohn’s fstula
Long-term relief reported
in small study. • 30
SGR repeal refocuses CMS on value
BY GREGORY
TWACHTMAN
Frontline Medical News
I
t’s value over volume for
Medicare now that the
Medicare Access and CHIP
Reauthorization Act of 2015
is law.
“AGA is pleased that the
SGR repeal has fnally happened and puts physicians
on a pathway toward value-based care,” said Dr. John
I. Allen, MBA, AGAF, president, AGA Institute. “AGA
will continue to work with
Medicare and private payers
on developing bundled payment models and other alternative payment models that
demonstrate the value of GI
services that we provide.”
“There are a lot of evolv-
ing issues to take care of
in this migration toward
models of payment delivery
that work positively toward
impacting quality of care,”
Dr. James Madara, CEO of
the American Medical Association, said April 15, the
day after the Senate passed
H.R. 2, the Medicare Access
and CHIP Reauthorization
See SGR repeal · page 41
2015 JAMES W. FRESTON CONFERENCE
A RENAISSANCE IN THE UNDERSTANDING
AND MANAGEMENT OF IBS
AUG. 29 & 30, 2015 • CHICAGO, IL
Learn what advances in IBS can help improve care
for your patients at www.gastro.org/frestonibs.
Funded by the Takeda Endowment in support of the James W. Freston Single Topic Conference.
125-134EDU_15-1
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NEWS
2
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
CLINICAL CHALLENGES AND IMAGES
What’s your diagnosis?
A
70-year-old man presented to
the emergency department because of abdominal pain with
vomiting for 1 day. The patient had
a past history of peptic ulcer disease
and underwent subtotal gastrectomy
> 20 years ago; he was afebrile and
his blood pressure was 181/110 mm
Hg. He reported no bloody or tarry
stool in recent days.
However, after nasogastric tube
The patient had a past history
of peptic ulcer disease
and underwent subtotal
gastrectomy > 20 years ago.
decompression, some cofee-ground
material was observed. Physical
examination showed a midline scar
at the epigastric region. Severe tenderness and distention of the upper
abdomen with hyperactive bowel
sounds were noted. The laboratory
values of liver functions and lipase
were within normal limits, but there
was leukocytosis with a white blood
count of 11,440/mcL. His hemoglobin was 13 g/dL (normal, 13-17).
Computed tomography (CT) was
then carried out (Figure A).
AGA InstItute
By Dr. Shih-Ming Huang, Dr. ShihWen Chang, and Dr. Yeu-Sheng Tyan.
Published previously in Gastroenterology
(2012;143;29, 272, 273).
The diagnosis appears on page 40.
U.S. experiencing drug-resistant shigellosis outbreak
BY DEEPAK CHITNIS
Frontline Medical News
T
he United States is currently experiencing an
outbreak of shigellosis caused by a strain of the
Shigella sonnei bacteria that is resistant to ciprofoxacin, the most commonly prescribed antimicrobial
treatment for shigellosis.
In its Morbidity and Mortality Weekly Report,
the Centers for Disease Control and Prevention
revealed that 243 individuals in 32 states and the
territory of Puerto Rico have come down with
shigellosis between May 2014 and February 2015.
Of those 243 cases, 126 isolates were tested and
109 (87%) of those were found to be nonsusceptible to ciprofoxacin. The largest clusters of the
disease were found in Massachusetts (45 cases),
in ChiEf
Colin W. Howden, M.D., AGAF
Editor
AssoCiAtE Editors
Joel V. Brill, M.D., AGAF
Barbara H. Jung, M.D.
Bryson Katona, M.D., Ph.D.
John A. Martin, M.D.
Kevin D. Mullen, M.D., FRCPI
David T. Rubin, M.D., AGAF
Editor EmEritus Charles J. Lightdale, M.D., AGAF
AGA institutE stAff
Managing Editor Brook A. Simpson
Special Content Editor Lindsey M. Brounstein
Publications Coordinator Jillian L. Schweitzer
Vice President of Publications Erin C. Dubnansky
offiCErs
of thE AGA institutE
President John I. Allen, M.D., MBA, AGAF
President-Elect Michael Camilleri, M.D., AGAF
Vice President Timothy C. Wang, M.D., AGAF
Secretary/Treasurer Francis M. Giardiello, M.D., AGAF
AGA Research Foundation Chair Martin Brotman, M.D., AGAF
Past President Anil K. Rustgi, M.D., AGAF
©2015 by the AGA Institute. All rights reserved. No part of
this publication may be reproduced or transmitted in any
form or by any means, electronic or mechanical, including
photocopy, recording, or any information storage and retrieval
system, without permission in writing from the publisher.
California (25 cases), and Pennsylvania (18 cases).
Ninety-fve of the cases associated with the current outbreak were traced back to the homeless
population of San Francisco; about half of the
remaining cases were attributed to international
travelers – specifcally, those visiting the Dominican Republic and India – who contracted the bacteria while abroad and unknowingly brought it to
the United States. The disease is known to spread
quickly in populations of children who attend
child care facilities, homeless individuals, and men
who have sex with men.
“These outbreaks show a troubling trend in Shigella infections in the United States,” Dr. Thomas Frieden, CDC director, said in a statement.
“Drug-resistant infections are harder to treat and
because Shigella spreads so easily between people,
Gi & hEpAtoloGy nEws is the offcial newspaper of the American Gastroenterological
Association (AGA) Institute and provides the gastroenterologist with timely and
relevant news and commentary about clinical developments and about the impact
of health care policy. Content for Gi & hEpAtoloGy nEws is developed through a
partnership of the newspaper’s medical board of editors (Editor in Chief and
Associate Editors), Frontline Medical Communications Inc. and the AGA Institute
Staff. “From the AGA” is provided exclusively by the AGA, AGA Institute, and FDHN.
All content is reviewed by the medical board of editors for accuracy, timeliness,
and pertinence. To add clarity and context to important developments in the feld,
select content is reviewed by and commented on by external experts selected by
the board of editors.
The ideas and opinions expressed in Gi & hEpAtoloGy nEws do not necessarily refect
those of the AGA Institute or the Publisher. The AGA Institute and Frontline Medical
Communications Inc. will not assume responsibility for damages, loss, or claims of
any kind arising from or related to the information contained in this publication,
including any claims related to the products, drugs, or services mentioned herein.
Advertisements do not constitute endorsement of products on the part of the AGA
Institute or Frontline Medical Communications Inc.
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the potential for more – and larger – outbreaks is a
real concern. We’re moving quickly to implement
a national strategy to curb antibiotic resistance
because we can’t take for granted that we’ll always
have the drugs we need to fght common infections.”
Shigellosis causes an estimated 500,000 cases of
diarrhea in the United States each year. To help
curb the growing number of shigellosis cases, the
CDC recommends that international travelers
wash their hands meticulously while abroad, and
follow strict dietary precautions, such as eating
hot foods and drinking beverages only from
sealed containers, especially when consuming
water.
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1 MOST PRESCRIBED,
#
BRANDED BOWEL
PREP KIT1
A CLEAN SWEEP
EFFECTIVE RESULTS IN ALL COLON SEGMENTS
>90% no residual stool in all colon segments compared
to Standard 4-Liter Prep2*†‡
· These results were statistically significant in the cecum (P=.010)2*§
· Significantly more subjects in SUPREP® group had no residual
fluid in 4 out of 5 colon segments2*‡
Help meet Gastroenterology Quality Improvement Consortium (GIQuIC) benchmarks for
85% quality cleansing3 with the split-dose efficacy of SUPREP ® Bowel Prep Kit.4
*This clinical trial was not included in the product labeling. †Standard 4-Liter Prep [sulfate-free PEG electrolyte lavage solution]. ‡Based on investigator grading. §Statistically significant difference.
References: 1. IMS Health, NPA Weekly, March 2015. 2. Rex DK, Di Palma JA, Rodriguez R, McGowan J, Cleveland M. A randomized clinical study comparing reduced-volume oral sulfate
solution with standard 4-liter sulfate-free electrolyte lavage solution as preparation for colonoscopy. Gastrointest Endosc. 2010;72(2):328-336. 3. Rex DK, Schoenfeld PS, Cohen J, et al. Quality
indicators for colonoscopy. Gastrointest Endosc. 2015;81(1):31-53. 4. SUPREP Bowel Prep Kit [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2012.
©2015 Braintree Laboratories, Inc.
GIHEP_3.indd 1
16-00590
March 2015
4/14/2015 4:30:57 PM
NEWS
4
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
CMS: Stage 3 meaningful use by 2018
Frontline Medical News
A
ll physicians and hospitals
would need to meet stage 3
meaningful use beginning in
2018, according to a recent proposal
by the Centers for Medicare & Medicaid Services.
In the agency’s Stage 3 proposed
rule, there would be no transition
period from earlier stages for those
just starting or those who were in
an earlier stage. CMS said that this is
“expected to be the fnal stage” and
will incorporate elements of the previous two stages.
That change comes along with the
proposal beginning in 2017 to permanently make the attestation period
a full year, with a few exceptions. A
full-year attestation period was supposed to go into efect for 2015 with
Stage 2, but CMS announced that it
would reduce attestation to a 90-day
period because of low participation.
The fnal year in which participants
in the EHR Incentive Programs can
receive bonus payments for meeting
meaningful use criteria is 2017; pen-
K oKouu /IstocKphoto . com
BY GREGORY TWACHTMAN
IMPORTANT SAFETY INFORMATION
SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common
adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache.
Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. Use caution
when prescribing for patients with a history of seizures, arrhythmias, impaired gag refex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may
affect renal function or electrolytes. Use can cause temporary elevations in uric acid. Uric acid fuctuations in patients with gout may precipitate an acute fare. Administration of osmotic laxative products may produce
mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely
monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to a fnal volume of 16 ounces and ingestion of
additional water as recommended is important to patient tolerance.
BRIEF SUMMARY: Before prescribing, please see full Prescribing Information and Medication Guide for SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution.
INDICATIONS AND USAGE: An osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS: Use is contraindicated in the following
conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. WARNINGS AND PRECAUTIONS:
SUPREP Bowel Prep Kit is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction,
bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired
gag refex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Pre-dose and post-colonoscopy ECG’s
should be considered in patients at increased risk of serious cardiac arrhythmias. Use can cause temporary elevations in uric acid. Uric acid fuctuations in patients with gout may precipitate an acute fare.
Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired
water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be
diluted with water to a fnal volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance. Pregnancy: Pregnancy Category C. Animal reproduction studies have
not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity. Pediatric Use: Safety and effectiveness in pediatric patients has not been established.
Geriatric Use: Of the 375 patients who took SUPREP Bowel Prep Kit in clinical trials, 94 (25%) were 65 years of age or older, while 25 (7%) were 75 years of age or older. No overall differences in safety
or effectiveness of SUPREP Bowel Prep Kit administered as a split-dose (2-day) regimen were observed between geriatric patients and younger patients. DRUG INTERACTIONS: Oral medication
administered within one hour of the start of administration of SUPREP may not be absorbed completely. ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal
distention, abdominal pain, nausea, vomiting and headache. Oral Administration: Split-Dose (Two-Day) Regimen: Early in the evening prior to the colonoscopy: Pour the contents of one bottle
of SUPREP Bowel Prep Kit into the mixing container provided. Fill the container with water to the 16 ounce fll line, and drink the entire amount. Drink two additional containers flled to the 16 ounce line with
water over the next hour. Consume only a light breakfast or have only clear liquids on the day before colonoscopy. Day of Colonoscopy (10 to 12 hours after the evening dose): Pour the
contents of the second SUPREP Bowel Prep Kit into the mixing container provided. Fill the container with water to the 16 ounce fll line, and drink the entire amount. Drink two additional containers flled to the
16 ounce line with water over the next hour. Complete all SUPREP Bowel Prep Kit and required water at least two hours prior to colonoscopy. Consume only clear liquids until after the colonoscopy.
STORAGE: Store at 20°-25°C (68°-77°F). Excursions permitted between 15°-30°C (59°-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185
For additional information, please call 1-800-874-6756 or visit www.suprepkit.com
©2015 Braintree Laboratories, Inc.
16-00590
March 2015
alties for failing to meet criteria have
already begun.
The proposed rule also contains a
number of more stringent requirements. On the patient engagement
front, the proposed rule calls for
25% of patients to access their data,
although it also allows for third-party providers to access a patient’s
account as a means of satisfying the
requirement.
Patient-generated data also are
highlighted, with a proposed requirement that physicians collect information via mobile devices or apps from
15% of their patients.
Under the proposed Stage 3 of
meaningful use, physicians and eligible hospitals must meet two of
three criteria: that more than 50% of
referrals or transitions of care involve
the passing of information by the
referring provider; that more than
40% of transitions or referrals received by a provider seeing a patient
for the frst time include information
imported into that new provider’s
EHR; or that for more than 80% of
those new patients seen in transition or by referral for the frst time,
a clinical reconciliation be done on
the information received during the
health information exchange, including a review of current medications,
medication allergies, and current and
active diagnoses.
The proposed rule is scheduled to
be published in the Federal Register
on March 30; comments will be accepted at www.regulations.gov until
May 29.
[email protected]
Pages 4a—4b u
NEWS
GIHEP NEW S. COM • M AY 2015
5
Mongersen has 55%-65% remission rates in Crohn’s
BY MARY ANN MOON
Frontline Medical News
M
ongersen, an oral SMAD7
antisense oligonucleotide formulated to deliver its active
ingredient primarily into the lumen
of the terminal ileum and right colon,
induced remission rates as high as
55%-65% in a small, brief, manufacturer-sponsored, phase II clinical trial, according to a report published online in
the New England Journal of Medicine.
In Crohn’s disease, gut infammation is characterized by abnormal
reductions in a particular immunosuppressive cytokine caused by increased
levels of SMAD7. Mongersen (formerly GED0301) downregulates SMAD7
using a classic antisense mechanism,
which in turn restores the proper
cytokine function and suppresses
infammation, said Dr. Giovanni Monteleone of the department of systems
medicine, University of Tor Vergata,
Rome, and his associates.
They assessed a 2-week course of
mongersen in 166 adults with active,
moderate to severe Crohn’s disease
who were treated and followed for
PERSPECTIVE
Clinical versus biologic remission
T
he clinical response reported by
Monteleone et al. is impressive,
but it was not confrmed by endoscopic evidence of mucosal healing
and it did not correlate with normalization of biomarkers such as
fecal calprotectin or C-reactive protein. In short, there is a lack of congruence between clinical remission
and biologic remission, an issue that
must be addressed in future studies
of this agent.
Also intriguing was the fnding that clinical response was
maintained for the duration of
follow-up even though mongersen
was only administered for 2 weeks
and is thought not to linger in tissues. This is a stark contrast to the
rapid recurrence of symptoms that
characterizes withdrawal of existing anti-infammatory drugs.
Severine Vermeire, M.D., Ph.D., is in
the department of gastroenterology at
Leuven (Belgium) University Hospital.
She reported receiving grant support
and personal fees from AbbVie, Merck
Sharp & Dohme, Pfzer, Genentech/
Roche, Takeda, and Mundipharma. Dr.
Vermeire made these remarks in an editorial accompanying Dr. Monteleone’s
report (N. Engl. J. Med. 2015 March 19
[doi:10.1056/NEJMe1415053]).
approximately 3 months at 17 medical centers in Italy and Germany. The
study participants were randomly assigned to receive one of three doses
of the agent or a matching placebo
in a double-blind fashion. The study’s
primary endpoint was the percentage of patients in remission at day
15 who remained in remission for at
least 2 more weeks. Remission was
defned as a Crohn’s Disease Activity
Index (CDAI) score of < 150.
Rates of remission were 65% in the
43 participants who received 160 mg
of mongersen, 55% in the 40 who
received 40 mg, 12% in the 41 who
received 10 mg, and 10% in the 42
who received placebo. Thus, remission rates at the two highest doses of
mongersen exceeded those achieved
in other phase II trials for Crohn’s
therapies, which ranged from 16% to
48%, the investigators said (N. Engl.
J. Med. 2015 March 19 [doi:10.1056/
NEJMoa1407250]).
Rates of attaining the secondary
endpoint of “clinical response,” defned as a decrease of 100 or more
points in the CDAI score at day 28,
also were signifcantly higher at the
two highest doses of mongersen –
72% and 58% – than with the lowest
dose (37%) or with placebo (17%).
No safety issues related to mongersen were identifed in this study, but a
2-week course of treatment in such
a small group of patients likely is not
adequate to determine safety. Adverse
events occurred in 65% of the active-treatment groups and 64% of the
placebo group and were mild. The nine
serious adverse events that occurred
were unrelated to study treatment, Dr.
Monteleone and his associates said.
Further study is needed to assess
longer durations of treatment and to
judge the efectiveness of the drug
based on endoscopic analyses of mucosal healing rather than on CDAI
score. It also will be important to determine whether higher doses or longer treatment courses of mongersen
raise the risk of fbrosis, given that the
targeted cytokine plays a profbrogenic role in many organs, they added.
This study was sponsored by Giuliani, under contract to Nogra Pharma. Dr. Monteleone reported ties to
Giuliani, Novo Nordisk, Teva, and others, and holds a patent on the use of
SMAD7 antisense oligonucleotides in
Crohn’s disease. His associates reported fnancial ties to numerous industry
sources.
[email protected]
AGA Resource
Review the AGA IBD Clinical
Service Line to learn more
about managing Crohn’s disease
at www.gastro.org/practice/
clinical-service-line/ibd-clinicalservice-line
New reprocessing instructions for TJF-Q180V duodenoscope
BY ELIZABETH MECHCATIE
Frontline Medical News
O
lympus, the manufacturer of the TJF-Q180V
duodenoscope, has issued new, validated instructions for reprocessing this particular model, as
part of the response to recent reports of a possible
association between multidrug-resistant bacterial
infections and improperly processed duodenoscopes, according to the Food and Drug
Administration.
The new instructions, which replace the
manual reprocessing instructions included
in the original labeling, and validation data
have been reviewed by the FDA as part of
its ongoing review of the device. The agency “recommends that any facilities that are using Olympus’
TJF-Q180V duodenoscope train staf on the new instructions and implement them as soon as possible,”
according to an FDA statement. The instructions
are provided in letters sent by Olympus to health
care and other facilities that use this particular model.
“Key changes” have been made to the procedures for precleaning, manual cleaning, and manu-
al high-level disinfection reprocessing procedures,
the FDA said.
The TJF-Q180 V duodenoscope was the model
used in four patients who had undergone an endoscopic retrograde cholangiopancreatography
(ERCP) procedure between August 2014 and
January 2015 with the same duodenoscope at Cedars-Sinai Medical Center in Los Angeles and had
been infected with carbapenem-resistant Enterobacteriaceae (CRE). This outbreak was
announced by the medical center in early
March in a statement that said the infections
occurred “despite the fact that Cedars-Sinai
meticulously followed the disinfection procedure for duodenoscopes” recommended
in instructions provided by Olympus and the FDA.
In February, the FDA frst announced that the
agency had received reports of multidrug-resistant
bacterial infections in patients who had undergone
ERCP procedures with duodenoscopes, despite
proper cleaning and disinfection of the devices and
that the “complex design of ERCP endoscopes
(also called duodenoscopes) may impede efective
reprocessing.”
In the latest statement, the FDA said it “is closely
monitoring the possible association between reprocessed duodenoscopes and the transmission of
infectious agents,” including multidrug-resistant
bacterial infections caused by CRE. If they are not
properly reprocessed, the statement adds, “residual
body fuids and organic debris may remain in microscopic crevices of the device following an attempted
cleaning and high-level disinfection. If these residual
fuids contain microbial contamination, subsequent
patients may be exposed to serious infections.”
Adverse events associated with duodenoscopes should be
reported to the FDA’s MedWatch Program at 800-3321088 or www.accessdata.fda.gov/scripts/medwatch.
[email protected]
AGA Resource
Read more about AGA’s eforts and recommendations to stop duodenoscope infections
at www.gastro.org/practice/patient-safety/
recommendations-to-stop-duodenoscopeinfections
6
NEWS
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
FROM THE AGA JOURNALS
Oxidized LDL predicted HCV interferon response
BY AMY KARON
Frontline Medical News
O
xidized low-density lipoprotein
prevented hepatitis C virus from
entering liver cells and predicted
interferon response among patients
with chronic HCV infection, researchers reported online in the May issue
of Cellular and Molecular Gastroenterology and Hepatology (2015 March
14 [doi:10.1016/j.jcmgh.2015.03.002]).
“Even as all-oral regimens begin to
reach the market, interferon-based
treatment will continue to be used in
cost-restrained settings. Thus, there
is a need for predictors of who is
likely to respond to interferon and
who will require a more expensive
direct-acting antiviral combination
regimen,” said Dr. Philipp Solbach of
Medizinische Hochschule Hannover
and the German Center for Infection
Research and his associates. Combinations of interferon and viral entry
inhibitors might beneft patients with
chronic HCV infection (CHC), the
investigators added.
Hepatitis C virus spreads between
hepatocytes with the help of several cell surface receptors, including
scavenger receptor class B type 1
(SR-BI). Research has shown that
oxidized low-density lipoprotein (oxLDL) noncompetitively inhibits the
interaction between SR-B1 and HCV.
To further study the role of oxLDL
in CHC pathology, the investigators
used a commercial enzyme-linked
immunosorbent assay test to measure serum levels in 379 patients with
genotype 1 CHC from the INDIV-2
study. Patients in that study received
a pegylated interferon-ribavirin (pegIFN/RBV) combination for 24-72
weeks, depending on baseline viral
load. Dr. Solbach and his associates
also studied the efects of oxLDL on
HCV replication in hepatoma cells.
Average serum oxLDL levels were
signifcantly higher among patients
who achieved SVR on peg-IFN/RBV
than in those who did not (7.1 mU/L
[standard deviation, 3.2] vs. 5.9 mU/L
[SD, 2.6]; P < .001), the researchers
reported. In the multivariate analysis,
oxLDL levels independently predicted
SVR, but were not associated with increased ALT or ferritin levels, both of
which point to liver infammation. Increased serum oxLDL also was linked
to decreased infected cell loss rate,
further supporting the idea that oxLDL helps inhibit cell-to-cell spread of
HCV in chronically infected patients.
Area under the receiver operative
curve (AUROC) values were similar
for LDL and oxLDL, indicating that
one value was a good clinical indicator of the other, the investigators
said. The optimal cutof points to
predict SVR in their model were 8.85
mU/L for oxLDL and 3.6 mmol/L
for LDL.
In the in vitro study, oxLDL did
not afect the sensitivity of HCV
replication to interferon, but strongly
inhibited the spread of HCV between
adjacent hepatocytes, the investigators reported. “We found that oxLDL
but not LDL potently inhibits cellto-cell spread between neighboring
cells,” they noted. “Cell-to-cell spread
is thought to be the dominant route
of new cell infection within the
chronically infected liver.”
Taken together, the fndings suggest that HCV needs to interact with
SR-BI in order to spread between
hepatocytes, that oxLDL can impede
that interaction and thereby limit infection of naive cells, and that oxLDL
D
espite the fact that signifcant
advances in the treatment of
hepatitis C have been made, it is
still a major global health burden.
In order to follow
up on their previous observation
that oxLDL acts as
a hepatitis C virus
(HCV) entry inhibitor by disrupting the interaction
between HCV and
one of its entry
factors, scavenger
receptor type B class I (SR-BI), Dr.
Solbach and his associates analyzed
the oxLDL levels of 379 patients
from the INDIV-2 study chronically
infected with HCV genotype 1.
The authors demonstrated that
baseline oxLDL serum levels were
an independent predictor of a
sustained virologic response in interferon-based treatment regimens
and that LDL is a sufcient surrogate marker.
Clinicians, especially in resource-limited environments, may
take oxLDL or LDL serum levels
into consideration for treatment
is neither an infammatory marker
nor a modulator of interferon response, Dr. Solbach and his associates said. “The slower second-phase
decline of viral load during interferon-based therapy is thought to refect
a declining pool of infected hepatocytes, and the slope of second-phase
decline and even more the estimated
viral kinetic parameter describing
the infected cell loss rate is predictive
of eventual SVR,” they added. “The
decisions, although these predictors are unlikely to broadly afect
treatment decisions in real-world
settings. The signifcance of this
study lies more in
adding to our understanding of the
pathophysiology
of HCV. The data
presented here
indicate that the
observed efect of
oxLDL is possibly
due to an oxLDL-mediated inhibition of HCV cell-to-cell spread.
Taken together with their previous
observation that oxLDL interferes
with the interaction of HCV and its
entry factor SR-BI, the authors provide additional evidence that SR-BI
may be needed for cell-to-cell spread
of HCV and might thereby have
implications for the further development of HCV entry inhibitors.
Dr. Markus von Schaewen and Dr.
Alexander Ploss are in the department
of molecular biology, Princeton University, Princeton, N.J. They had no
conficts of interest.
presence of an agent reducing the
rate at which naive cells get infected
might thus be benefcial.”
The Germany Center for Infection Research partially funded the
study. Five coauthors reported having
served as clinical researchers, consultants, or speakers for MSD/Merck
and Roche. The other authors declared no conficts of interest.
[email protected]
Acid exposure time most useful in pH-impedance testing
BY AMY KARON
Frontline Medical News
P
H-impedance testing best predicted response to
refux treatment when patients were of proton
pump inhibitors, and abnormal acid exposure time
was the single most useful testing parameter, a
prospective study has found.
“Impedance-based refux parameters complement but do not replace acid-based parameters in
predicting symptom outcome from both medical
and surgical antirefux therapy,” wrote Dr. Amit
Patel and his associates at the Washington University at St. Louis School of Medicine. The study ap-
pears in the May issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2014.08.02).
“Because abnormal acid refux time and symptom-refux correlation parameters are detected
more often when testing is performed of therapy,
pH-impedance testing of antisecretory therapy
maximizes prediction of symptomatic outcome
from GERD [gastroesophageal refux disease] therapy,” the researchers wrote.
Clinicians continue to debate the role of
pH-impedance testing in management of GERD,
whether testing should be performed on or of antisecretory therapy, and which testing parameters
are most useful for predicting treatment response,
the investigators noted. Therefore, they followed
187 adults with persistent GERD symptoms who
underwent pH-impedance testing at their center
during a 5-year period. Average age of patients
was 54 years, almost 71% were female, and none
had histopathologic evidence of esophageal motor
disorders. Almost half had been of proton pump
inhibitors for 7 days when tested, and 68% were
managed medically as opposed to surgically.
Global symptom assessment (GSAS) and
dominant symptom intensity (DSI) scores both
improved signifcantly during an average of 40
months of follow-up, the researchers said. After
Continued on following page
NEWS
GIHEP NEW S. COM • M AY 2015
7
FROM THE AGA JOURNALS
Capsule colonoscopy improved, but limitations persist
BY AMY KARON
Frontline Medical News
W
hen compared with conventional colonoscopy, capsule
colonoscopy had a sensitivity
of 88% and a specifcity of 82% for
detecting adenomas of at least 6 mm
in asymptomatic subjects, a multicenter prospective study showed.
But the capsule detected only 29%
of subjects who had sessile serrated
polyps of at least 6 mm, and required
more extensive bowel preparation
than did conventional colonoscopy, Dr.
Douglas K. Rex, AGAF, at Indiana University Hospital in Indianapolis and his
associates reported in the May issue of
Gastroenterology (2015 [doi:10.1053/j.
gastro.2015.01.025]). “Given these
considerations ... colonoscopy remains
the gold standard for the detection of
colorectal polyps,” said the researchers.
“The capsule is a good test for the detection of patients with conventional
adenomas 6 mm or larger in size and
appears to be an appropriate imaging
choice for patients who cannot undergo colonoscopy or had incomplete
colonoscopy.”
Capsule endoscopy is useful for
small-bowel imaging, but adapting the
technology for colorectal studies has
been difcult. A frst-generation capsule detected only 74% of advanced adenomas in one prospective multicenter
trial. Since then, the PillCam COLON
2 capsule has been updated with motion detection, variable frame speed,
and a wider angle view. In smaller studies, it detected up to 89% of subjects
with polyps of at least 6 mm, but its
specifcity was as low as 64%.
To further investigate the technology, researchers at 16 centers in the
United States and Israel compared
the second-generation capsule with
conventional colonoscopy in an average-risk screening population of
884 asymptomatic subjects. Endos-
copists were blinded as to technique,
but performed unblinded follow-up
colonoscopies in subjects who were
positive on capsule but negative on
conventional colonoscopy.
The capsule’s sensitivity was 81%
(95% confdence interval, 77%-84%)
and its specifcity was 93% (91%95%) for detecting subjects who
had polyps of at least 6 mm, the
researchers reported. Sensitivity was
80% (74%-86%) and specifcity was
97% (96%-98%) for detecting subjects
with polyps of at least 10 mm. For
conventional adenomas of at least 6
mm, sensitivity was 88% (82%-93%)
and specifcity was 82% (80%-83%),
I
adenomas,” the researchers reported.
Prior studies of the capsule did not
look for serrated lesions; in the current
study sensitivities were only 29% and
33% for 6-mm and 10-mm lesions, respectively.
The software used to measure
polyps during capsule colonoscopy
had a 40% error range when tested
on balls of known size, the researchers said. Therefore, there is a strict
location-matching rule within the
colon, but a liberal size rule that only
required measurements to fall within
50% of one another to be considered
a match. “Any set of matching rules
for polyps detected by the capsule and
n the United States, colonoscopy is the primary
screening test for colorectal cancer. However, because of issues with colonoscopy uptake, costs, and the
small but fnite risk of complications, the concept of
a relatively noninvasive structural examination of the
colon that can detect colorectal neoplasia is
appealing to both patients and physicians. Although capsule colonoscopy has emerged as
a potential noninvasive tool for examining the
entire colon, there are limited data on its accuracy for detecting conventional adenomas
or sessile serrated polyps, particularly in an
average-risk screening population.
In the May issue of Gastroenterology, Dr.
Rex and colleagues report their results from
a large, multicenter, prospective study evaluating the new second-generation capsule colonoscopy
(PillCam COLON 2, Given Imaging) for detecting
colorectal neoplasia in an average-risk screening population. Using optical colonoscopy as the reference
standard, the capsule colonoscopy performed well for
detecting conventional adenomas 6 mm or larger with
a sensitivity and specifcity of 88% and 82%, respective-
and for adenomas of 10 mm or larger, sensitivity was 92% (82%-97%)
and specifcity was 95% (94%-95%).
“Lesions in the serrated class were
not detected well by the capsule in this
study, compared with conventional
Continued from previous page
the researchers controlled for demographics,
symptoms at presentation, use of proton pump
inhibitors (PPI), and parameters that predicted
treatment response in the univariate analyses,
only abnormal acid exposure time (AET) predicted linear improvement in DSI scores (P =.027),
while abnormal AET (P =.002) and symptom
association probability (P =.026) predicted significant improvements in linear and dichotomous
GSS, they reported. Abnormal AET and being of
PPIs during testing also more than doubled the
ly seen on capsule were not visualized
on regular colonoscopy. “In these
cases, a polyp that should be a true
positive for the capsule was counted as
false,” they added. “Both colonoscopy
and capsule are inferior for localization, compared with CT colonography.
Inaccurate localization by one or both
tests in this study could have reduced
the sensitivity of the capsule.”
The investigators had to exclude 77
patients because of inadequate cleansing and short transit times related to
using sodium phosphate as a boost.
The Food and Drug Administration label for the capsule is expected to refect
those limitations, they added.
ly. In addition, the sensitivity and specifcity of capsule
colonoscopy for conventional adenomas 10 mm or
larger were 92% and 95%, respectively. However, despite the high performance characteristics for detection
of conventional adenomas, the capsule colonoscopy
had limited accuracy for detecting sessile serrated polyps 10 mm or larger, with a sensitivity
of 33%. Furthermore, nearly 10% of the enrolled subjects were excluded from the analysis
due to poor bowel preparation and rapid transit
time.
These issues aside, the Rex study provides
important information about alternative
screening modalities for detection of colorectal
neoplasia, particularly for gastroenterologists
who may be hesitant or unwilling to perform
an optical colonoscopy in high-risk patients with signifcant comorbidities or in patients who had an incomplete colonoscopy.
Dr. Jefrey Lee, MAS, is assistant clinical professor of medicine, division of gastroenterology, University of California,
San Francisco. He has no conficts of interest.
colonoscopy might operate to increase
or decrease the calculated sensitivity of
the capsule incorrectly,” they added.
Also, the adenoma detection rate for
conventional colonoscopy was only
39%, and some polyps that were clear-
odds of at least a 50% improvement in GSS.
In contrast, dichotomous refux exposure time
did not predict response in any of the analyses, said
the investigators. “Established thresholds for the
total number of refux events did not predict linear
or dichotomous global symptom severity improvement,” they added. “Our data therefore suggest that
performing pH-impedance testing of PPI therapy
increases the yield of abnormal AET and symptom-refux association with refux events, facilitating
predicting value for symptom improvement with
both medical and surgical antirefux therapy.”
The researchers could not corroborate patients’
Given Imaging funded the study and
paid consulting or other fees to Dr. Rex
and six coauthors. The other authors reported no relevant conficts of interest.
[email protected]
compliance with antisecretory therapy, assess the
reasons physicians chose medical or surgical management, or evaluate the impact of the placebo effect or other factors unrelated to refux, they said.
The study was partly funded by the National
Institute for Diabetes and Digestive and Kidney
Diseases, the National Institutes of Health, and the
Washington University Department of Medicine
Mentors in Medicine and Clinical Science Training
and Research programs. The authors declared no
relevant conficts of interest.
[email protected]
8
NEWS
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
FROM THE AGA JOURNALS
Cirrhosis mortality has dropped, except with sepsis
BY AMY KARON
Frontline Medical News
ulation’s increasing age and medical
complexity. Hospital mortality rates
were higher for subgroups of cirrhosis
patients with hepatorenal syndrome,
hepatocellular carcinoma, variceal
bleeding, and spontaneous bacterial
peritonitis, but independent mortality
risks for each of these conditions fell
progressively over time.
H
ospital mortality among patients with cirrhosis fell by
41% in the United States between 2002 and 2010, far outpacing
improvements in survival among
inpatients who did not have cirrhosis, researchers reported in the May
issue of Gastroenterology (2015
[doi:10.1053/j.gastro.2015.01.032]).
The drop occurred even though cirrhosis inpatients were older and had
more comorbidities by the end, compared with the beginning of the study,
said Monica Schmidt at the University
of North Carolina Liver Center and
the Gillings School of Global Public
Health in Chapel Hill, N.C., and her
associates.
The fnding was “remarkably consistent across several cirrhosis complications, and [suggested] improving
cirrhosis care that may extend beyond
general improvements in inpatient
care,” the researchers added. “On the
other hand, sepsis had an increasing
mortality risk, suggesting that cirrhotic patients may need a more tailored
approach to sepsis,” they said.
New treatments have emerged
in the past 10-15 years for several
complications of cirrhosis, including
hepatorenal syndrome, variceal bleeding, spontaneous bacterial peritonitis,
ascites, and hepatocellular carcinoma,
Ms. Schmidt and her associates noted.
To study the extent to which these
advances and updated guidelines have
entered hospital practice, they examined 781,515 hospitalizations with a
diagnosis of cirrhosis, and equal numbers of hospitalizations without cirrhosis or with congestive heart failure.
Data were from the National Inpatient
Sample of the Healthcare Cost and
Utilization Project, which includes 46
states and is the single largest all-payer
inpatient database in the country. Cohorts were matched by age, sex, and
year of hospital discharge from 2002
through 2010.
Hospital mortality among cirrhosis
patients dropped by 41% (from 9.1%
to 5.4%) during the 8 years of the
study, compared with declines of 44%
for inpatients with congestive heart
failure and 19% for inpatients without cirrhosis, the investigators said.
Furthermore, the independent risk of
dying in the hospital among cirrhosis
patients declined steadily to 0.50 by
the end of the study (95% confdence
interval, 0.48-0.52), despite the pop-
The person depicted is a model used for
illustrative purposes only.
IMPORTANT SAFETY INFORMATION FOR SIMPONI® (golimumab)
SERIOUS INFECTIONS
Patients treated with SIMPONI® are at increased risk for developing serious infections that may lead
to hospitalization or death. Most patients who developed these infections were taking concomitant
immunosuppressants such as methotrexate or corticosteroids. Discontinue SIMPONI® if a patient
develops a serious infection.
Reported infections with TNF blockers, of which SIMPONI® is a member, include:
• Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with
disseminated or extrapulmonary disease. Patients should be tested for latent TB before SIMPONI®
use and during therapy. Treatment for latent infection should be initiated prior to SIMPONI® use.
NEWS
GIHEP NEW S. COM • M AY 2015
In contrast, cirrhosis inpatients with sepsis were
22% more likely to die in the
hospital in 2010 than in 2002
(relative risk in 2002, 3.6; 95%
CI, 3.3-3.95; RR in 2010, 4.6; 95%
CI, 4.4-4.8), the researchers found.
The increase in mortality risk related to sepsis in 2010 exceeded even
that for hepatorenal syndrome, they
said. The unexpected fnding contradicted a report of declining overall
sepsis-related mortality, which was
based on the same data source
and a similar time period, the
investigators noted. “Cirrhosis patients have particularly
poor hemodynamic reserve,
with wider perturbations in immune
infammatory and compensatory responses that could hinder survival,”
they commented. “The Surviving
UC IS OVERWHELMING
TREATMENT SHOULDN’T BE
The injection experience she wants,
proven e�fcacy she needs1*
Most common adverse reactions are upper respiratory tract infection, nasopharyngitis, and injection-site reactions.
SIMPONI® (golimumab) is indicated in adults with moderately to severely active ulcerative colitis (UC)
for inducing and maintaining clinical response, improving endoscopic appearance of the mucosa during
induction, inducing clinical remission, and achieving and sustaining clinical remission in induction responders
who have demonstrated corticosteroid dependence or who have had an inadequate response to or failed to
tolerate oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine.
For more information, visit www.injectionexperience.com
*The safety and e�fcacy of SIMPONI® in UC were established in a Phase 2/3 induction study and a Phase 3 maintenance study.2,3
• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis,
blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections
may present with disseminated, rather than localized, disease. Consider empiric anti-fungal therapy
in patients at risk for invasive fungal infections who develop severe systemic illness.
• Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.
The risks and benefits of treatment with SIMPONI® should be carefully considered prior to initiating
therapy in patients with chronic or recurrent infection. Do not start SIMPONI® in patients with clinically
important active infections, including localized infections. Closely monitor patients for the development
of signs and symptoms of infection during and a�ter treatment with SIMPONI®, including the possible
development of TB in patients who tested negative for latent TB infection prior to initiating therapy,
who are on treatment for latent TB, or who were previously treated for TB infection.
(CONTINUED ON THE NEXT PAGE)
9
Sepsis campaign may need guidelines
that specifcally target cirrhosis patients.”
The National Institutes of Health
partly funded the study. The authors
reported having no relevant conficts
of interest.
[email protected]
10
NEWS
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
FROM THE AGA JOURNALS
Probiotics showed slight promise in postresection Crohn’s
BY AMY KARON
Frontline Medical News
A
mixture of eight probiotic bacterial strains only somewhat outperformed placebo for preventing
endoscopic recurrence after ileal resection in Crohn’s disease patients, according to a multicenter, randomized trial.
After 90 days of treatment, 9.3%
of patients who received the probiotic mixture (VSL#3) had developed
IMPORTANT SAFETY INFORMATION FOR SIMPONI® (golimumab) (CONTINUED)
Risk of infection may be higher in patients greater than 65 years of age, patients with co-morbid conditions
and/or patients taking concomitant immunosuppressant therapy. Other serious infections observed in patients
treated with SIMPONI® included sepsis, pneumonia, cellulitis, abscess and hepatitis B infection.
MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients
treated with TNF blockers of which SIMPONI® is a member. Approximately half the cases were lymphomas,
including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies,
including rare malignancies usually associated with immunosuppression and malignancies not usually
observed in children or adolescents. Malignancies occurred after a median of 30 months after the frst dose of
therapy. Most of the patients were receiving concomitant immunosuppressants.
In the controlled portions of clinical trials of all TNF-blocking agents including SIMPONI®, more cases of
lymphoma have been observed among patients receiving TNF-blocking treatment compared with control
patients. In the Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA), and Ankylosing Spondylitis (AS) clinical trials,
the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined
SIMPONI® group compared with an incidence of 0 (95% CI: 0, 0.96) in the placebo group. In clinical trials,
the incidence of malignancies other than lymphoma was not increased with exposure to SIMPONI® and
was similar to what would be expected in the general population. In controlled and uncontrolled portions of
the Phase 2/3 studies in ulcerative colitis (UC) with a mean follow-up of approximately 1 year, there were no
cases of lymphoma with SIMPONI®. Cases of acute and chronic leukemia have been reported with postmarketing
TNF-blocker use. The risks and benefts of TNF-blocker therapy should be considered prior to initiating therapy
in patients with a known malignancy or who develop a malignancy.
Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been
reported in patients treated with TNF blockers. These cases have had a very aggressive disease course and have
been fatal. Nearly all reported cases have occurred in patients with Crohn’s disease or UC, and the majority were
in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or
6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. A risk for the development for
HSTCL in patients treated with TNF blockers cannot be excluded.
Melanoma has been reported in patients treated with TNF-blocking agents, including SIMPONI®. Merkel cell
carcinoma has been reported in patients treated with TNF-blocking agents. Periodic skin examination is
recommended for all patients, particularly those with risk factors for skin cancer.
HEPATITIS B REACTIVATION
The use of TNF-blocking agents including SIMPONI® has been associated with reactivation of hepatitis B
virus (HBV) in patients who are chronic hepatitis B carriers. In some instances, HBV reactivation occurring in
conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients
who received concomitant immunosuppressants.
All patients should be tested for HBV infection before initiating TNF-blocker therapy. For patients who test
positive for hepatitis B surface antigen, consult a physician with expertise in the treatment of hepatitis B
before initiating TNF-blocker therapy. Exercise caution when prescribing SIMPONI® for patients identifed as
carriers of HBV and closely monitor for active HBV infection during and following termination of therapy with
SIMPONI®. Discontinue SIMPONI® in patients who develop HBV reactivation, and initiate antiviral therapy
with appropriate supportive treatment. Exercise caution when considering resumption of SIMPONI®, and
monitor patients closely.
HEART FAILURE
Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported. Exercise caution
and monitor patients with heart failure. Discontinue SIMPONI® if new or worsening symptoms of heart
failure appear.
NEWS
GIHEP NEW S. COM • M AY 2015
severe endoscopic recurrence, compared with 15.7% of the placebo
group (P = .19), reported Dr. Richard
Fedorak of the University of Alberta,
Edmonton, and his associates.
The recurrence rate for the placebo group was about two-thirds
lower than what the researchers had
expected based on the sample size
calculation, they noted. But the probiotic blend was linked to signifcant
decreases in colonic mucosal levels
of proinfammatory cytokines, they
reported in the May issue of Clinical
Gastroenterology and Hepatology
(doi:10.1016/j.cgh.2014.10.031).
Probiotics have been tested as a
preventive therapy for Crohn’s disease
because patients with active disease
have less diverse intestinal microbiota,
compared with those with quiescent
disease or healthy controls. Past studies
of single-strain probiotics have shown
them to be no better than placebo for
preventing endoscopic recurrence.
But in one small study, rifampin
followed by VSL#3 outperformed me-
DEMYELINATING DISORDERS
TNF-blocking agents, of which SIMPONI® is a member, have been associated with rare cases of new-onset
or exacerbation of demyelinating disorders, including multiple sclerosis (MS) and Guillain-Barré syndrome.
Cases of central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely
been reported with SIMPONI®. Exercise caution in considering the use of SIMPONI® in patients with these
disorders. Consider discontinuation if these disorders develop.
HEMATOLOGIC CYTOPENIAS
There have been reports of pancytopenia, leukopenia, neutropenia, and thrombocytopenia in patients
receiving SIMPONI® in clinical trials. Additionally, aplastic anemia has been reported in patients receiving
TNF-blocking agents, of which SIMPONI® is a member. Exercise caution when using SIMPONI® in patients
who have or had signifcant cytopenias.
USE WITH OTHER DRUGS
The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious
infections; therefore the use of SIMPONI® in combination with these products is not recommended. Care
should be taken when switching from one biologic to another since overlapping biological activity may further
increase the risk of infection. A higher rate of serious infections has also been observed in RA patients treated
with rituximab who received subsequent treatment with a TNF blocker. The concomitant use of SIMPONI®
with biologics approved to treat RA, PsA, or AS is not recommended because of the possibility of an increased
risk of infection.
VACCINATIONS/THERAPEUTIC INFECTIOUS AGENTS
People receiving SIMPONI® can receive vaccinations, except for live vaccines. Use of live vaccines could result
in clinical infections, including disseminated infections. Administration of live vaccines to infants exposed to
SIMPONI® in utero is not recommended for 6 months following the mother’s last SIMPONI® injection during
pregnancy due to an increased risk of infection. It is recommended that therapeutic infectious agents not be
given concurrently with SIMPONI® due to the possibility of clinical infections, including disseminated infections.
HYPERSENSITIVITY REACTIONS
Serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported with SIMPONI®,
some occurring after the frst dose. If an anaphylactic or other serious allergic reaction occurs, discontinue SIMPONI®
immediately and institute appropriate therapy.
025952-141204
ADVERSE REACTIONS
The most serious adverse reactions were serious infections and malignancies.
Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in
the combined Phase 3 trials through Week 16, occurring in 7% and 6% of patients treated with SIMPONI® as
compared with 6% and 5% of patients in the control group, respectively. The rate of injection-site reactions
was 6% with patients treated with SIMPONI® compared with 2% of patients in the control group.
In the Phase 2/3 trials in UC evaluating SIMPONI®-treated patients, no new adverse drug reactions were
identifed, and the frequency of adverse drug reactions was similar to the safety profle observed in patients
with RA, PsA, and AS.
Please see the Brief Summary of Prescribing Information on the following pages.
References: 1. SIMPONI® (golimumab) Prescribing Information. Janssen Biotech, Inc.
2. Sandborn WJ, Feagan BG, Marano C, et al; PURSUIT-SC Study Group. Subcutaneous
golimumab induces clinical response and remission in patients with moderate-to-severe
ulcerative colitis. Gastroenterology. 2014;146:85-95. 3. Sandborn WJ, Feagan BG, Marano C, et
al; PURSUIT-Maintenance Study Group Subcutaneous golimumab maintains clinical response
in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146:96-109.
© Janssen Biotech, Inc. 2015 03/15 029681-150213
11
salamine at 1 year (Gastroenterology
2000;118:A781), the researchers noted.
“This mixture could confer protective
efects where single-strain or lactobacillus-only formulations had failed,” they
hypothesized.
To test that theory, the investigators
randomized 120 patients with Crohn’s
Continued on following page
12
NEWS
Continued from previous page
disease who had undergone ileal resection to twice-daily VSL#3 or placebo.
Treatment began within 30 days after
surgery and continued for 90 days, after
which all patients received open-label
VSL#3 for another 9 months.
Among patients who had nonsevere
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
endoscopic lesions at day 90, 1-year
rates of severe endoscopic recurrence
were 10% for the early VSL#3 group,
compared with 26.7% for the late
VSL#3 group (P = .09), said the researchers. Likewise, combined rates of
severe recurrence on days 90 and 365
were not signifcantly diferent, they
reported. But the early VSL#3 group
had lower mucosal levels of 13 proinfammatory cytokines than the patients
who received placebo until day 90 (P <
.05). Measures of Crohn’s disease activity and disease-related quality of life
scores were similar for both groups.
“Future larger studies will be needed
to confrm the efect of VSL#3 in prevention of postoperative recurrence.”
Brief Summary of Prescribing Information for SIMPONI® (golimumab)
SIMPONI® Injection, solution for subcutaneous use
See package insert for full Prescribing Information.
WARNING: SERIOUS INFECTIONS AND MALIGNANCY
SERIOUS INFECTIONS
Patients treated with SIMPONI® are at increased risk for developing serious
infections that may lead to hospitalization or death (see Warnings and
Precautions). Most patients who developed these infections were taking
concomitant immunosuppressants such as methotrexate or corticosteroids.
Discontinue SIMPONI if a patient develops a serious infection.
Reported infections with TNF-blockers, of which SIMPONI is a member,
include:
• Active tuberculosis, including reactivation of latent tuberculosis.
Patients with tuberculosis have frequently presented with disseminated
or extrapulmonary disease. Test patients for latent tuberculosis before
SIMPONI use and during therapy. Initiate treatment for latent TB prior to
SIMPONI use.
• Invasive fungal infections including histoplasmosis, coccidioidomycosis,
candidiasis, aspergillosis, blastomycosis and pneumocystosis. Patients
with histoplasmosis or other invasive fungal infections may present
with disseminated, rather than localized, disease. Antigen and antibody
testing for histoplasmosis may be negative in some patients with active
infection. Consider empiric anti-fungal therapy in patients at risk for
invasive fungal infections who develop severe systemic illness.
• Bacterial, viral, and other infections due to opportunistic pathogens,
including Legionella and Listeria.
Consider the risks and benefits of treatment with SIMPONI prior to initiating
therapy in patients with chronic or recurrent infection.
Monitor patients closely for the development of signs and symptoms
of infection during and after treatment with SIMPONI, including the
possible development of tuberculosis in patients who tested negative for
latent tuberculosis infection prior to initiating therapy (see Warnings and
Precautions).
MALIGNANCY
Lymphoma and other malignancies, some fatal, have been reported in
children and adolescent patients treated with TNF blockers, of which
SIMPONI is a member (see Warnings and Precautions).
INDICATIONS AND USAGE: Rheumatoid Arthritis SIMPONI, in combination with
methotrexate, is indicated for the treatment of adult patients with moderately
to severely active rheumatoid arthritis. Psoriatic Arthritis SIMPONI, alone or in
combination with methotrexate, is indicated for the treatment of adult patients
with active psoriatic arthritis. Ankylosing Spondylitis SIMPONI is indicated for
the treatment of adult patients with active ankylosing spondylitis. Ulcerative
Colitis SIMPONI is indicated in adult patients with moderately to severely active
ulcerative colitis who have demonstrated corticosteroid dependence or who
have had an inadequate response to or failed to tolerate oral aminosalicylates,
oral corticosteroids, azathioprine, or 6-mercaptopurine for: • inducing and
maintaining clinical response • improving endoscopic appearance of
the mucosa during induction • inducing clinical remission • achieving and
sustaining clinical remission in induction responders (see Clinical Studies).
CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Serious
Infections Patients treated with SIMPONI are at increased risk for developing
serious infections involving various organ systems and sites that may lead to
hospitalization or death. Opportunistic infections due to bacterial, mycobacterial,
invasive fungal, viral, or parasitic organisms including aspergillosis,
blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis,
listeriosis, pneumocystosis, and tuberculosis have been reported with
TNF-blockers. Patients have frequently presented with disseminated rather than
localized disease. The concomitant use of a TNF-blocker and abatacept or
anakinra was associated with a higher risk of serious infections; therefore, the
concomitant use of SIMPONI and these biologic products is not recommended
(see Warnings and Precautions and Drug Interactions). Treatment with
SIMPONI should not be initiated in patients with an active infection, including
clinically important localized infections. Patients greater than 65 years of age,
patients with co-morbid conditions and/or patients taking concomitant
immunosuppressants such as corticosteroids or methotrexate may be at greater
risk of infection. Consider the risks and benefits of treatment prior to initiating
SIMPONI in patients: • with chronic or recurrent infection; • who have been
exposed to tuberculosis; • with a history of an opportunistic infection;
• who have resided or traveled in areas of endemic tuberculosis or endemic
mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis;
or • with underlying conditions that may predispose them to infection.
Monitoring Closely monitor patients for the development of signs and symptoms
of infection during and after treatment with SIMPONI. Discontinue SIMPONI if
a patient develops a serious infection, an opportunistic infection, or sepsis. For
a patient who develops a new infection during treatment with SIMPONI, perform
a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy and closely
monitor them. Serious Infection in Clinical Trials In controlled Phase 3 trials
through Week 16 in patients with RA, PsA, and AS, serious infections were
observed in 1.4% of SIMPONI-treated patients and 1.3% of control-treated
patients. In the controlled Phase 3 trials through Week 16 in patients with RA,
PsA, and AS, the incidence of serious infections per 100 patient-years of
follow-up was 5.7 (95% CI: 3.8, 8.2) for the SIMPONI group and 4.2 (95% CI: 1.8,
The study was funded by VSL Pharmaceuticals, the Canadian Institutes of
Health Research, and Crohn’s and Colitis Foundation of Canada. Dr. Fedorak
reported serving on a speakers bureau
for VSL Pharmaceuticals. The other authors declared no conficts of interest.
[email protected]
SIMPONI® (golimumab)
8.2) for the placebo group. In the controlled Phase 2/3 trial through Week 6 of
SIMPONI induction in UC, the incidence of serious infections in SIMPONI
200/100 mg-treated patients was similar to the incidence of serious infections
in placebo-treated patients. Through Week 60, the incidence of serious
infections was similar in patients who received SIMPONI induction and 100 mg
during maintenance compared with patients who received SIMPONI induction
and placebo during the maintenance portion of the UC trial. Serious infections
observed in SIMPONI-treated patients included sepsis, pneumonia, cellulitis,
abscess, tuberculosis, invasive fungal infections, and hepatitis B infection.
Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis
infections have been observed in patients receiving TNF-blockers, including
patients who have previously received treatment for latent or active
tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent
infection prior to initiating SIMPONI and periodically during therapy. Treatment
of latent tuberculosis infection prior to therapy with TNF-blockers has been
shown to reduce the risk of tuberculosis reactivation during therapy. Prior to
initiating SIMPONI, assess if treatment for latent tuberculosis is needed; an
induration of 5 mm or greater is a positive tuberculin skin test, even for patients
previously vaccinated with Bacille Calmette-Guerin (BCG). Consider antituberculosis therapy prior to initiation of SIMPONI in patients with a past history
of latent or active tuberculosis in whom an adequate course of treatment cannot
be confirmed, and for patients with a negative test for latent tuberculosis but
having risk factors for tuberculosis infection. Consultation with a physician with
expertise in the treatment of tuberculosis is recommended to aid in the decision
whether initiating anti-tuberculosis therapy is appropriate for an individual
patient. Cases of active tuberculosis have occurred in patients treated with
SIMPONI during and after treatment for latent tuberculosis. Monitor patients for
the development of signs and symptoms of tuberculosis including patients who
tested negative for latent tuberculosis infection prior to initiating therapy,
patients who are on treatment for latent tuberculosis, or patients who were
previously treated for tuberculosis infection. Consider tuberculosis in the
differential diagnosis in patients who develop a new infection during SIMPONI
treatment, especially in patients who have previously or recently traveled to
countries with a high prevalence of tuberculosis, or who have had close contact
with a person with active tuberculosis. In the controlled and uncontrolled
portions of the Phase 2 RA and Phase 3 RA, PsA, and AS trials, the incidence
of active TB was 0.23 and 0 per 100 patient-years in 2347 SIMPONI-treated
patients and 674 placebo-treated patients, respectively. Cases of TB included
pulmonary and extra pulmonary TB. The overwhelming majority of the TB cases
occurred in countries with a high incidence rate of TB. In the controlled Phase
2/3 trial of SIMPONI induction through Week 6 in UC, no cases of TB were
observed in SIMPONI 200/100 mg-treated patients or in placebo-treated
patients. Through Week 60, the incidence per 100 patient-years of TB in patients
who received SIMPONI induction and 100 mg during the maintenance portion of
the UC trial was 0.52 (95% CI: 0.11, 1.53). One case of TB was observed in the
placebo maintenance group in a patient who received SIMPONI intravenous
(IV) induction. Invasive Fungal Infections If patients develop a serious systemic
illness and they reside or travel in regions where mycoses are endemic,
consider invasive fungal infection in the differential diagnosis. Consider
appropriate empiric antifungal therapy and take into account both the risk for
severe fungal infection and the risks of antifungal therapy while a diagnostic
workup is being performed. Antigen and antibody testing for histoplasmosis may
be negative in some patients with active infection. To aid in the management of
such patients, consider consultation with a physician with expertise in the
diagnosis and treatment of invasive fungal infections. Hepatitis B Virus
Reactivation The use of TNF-blockers including SIMPONI has been associated
with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis
B carriers (i.e., surface antigen positive). In some instances, HBV reactivation
occurring in conjunction with TNF-blocker therapy has been fatal. The majority
of these reports have occurred in patients who received concomitant immunosuppressants. All patients should be tested for HBV infection before initiating
TNF-blocker therapy. For patients who test positive for hepatitis B surface
antigen, consultation with a physician with expertise in the treatment of
hepatitis B is recommended before initiating TNF-blocker therapy. The risks and
benefits of treatment should be considered prior to prescribing TNF-blockers,
including SIMPONI, to patients who are carriers of HBV. Adequate data are
not available on whether anti-viral therapy can reduce the risk of HBV
reactivation in HBV carriers who are treated with TNF-blockers. Patients who
are carriers of HBV and require treatment with TNF-blockers should be closely
monitored for clinical and laboratory signs of active HBV infection throughout
therapy and for several months following termination of therapy. In patients who
develop HBV reactivation, TNF-blockers should be stopped and antiviral therapy
with appropriate supportive treatment should be initiated. The safety of
resuming TNF-blockers after HBV reactivation has been controlled is not known.
Therefore, prescribers should exercise caution when considering resumption of
TNF-blockers in this situation and monitor patients closely. Malignancies
Malignancies, some fatal, have been reported among children, adolescents,
and young adults who received treatment with TNF-blocking agents (initiation
of therapy ≤ 18 years of age), of which SIMPONI is a member. Approximately
half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s
lymphoma. The other cases represented a variety of malignancies, including
rare malignancies that are usually associated with immunosuppression, and
malignancies that are not usually observed in children and adolescents. The
malignancies occurred after a median of 30 months (range 1 to 84 months) after
the first dose of TNF blocker therapy. Most of the patients were receiving
concomitant immunosuppressants. These cases were reported post-marketing
and are derived from a variety of sources, including registries and spontaneous
NEWS
GIHEP NEW S. COM • M AY 2015
S
tudies from the last decade implicate aberrant immune response
to gut bacteria in susceptible hosts as
a trigger of mucosal infammation in
Crohn’s disease and ulcerative colitis.
It therefore seems plausible to be
able to “reset” the mucosal immune
response by manipulating intestinal
fora with probiotics.
A formulation of eight diferent
strains of probiotic bacterial species
called VSL#3 has been shown to
alleviate symptoms and maintain
remission in UC and pouchitis. Prior
studies assessing efcacy of probiotics
in the treatment of CD used formulations with individual strains of bacteria (Saccharomyces, lactobacillus, and
Escherichia coli Nissle 1971) and failed
to show any beneft over placebo.
In the recent study by Fedorak
SIMPONI® (golimumab)
SIMPONI® (golimumab)
postmarketing reports. The risks and benefits of TNF-blocker treatment
including SIMPONI should be considered prior to initiating therapy in patients
with a known malignancy other than a successfully treated non-melanoma skin
cancer (NMSC) or when considering continuing a TNF-blocker in patients who
develop a malignancy. In the controlled portions of clinical trials of TNF-blockers
including SIMPONI, more cases of lymphoma have been observed among
patients receiving anti-TNF treatment compared with patients in the control
groups. During the controlled portions of the Phase 2 trials in RA, and the Phase
3 trials in RA, PsA and AS, the incidence of lymphoma per 100 patient-years of
follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI group
compared with an incidence of 0 (95% CI: 0., 0.96) in the placebo group. In the
controlled and uncontrolled portions of these clinical trials in 2347 SIMPONItreated patients with a median follow-up of 1.4 years, the incidence of lymphoma
was 3.8-fold higher than expected in the general U.S. population according to
the SEER database (adjusted for age, gender, and race).1 Through Week 60 of
the UC trials, there were no cases of lymphoma with SIMPONI. Patients with RA
and other chronic inflammatory diseases, particularly patients with highly active
disease and/or chronic exposure to immunosuppressant therapies, may be at
higher risk (up to several fold) than the general population for the development
of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and
chronic leukemia have been reported with postmarketing TNF-blocker use in
rheumatoid arthritis and other indications. Even in the absence of TNF blocker
therapy, patients with rheumatoid arthritis may be at a higher risk (approximately
2-fold) than the general population for the development of leukemia. Rare postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported
in patients treated with TNF-blocking agents. This rare type of T-cell lymphoma
has a very aggressive disease course and is usually fatal. Nearly all of the
reported TNF-blocker associated cases have occurred in patients with Crohn’s
disease or ulcerative colitis. The majority were in adolescent and young adult
males. Almost all these patients had received treatment with azathioprine (AZA)
or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to
diagnosis. The potential risk with the combination of AZA or 6-MP and SIMPONI
should be carefully considered. A risk for the development for hepatosplenic
T-cell lymphoma in patients treated with TNF-blockers cannot be excluded.
During the controlled portions of the Phase 2 trial in RA, and the Phase 3 trials
in RA, PsA and AS, the incidence of malignancies other than lymphoma per 100
patient-years of follow-up was not elevated in the combined SIMPONI group
compared with the placebo group. In the controlled and uncontrolled portions
of these trials, the incidence of malignancies, other than lymphoma, in
SIMPONI-treated patients was similar to that expected in the general U.S.
population according to the SEER database (adjusted for age, gender, and
race).1 In the 6-week placebo-controlled portions of the SIMPONI Phase 2/3
clinical trials in UC, the incidence of non-lymphoma malignancies (excluding
non-melanoma skin cancer) was similar between the SIMPONI and the placebo
group. Through Week 60, the incidence of non-lymphoma malignancies
(excluding non-melanoma skin cancer) was similar to the general U.S.
population according to the SEER database (adjusted for age, gender, and
race).1 Short follow-up periods, such as those of one year or less in the studies
above, may not adequately reflect the true incidence of malignancies. It is not
known if SIMPONI treatment influences the risk for developing dysplasia or
colon cancer. All patients with ulcerative colitis who are at increased risk for
dysplasia or colon carcinoma (for example, patients with long-standing
ulcerative colitis or primary sclerosing cholangitis), or who had a prior history
of dysplasia or colon carcinoma should be screened for dysplasia at regular
intervals before therapy and throughout their disease course. This evaluation
should include colonoscopy and biopsies per local recommendations. In
patients with newly diagnosed dysplasia treated with SIMPONI, the risks and
benefits to the individual patient must be carefully reviewed and consideration
should be given to whether therapy should be continued. Melanoma has been
reported in patients treated with TNF-blocking agents, including SIMPONI.
Merkel cell carcinoma has been reported in patients treated with TNF-blocking
agents. Periodic skin examination is recommended for all patients, particularly
those with risk factors for skin cancer. In controlled trials of other TNF-blockers
in patients at higher risk for malignancies (e.g., patients with COPD, patients
with Wegener’s granulomatosis treated with concomitant cyclophosphamide)
a greater portion of malignancies occurred in the TNF-blocker group compared
to the controlled group. In an exploratory 1-year clinical trial evaluating the use
of 50, 100 and 200 mg of SIMPONI in 309 patients with severe persistent asthma,
6 patients developed malignancies other than NMSC in the SIMPONI groups
compared to none in the control group. Three of the 6 patients were in the
200 mg SIMPONI group. Congestive Heart Failure Cases of worsening
congestive heart failure (CHF) and new onset CHF have been reported with TNFblockers, including SIMPONI. In several exploratory trials of other TNF-blockers
in the treatment of CHF, there were greater proportions of TNF-blocker treated
patients who had CHF exacerbations requiring hospitalization or increased
mortality. SIMPONI has not been studied in patients with a history of CHF and
SIMPONI should be used with caution in patients with CHF. If a decision is made
to administer SIMPONI to patients with CHF, these patients should be closely
monitored during therapy, and SIMPONI should be discontinued if new or
worsening symptoms of CHF appear. Demyelinating Disorders Use of TNFblockers, of which SIMPONI is a member, has been associated with rare cases
of new onset or exacerbation of central nervous system (CNS) demyelinating
disorders, including multiple sclerosis (MS) and peripheral demyelinating
disorders, including Guillain-Barré syndrome. Cases of central demyelination,
MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely
been reported in patients treated with SIMPONI (see Adverse Reactions).
Prescribers should exercise caution in considering the use of TNF-blockers,
including SIMPONI, in patients with central or peripheral nervous system
demyelinating disorders. Discontinuation of SIMPONI should be considered if
these disorders develop. Use with Abatacept In controlled trials, the concurrent
administration of another TNF-blocker and abatacept was associated with a
greater proportion of serious infections than the use of a TNF-blocker alone;
and the combination therapy, compared to the use of a TNF-blocker alone, has
not demonstrated improved clinical benefit in the treatment of RA. Therefore,
the combination of TNF-blockers including SIMPONI and abatacept is not
recommended (see Drug Interactions). Use with Anakinra Concurrent
administration of anakinra (an interleukin-1 antagonist) and another
TNF-blocker, was associated with a greater portion of serious infections and
neutropenia and no additional benefits compared with the TNF-blocker alone.
Therefore, the combination of anakinra with TNF-blockers, including SIMPONI,
is not recommended (see Drug Interactions). Switching Between Biological
Disease Modifying Antirheumatic Drugs Care should be taken when switching
from one biological product to another biological product since overlapping
biological activity may further increase the risk of infection. Hematologic
Cytopenias There have been post-marketing reports of pancytopenia,
leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients
receiving TNF-blockers. In clinical trials, cases of pancytopenia, leukopenia,
neutropenia, and thrombocytopenia have also occurred in SIMPONI-treated
patients. Caution should be exercised when using TNF-blockers, including
SIMPONI, in patients who have or have had significant cytopenias.
Vaccinations/Therapeutic Infectious Agents Live Vaccines Patients treated
with SIMPONI may receive vaccinations, except for live vaccines. In patients
receiving anti-TNF therapy, limited data are available on the response to live
vaccination, or on the secondary transmission of infection by live vaccines. Use
of live vaccines could result in clinical infections, including disseminated
infections. Therapeutic Infectious Agents Other uses of therapeutic infectious
agents such as live attenuated bacteria (e.g., BCG bladder instillation for the
treatment of cancer) could result in clinical infections, including disseminated
infections. It is recommended that therapeutic infectious agents not be given
concurrently with SIMPONI. Non-live Vaccines In the Phase 3 PsA trial, after
pneumococcal vaccination, a similar proportion of SIMPONI-treated and
placebo-treated patients were able to mount an adequate immune response of
at least a 2-fold increase in antibody titers to pneumococcal polysaccharide
vaccine. In both SIMPONI-treated and placebo-treated patients, the proportions
of patients with response to pneumococcal vaccine were lower among patients
receiving MTX compared with patients not receiving MTX. The data suggest
that SIMPONI does not suppress the humoral immune response to the
pneumococcal vaccine. Hypersensitivity Reactions In post-marketing
experience, serious systemic hypersensitivity reactions (including anaphylactic
reaction) have been reported following SIMPONI administration. Some of these
reactions occurred after the first administration of SIMPONI. If an anaphylactic
or other serious allergic reaction occurs, administration of SIMPONI should be
discontinued immediately and appropriate therapy instituted. ADVERSE
REACTIONS: Clinical Trials Experience Because clinical trials are conducted
under widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in clinical practice. The
safety data described below are based on 5 pooled, randomized, double-blind,
controlled Phase 3 trials in patients with RA, PsA, and AS (Trials RA-1, RA-2,
RA-3, PsA, and AS) (see Clinical Studies). These 5 trials included 639 controltreated patients and 1659 SIMPONI-treated patients including 1089 with RA,
292 with PsA, and 278 with AS. The safety data in 1233 SIMPONI-treated patients
with ulcerative colitis from 3 pooled, randomized, double-blind, controlled Phase
2/3 trials are also described below (Trials UC-1, UC-2, and UC-3) (see Clinical
Studies). The proportion of patients who discontinued treatment due to adverse
reactions in the controlled Phase 3 trials through Week 16 in RA, PsA and AS
was 2% for SIMPONI-treated patients and 3% for placebo-treated patients.
The most common adverse reactions leading to discontinuation of SIMPONI
in the controlled Phase 3 trials in RA, PsA and AS through Week 16 were
sepsis (0.2%), alanine aminotransferase increased (0.2%), and aspartate
aminotransferase increased (0.2%). The most common adverse drug reactions
leading to discontinuation through Week 60 of the UC trials in patients who
received SIMPONI induction and 100 mg during maintenance compared with
patients who received SIMPONI induction and placebo during maintenance
were tuberculosis (0.3% vs 0.6%) and anemia (0.3% vs 0%), respectively. The
most serious adverse reactions were: • Serious Infections (see Warnings and
Precautions) • Malignancies (see Warnings and Precautions) Upper respiratory
tract infection and nasopharyngitis were the most common adverse reactions
reported in the combined Phase 3 RA, PsA and AS trials through Week 16,
occurring in 7% and 6% of SIMPONI-treated patients as compared with 6%
and 5% of control-treated patients, respectively. Infections In controlled Phase
3 trials through Week 16 in RA, PsA, and AS, infections were observed in 28% of
SIMPONI-treated patients compared to 25% of control-treated patients. For
serious infections, see the Warnings and Precautions section (see Warnings
and Precautions). In the controlled Phase 2/3 trial of SIMPONI induction
through Week 6 in UC, the rates of infections were similar in SIMPONI
200/100 mg-treated patients and placebo-treated patients, or approximately
12%. Through Week 60, the incidence per patient year of infections was similar
in patients who received SIMPONI induction and 100 mg during maintenance
compared with patients who received SIMPONI induction and placebo during
the maintenance portion of the UC trial. Demyelinating Disorders In the
controlled Phase 2/3 trial of SIMPONI induction through Week 6, no cases of
demyelination were observed in SIMPONI 200/100 mg-treated patients or
placebo-treated patients. Through Week 60, there were no cases of
13
and colleagues, the probiotic formulation VSL#3 did not decrease
the likelihood of developing severe
endoscopic lesions (Rutgeert’s grade
3 or 4) at 90 days following surgery
for CD, when compared to placebo.
Continued on following page
14
NEWS
Continued from previous page
Patients in the VSL#3 arm demonstrated lower levels of infammatory
cytokines in the colonic mucosal
biopsies; however, this did not
translate to a signifcant diference
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
over placebo in the rates of severe
endoscopic recurrence at 3 and 12
months following surgery.
While probiotics are safe and well
tolerated, data supporting efcacy in
CD are sparse at best. This may in
part be due to variations in the bacte-
rial communities found in the colon
and small bowel, and following loss
of the ileo-cecal valve postoperatively.
Until larger studies are undertaken to
investigate the potential for probiotics
in the management of CD, immune
modulators and biologic therapies
remain the mainstay of treatment.
Dr. Manreet Kaur is assistant professor,
department of medicine, division of
gastroenterology and hepatology, Baylor
University, Houston. She has no conficts of interest.
SIMPONI® (golimumab)
SIMPONI® (golimumab)
demyelination in the SIMPONI 100 mg group during maintenance. One case of
CNS demyelination was observed in the placebo maintenance group in a patient
who received SIMPONI 400/200 mg during induction. Liver Enzyme Elevations
There have been reports of severe hepatic reactions including acute liver failure
in patients receiving TNF-blockers. In controlled Phase 3 trials of SIMPONI in
patients with RA, PsA, and AS through Week 16, ALT elevations ≥ 5 x ULN
occurred in 0.2% of control-treated patients and 0.7% of SIMPONI-treated
patients and ALT elevations ≥ 3 x ULN occurred in 2% of control-treated patients
and 2% of SIMPONI-treated patients. Since many of the patients in the Phase 3
trials for RA, PsA, and AS were also taking medications that cause liver enzyme
elevations (e.g., NSAIDs, MTX), the relationship between SIMPONI and liver
enzyme elevation is not clear. In Phase 2/3 UC trials, the incidence of ALT
elevations ≥ 5 x ULN was similar in SIMPONI-treated patients and placebotreated patients, or approximately 1%, with an average duration of follow-up of
46 weeks and 18 weeks, respectively. ALT elevations ≥ 3 x ULN occurred in 2.0%
of SIMPONI-treated patients compared with 1.5% of placebo-treated patients
with an average duration of follow-up of 46 weeks and 18 weeks, respectively.
Autoimmune Disorders and Autoantibodies The use of TNF-blockers, including
SIMPONI, has been associated with the formation of autoantibodies and, rarely,
with the development of a lupus-like syndrome. In the controlled Phase 3 trials
in patients with RA, PsA, and AS through Week 14, there was no association of
SIMPONI treatment and the development of newly positive anti-dsDNA
antibodies. In Phase 3 trials in RA, PsA, and AS through 1 year of follow up, 4.0%
of SIMPONI-treated patients and 2.6% of control patients were newly ANApositive (at titers of 1:160 or greater). The frequency of anti-dsDNA antibodies at
1 year of follow up was uncommon in patients who were anti-dsDNA negative
at baseline. Through Week 60 of the UC trials, 3.5% of patients who received
SIMPONI induction and 100 mg during maintenance were newly ANA-positive
(at titers of 1:160 or greater) compared with 3.5% of patients who received
SIMPONI induction and placebo during the maintenance portion of the UC trial.
The frequency of anti-dsDNA antibodies at 1 year of follow up in patients who
were anti-dsDNA negative at baseline was 0.5% in patients receiving SIMPONI
induction and 100 mg during maintenance compared with 0% in patients who
received SIMPONI induction and placebo during maintenance. Injection Site
Reactions In controlled Phase 3 trials through Week 16 in RA, PsA and AS, 6%
of SIMPONI-treated patients had injection site reactions compared with 2% of
control-treated patients. The majority of the injection site reactions were mild
and the most frequent manifestation was injection site erythema. In the
controlled Phase 2/3 trial through Week 6 in UC, 3.4% of SIMPONI-treated
patients had injection site reactions compared with 1.5% in control-treated
patients. The majority of the injection site reactions were mild and moderate
and the most frequent manifestation was injection site erythema. In controlled
Phase 2 and 3 trials in RA, PsA, AS, and Phase 2/3 UC trials, no patients treated
with SIMPONI developed anaphylactic reactions. Immunogenicity Antibodies
to SIMPONI were detected in 57 (4%) of SIMPONI-treated patients across the
Phase 3 RA, PsA, and AS trials through Week 24. Similar rates were observed
in each of the three indications. Patients who received SIMPONI with
concomitant MTX had a lower proportion of antibodies to SIMPONI than
patients who received SIMPONI without MTX (approximately 2% versus 7%,
respectively). The presence of serum concentrations of golimumab can interfere
with the detection of antibodies to SIMPONI leading to inconclusive results. In
UC trials, 34 (3%), 341 (28%) and 823 (69%) of SIMPONI-treated subjects were
positive, negative and inconclusive for antibodies to SIMPONI, respectively.
Treatment with concomitant immunomodulators (AZA, 6-MP and MTX) resulted
in a lower proportion of patients with antibodies to SIMPONI than patients
receiving SIMPONI without immunomodulators (2% versus 4%, respectively).
Of the patients with a positive antibody response to SIMPONI in the Phase 2
and 3 trials, most were determined to have neutralizing antibodies to golimumab
as measured by a cell-based functional assay. The small number of patients
positive for antibodies to SIMPONI limits the ability to draw definitive
conclusions regarding the relationship between antibodies to golimumab and
clinical efficacy or safety measures. The data above reflect the percentage of
patients whose test results were considered positive for antibodies to SIMPONI
in an ELISA assay, and are highly dependent on the sensitivity and specificity
of the assay. Additionally, the observed incidence of antibody positivity in an
assay may be influenced by several factors including sample handling, timing
of sample collection, concomitant medications, and underlying disease. For
these reasons, comparison of the incidence of antibodies to SIMPONI with the
incidence of antibodies to other products may be misleading. Other Adverse
Reactions The adverse drug reactions that occurred at a rate of at least 1% in the
SIMPONI ± DMARD group and with a higher incidence than in the placebo ±
DMARD group during the controlled period of the 5 pooled Phase 3 trials through
Week 16 in patients with RA, PsA, and AS are summarized below. Patients may
have taken concomitant MTX, sulfasalazine, hydroxychloroquine, low dose
corticosteroids (≤ 10 mg of prednisone/day or equivalent), and/or NSAIDs during
the trials). The numbers (percentages) of adverse drug reactions for SIMPONI ±
DMARDs-treated patients (n=1659) and Placebo ± DMARDs-treated patients
(n=639), respectively, were: Infections and Infestations: Upper respiratory tract
infection (nasopharyngitis, pharyngitis, laryngitis, and rhinitis) 16%, 13%; Viral
infections (such as infuenza and herpes) 5%, 3%; Bronchitis 2%, 1%; Superfcial
fungal infections 2%, 1%; Sinusitis 2%, 1%; General disorders and administration
site conditions: Injection site reaction (injection site erythema, urticaria, induration,
pain, bruising, pruritus, irritation, paresthesia) 6%, 2%; Investigations: Alanine
aminotransferase increased 4%, 3%; Aspartate aminotransferase increased 3%,
2%; Vascular disorders: Hypertension 3%, 2%; Nervous system disorders: Dizziness
2%, 1%; Paresthesia 2%, 1%; Gastrointestinal Disorders: Constipation 1%, <1%.
Less common clinical trial adverse drug reactions Adverse drug reactions
that occurred <1% in SIMPONI-treated patients during the SIMPONI clinical
trials that do not appear in the Warnings and Precautions section included the
following events listed by system organ class: Infections and infestations:
Septic shock, atypical mycobacterial infection, pyelonephritis, arthritis bacterial,
bursitis infective Neoplasms benign, malignant and unspecified: Leukemia Skin
and subcutaneous tissue disorders: Psoriasis (new onset or worsening, palmar/
plantar and pustular), vasculitis (cutaneous) Vascular disorders: Vasculitis
(systemic) Other clinical trial adverse drug reactions in ulcerative colitis
clinical trials In the Phase 2/3 trials in UC evaluating 1233 SIMPONI-treated
patients, no new adverse drug reactions were identified and the frequency of
adverse drug reactions was similar to the safety profile observed in patients
with RA, PsA and AS. Post-marketing Experience The following adverse
reactions have been identified during post-approval use of SIMPONI. 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 SIMPONI exposure. Immune System Disorders: Serious systemic
hypersensitivity reactions (including anaphylactic reaction) (see Warnings and
Precautions), sarcoidosis Neoplasms benign, malignant and unspecified:
Melanoma (see Warnings and Precautions) Respiratory, thoracic and
mediastinal disorders: Interstitial lung disease Skin and subcutaneous tissue
disorders: Skin exfoliation, rash, bullous skin reactions DRUG INTERACTIONS:
Methotrexate For the treatment of RA, SIMPONI should be used with
methotrexate (MTX) (see Clinical Studies). Since the presence or absence of
concomitant MTX did not appear to influence the efficacy or safety of SIMPONI
in the treatment of PsA or AS, SIMPONI can be used with or without MTX in
the treatment of PsA and AS (see Clinical Studies and Clinical Pharmacology).
Biological Products for RA, PsA, and/or AS An increased risk of serious
infections has been seen in clinical RA trials of other TNF-blockers used in
combination with anakinra or abatacept, with no added benefit; therefore, use
of SIMPONI with abatacept or anakinra is not recommended (see Warnings and
Precautions). A higher rate of serious infections has also been observed in RA
patients treated with rituximab who received subsequent treatment with a
TNF-blocker. The concomitant use of SIMPONI with biologics approved to
treat RA, PsA, or AS is not recommended because of the possibility of an
increased risk of infection. Live Vaccines/Therapeutic Infectious Agents Live
vaccines should not be given concurrently with SIMPONI (see Warnings and
Precautions). Therapeutic infectious agents should not be given concurrently
with SIMPONI (see Warnings and Precautions). Infants born to women treated
with SIMPONI during their pregnancy may be at increased risk of infection for
up to 6 months. Administration of live vaccines to infants exposed to SIMPONI
in utero is not recommended for 6 months following the mother’s last SIMPONI
injection during pregnancy (see Use in Specific Populations). Cytochrome P450
Substrates The formation of CYP450 enzymes may be suppressed by increased
levels of cytokines (e.g., TNFα) during chronic inflammation. Therefore, it is
expected that for a molecule that antagonizes cytokine activity, such as
golimumab, the formation of CYP450 enzymes could be normalized. Upon
initiation or discontinuation of SIMPONI in patients being treated with CYP450
substrates with a narrow therapeutic index, monitoring of the effect (e.g.,
warfarin) or drug concentration (e.g., cyclosporine or theophylline) is
recommended and the individual dose of the drug product may be adjusted as
needed. USE IN SPECIFIC POPULATIONS: Pregnancy Pregnancy Category B –
There are no adequate and well-controlled trials of SIMPONI in pregnant
women. Because animal reproduction and developmental studies are not
always predictive of human response, it is not known whether SIMPONI can
cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. SIMPONI should be used during pregnancy only if
clearly needed. An embryofetal developmental toxicology study was performed
in which pregnant cynomolgus monkeys were treated subcutaneously with
golimumab during the first trimester with doses up to 50 mg/kg twice weekly
(360 times greater than the maximum recommended human dose-MRHD) and
has revealed no evidence of harm to maternal animals or fetuses. Umbilical
cord blood samples collected at the end of the second trimester showed that
fetuses were exposed to golimumab during gestation. In this study, in utero
exposure to golimumab produced no developmental defects to the fetus.
A pre- and post-natal developmental study was performed in which pregnant
cynomolgus monkeys were treated with golimumab during the second and third
trimesters, and during lactation at doses up to 50 mg/kg twice weekly (860 times
and 310 times greater than the maximal steady state human blood levels for
maternal animals and neonates, respectively) and has revealed no evidence of
harm to maternal animals or neonates. Golimumab was present in the neonatal
serum from the time of birth and for up to six months postpartum. Exposure to
golimumab during gestation and during the postnatal period caused no
developmental defects in the infants. IgG antibodies are known to cross the
placenta during pregnancy and have been detected in the serum of infants born
to patients treated with these antibodies. Since SIMPONI is an IgG antibody,
infants born to women treated with SIMPONI during their pregnancy may be at
increased risk of infection for up to 6 months. Administration of live vaccines to
infants exposed to SIMPONI in utero is not recommended for 6 months following
the mother’s last SIMPONI injection during pregnancy (see Warnings and
Precautions). Nursing Mothers It is not known whether SIMPONI is excreted in
human milk or absorbed systemically after ingestion. Because many drugs and
immunoglobulins are excreted in human milk, and because of the potential for
NEWS FROM THE AGA
GIHEP NEW S. COM • M AY 2015
15
Consensus statement on dysplasia in IBD patients
A
GA and ASGE have issued updated recommendations for the
surveillance and management
of dysplasia in patients with IBD. The
consensus statement represents an
efort to unify consensus recommenda-
tions to address two primary issues: 1)
how should surveillance to detect dysplasia be performed; and 2) how should
dysplasia be managed.
The consensus statement addresses
the optimal types of endoscopic pro-
cedures and equipment to be used,
recommended practices for removal of
lesions, or referral for the more invasive
surgical procedure, colectomy. In particular, the updated recommendations
refect a shift to chromoendoscopy for
SIMPONI® (golimumab)
SIMPONI® (golimumab)
adverse reactions in nursing infants from SIMPONI, a decision should be
made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother. In the pre- and post-natal
development study in cynomolgus monkeys in which golimumab was
administered subcutaneously during pregnancy and lactation, golimumab
was detected in the breast milk at concentrations that were approximately
400-fold lower than the maternal serum concentrations. Pediatric Use Safety
and effectiveness of SIMPONI in pediatric patients less than 18 years of age
have not been established. Geriatric Use In the Phase 3 trials in RA, PsA, and
AS, there were no overall differences in SAEs, serious infections, and AEs in
SIMPONI-treated patients ages 65 or older (N = 155) compared with younger
SIMPONI-treated patients. In UC, there were insufficient numbers of patients
aged 65 and over to determine whether they respond differently from patients
aged 18 to 65. Because there is a higher incidence of infections in the
geriatric population in general, caution should be used in treating geriatric
patients with SIMPONI. OVERDOSAGE: In a clinical trial, 5 patients received
protocol-directed single infusions of 10 mg/kg of intravenous SIMPONI
without serious adverse reactions or other significant reactions. The highest
weight patient was 100 kg, and therefore received a single intravenous
infusion of 1000 mg of SIMPONI. There were no SIMPONI overdoses in the
clinical trials. PATIENT COUNSELING INFORMATION: See FDA-approved
patient labeling (Medication Guide and Instructions for Use) Patients should
be advised of the potential benefits and risks of SIMPONI. Physicians should
instruct their patients to read the Medication Guide before starting SIMPONI
therapy and to read it each time the prescription is renewed. Infections
Inform patients that SIMPONI may lower the ability of their immune system
to fight infections. Instruct the patient of the importance of contacting their
doctor if they develop any symptoms of infection, including tuberculosis,
invasive fungal infections, and hepatitis B reactivation. Malignancies
Patients should be counseled about the risk of lymphoma and other
malignancies while receiving SIMPONI. Allergic Reactions Advise latexsensitive patients that the needle cover on the prefilled syringe as well as
the prefilled syringe in the prefilled SmartJect autoinjector contains dry
natural rubber (a derivative of latex). Other Medical Conditions Advise
patients to report any signs of new or worsening medical conditions such as
congestive heart failure, demyelinating disorders, autoimmune diseases,
liver disease, cytopenias, or psoriasis. Instructions for Safe Administration
The first self-injection should be performed under the supervision of a
qualified healthcare professional. If a patient or caregiver is to administer
SIMPONI, he/she should be instructed in injection techniques and their
ability to inject subcutaneously should be assessed to ensure the proper
administration of SIMPONI. Advise the patient to read the FDA-approved
Instructions for Use and provide the following instructions to patients: • Prior
to use, remove the prefilled syringe or the prefilled SmartJect autoinjector
from the refrigerator and allow SIMPONI to sit at room temperature outside
of the carton for 30 minutes and out of the reach of children. • Do not warm
SIMPONI in any other way. For example, do not warm SIMPONI in a
microwave or in hot water. • Do not remove the prefilled syringe needle cover
or SmartJect autoinjector cap while allowing SIMPONI to reach room
temperature. Remove these immediately before injection. • Do not pull the
autoinjector away from the skin until you hear a first “click” sound and then
a second “click” sound (the injection is finished and the needle is pulled
back). It usually takes about 3 to 6 seconds but may take up to 15 seconds for
you to hear the second “click” after the first “click”. If the autoinjector is
pulled away from the skin before the injection is completed, a full dose of
SIMPONI may not be administered. • A puncture-resistant container for
disposal of needles and syringes should be used. Patients or caregivers
should be instructed in the technique of proper syringe and needle disposal,
and be advised not to reuse these items.
REFERENCES: 1. SEER [database online]. US Population Data – 1969-2004.
Bethesda, MD: National Cancer Institute. Release date: January 3, 2007.
Available at: http//seer.cancer.gov/popdata/.
© Janssen Biotech, Inc. 2014
Horsham, PA 19044 1-800-JANSSEN (1-800-526-7736)
US License No. 1864
Revised: 12/2014
025953-141204
patients with IBD during screening
and surveillance to better visualize the
tissue. Chromoendoscopy involves the
use of dye sprayed onto the mucosa
during the procedure. The new recommendations were
developed by an international group
of experts and stakeholders in IBD
surveillance, in accordance with suggested standards from the Institute of
Medicine. Existing guidelines on this
topic, which were written by numerous expert groups, were considered,
and in some cases, accepted in the
new consensus statement. The consensus statement was
published in the March issues of Gastroenterology and GIE: Gastrointestinal
Endoscopy. [email protected]
Fellows application
period open: 2016
A
GA honors superior professional
achievement in clinical private or
academic practice and in research with
fellowship in the organization. Fellowships are awarded to members whose
accomplishments and contributions
demonstrate personal commitment to
the feld of gastroenterology.
AGA Fellows will be acknowledged
in several ways, including a certifcate and the privilege of using the
prestigious designation “AGAF” in
professional activities. Learn more and
complete the online application today
at www.gastro.org/about/aga-fellows-program. The deadline for submissions is Friday, July 24, 2015.
[email protected]
New AGA guideline:
pancreatic cysts
A
new AGA guideline provides
direction to GIs and their patients with pancreatic cysts identifed
during abdominal imaging. The
guideline recommends that most patients with asymptomatic pancreatic
cysts should be conservatively monitored with a longer surveillance period and more consideration of risks
and benefts to patients before moving to surgery. To view this guideline,
as well as the accompanying technical review and clinical decision tool,
visit www.gastro.org/guidelines.
[email protected]
NEWS FROM THE AGA
16
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
Innovation to help patients with chronic liver disease
T
he American Gastroenterological Association (AGA) Research
Foundation is pleased to announce that Ashish Nimgaonkar,
MBBS, MTech, MS, from John
Hopkins University, has received the
inaugural AGA–Boston Scientifc
Career Development Technology
& Innovation Award. This award is
graciously supported by a grant from
Boston Scientifc, a leading innovator
of medical solutions.
“Dr. Nimgaonkar’s research represents a potential breakthrough
in the treatment of patients with
chronic liver disease,” said Dr. Martin
Brotman, AGAF, chair, AGA Research
Foundation. “The AGA Research
Download the new AGA Publication Apps!
Delivering convenient and interactive
news and features on the go.
P R E M I E R E
The
I S S U E
NEW GASTROENTEROLOGIST
INSIGHTS FOR FELLOWS & YOUNG GIs
A Quarterly Supplement to GI & Hepatology News | Spring 2015
16 Postfellowship Pathways
Advanced Endoscopy Fellowship
26 Protecting Your Future
A Discussion About Disability
Insurance for GIs
HCV Update
The Current State
of Hepatitis C
Therapy 8
The
NEW GASTROENTEROLOGIST
INSIGHTS FOR FELLOWS & YOUNG GIs
A Quarterly Supplement to GI & Hepatology News
Full interactive digital editions.
FREE download available for iOS, Android, and Amazon Kindle.
GIHEPNEWS.COM
Foundation is proud to support Dr.
Nimgaonkar as he works to enhance
this technology and bring it one step
closer to clinical practice.”
Dr. Nimgaonkar’s research focuses
on developing technology to manage
patients with refractory ascites – a
condition in which fuid builds up in
the abdomen. This fuid accumulation eventually becomes resistant to
medical therapy and the only defnitive treatment at this stage is liver
transplantation, which is limited by
organ availability. Patients with refractory ascites experience considerable
deterioration in quality of life from
abdominal discomfort and difculty
breathing. The only option for them
is removal of this fuid every few
weeks in a hospital or clinical setting.
Dr. Nimgaonkar and his colleagues
have developed a wireless implantable
shunt technology to pull the fuid
from the peritoneal space into the
stomach. With this approach, patients
can manage their fuid drainage needs
at home – signifcantly improving
their quality of life, as well as reducing
the cost of care associated with frequent hospital visits.
Dr. Nimgaonkar and colleagues
have demonstrated proof-of-concept
for this approach in animal models
and built shunt prototypes. The
AGA–Boston Scientifc Career Development Technology & Innovation
Award will enable Dr. Nimgaonkar to
continue to refne and test this newly
developed technology.
“This award enables young investigators to develop their research careers
and ensures that their valuable time
is spent researching unique and novel
technology for clinical care,” said David
Pierce, senior vice president and president, endoscopy, Boston Scientifc. “We
are pleased to support this project and
wish Dr. Nimgaonkar much success in
his endeavors.”
The AGA–Boston Scientifc Career
Development Technology & Innovation Award provides Dr. Nimgaonkar
with $180,000 over 2 years – ensuring
that a major proportion of his time is
protected for research.
AGA announced its partnership
with Boston Scientifc in September 2013. In addition to funding
this award, Boston Scientifc’s grant
provides ongoing support to AGA’s
central initiatives in technology and
research, including the AGA Center
for GI Innovation and Technology,
the annual AGA Technology Summit, and the AGA Research Foundation Corporate Roundtable.
[email protected]
Pages 16a—16b u
NEWS FROM THE AGA
GIHEP NEW S. COM • M AY 2015
17
AGA Strategic Plan 2015-2020: Something that matters
Publications
Lead the GI/hepatology category of scientifc
journals in rank, reach and accessibility while
meeting the readership needs of basic and clinical
investigators, practitioners, young GIs and
trainees.
• Achieve and maintain high-impact factors for all
journals.
• Rank highest in the feld for meeting the readership needs of basic and clinical investigators, practitioners, young GIs and trainees.
• Expand journals’ reach via new content dissemination technologies.
• Increase usage of the journals’ digital platforms.
BY JOHN I. ALLEN, M.D., MBA, AGAF,
PRESIDENT, AGA INSTITUTE
Overview of the plan
Two words describe each of the 3 fundamental
AGA areas as illustrated in the triangular portion
of the plan (Figure 1). For example practice and
quality were paired intentionally to emphasize
their close connection and the AGA’s increasing
commitment to increasing the “value” (defned as
quality per unit cost) of our GI and liver care.
Research is critical to our advancing science, but
needs to be coupled with AGA’s commitment to
promote innovation in medical device and therapeutic advances, through the AGA Center for GI
Innovation and Technology and the AGA Center
for Diagnostics and Therapeutics.
Finally, education must be paired with training
our physician and provider workforce in new and
emerging technologies. The plan includes specifc
reference to patients. Throughout the four goals
and supporting strategies, patient engagement,
patient voice and patient experience all are emphasized.
AGA Strategic Plan at a glance
Practice & quality
Defne optimal clinical practice and help gastroenterologists provide high-quality, high-value care.
• Within the framework of the Triple Aim, defne
high-value care for GI disorders.
• Increase the number of gastroenterologists reporting on quality of care.
• Build and engage an active grassroots network to
communicate and advise AGA of emerging practice issues and trends.
• Address evolving practice and reimbursement
models in all practice settings.
AGA InstItute
I
’m proud to share with you the new strategic
plan of the American Gastroenterological Association (AGA). Thanks to the hundreds of
members who worked to ensure that the plan is
responsive to the needs of thousands in the gastroenterology community.
Throughout the process of developing the strategic plan, the phrase “start something that matters1” echoed through my head. In 1897, a group
of physicians started the AGA to make a diference
in the lives of their colleagues and their patients.
Since that time, AGA has been the driving force
behind advances that matter in gastroenterology
and Hepatology research and practice. We have
made staggering scientifc discoveries and applied
them to improve patient care. However, we still
have so much more to learn, and that’s why the
AGA Strategic Plan matters.
AGA, at our heart, is a learning organization.
This new strategic plan will lead us to new discoveries in GI science, new tools to improve patient
care, new ways to educate ourselves and the gastroenterologists of the future. Together we will
shape a bright future for gastroenterology and our
patients.
Ultimately, the AGA Strategic Plan will mobilize
the resources of our organization to fulfll our
mission of advancing the science and practice of
gastroenterology.
Figure 1. Diagrammatic representation of the AGA
Strategic Plan. Key sections are linked together
(such as Practice and Quality) to represent the need
to coordinate them organizationally.
Research & innovation
Foster scientifc discovery and the application of
new knowledge to improve care of patients with
digestive disease.
• Target junior faculty engaged in research for special support.
• Increase strategic innovation and research collaborations to promote high-value clinical care.
• Support promising advances in research and innovation.
Education & training
Engage members and other GI health providers
through personalized education across the continuum of their careers.
• Help members satisfy requirements for certifcation, recertifcation, continuing medical education
and licensure.
• Educate members about emerging technologies,
procedures and scientifc discoveries to improve
patient care.
• Help members and other learners develop their
careers and navigate transitions.
• Use state-of-the-art and innovative technology
platforms for learning.
AGA section
Advocacy
Infuence public policies to support quality patient care, improve the practice of gastroenterology, and advance digestive disease research and
education.
• Pursue policies that ensure patients have access
to appropriate, afordable, high-value GI care.
• Increase opportunities for funding digestive disease research.
• Develop a grassroots network to advocate for
improvements in patient care, increased research
funding and the viability of GI practice.
• Strongly advocate for sufcient federal funding
of academic training programs.
Organizational vitality
Maintain a robust and diverse membership, develop society leaders, foster strategic collaborations,
and maintain an infrastructure that supports AGA’s
mission and goals.
• Increase AGA’s membership.
• Develop a sustainable global strategy.
• Conduct leadership development and prepare
members to serve in volunteer leadership positions
within AGA.
• Strive for diversity at all levels within the association, including governance, committee structure,
stafng and program development. Diversity is an
inclusive concept that encompasses race, ethnicity,
national origin, religion, gender, age, sexual orientation and disability.
The planning process
In revising the plan, AGA leadership decided to
focus in some interesting and innovative ways.
Before Digestive Disease Week (DDW) 2014,
Anil Rustgi (immediate past president) and I appointed 4 task forces each composed of scientists,
academic clinicians, community practitioners,
and AGA staf. The task forces were assigned to
consider 1 of 3 topics, refected in the triangular
fgure of our plan (Figure 1): research and innovation, practice and quality, and education and
training. We also assigned AGA leadership and
staf to focus on additional AGA areas including
advocacy, publications, communications and organizational vitality.
The task forces identifed key goals and strategies
at meetings during DDW and subsequent teleconferences. Input from more than 75 members and
staf helped shape the initial plan. In July 2014,
the AGA Governing Board met for a 3-day retreat
during which ideas were distilled into the plan we
have today.
Reference
1. Mycoskie B. Start something that matters. New
York, NY: Spiegel and Grau, 2011.
Acknowledgements
Thanks to everyone who contributed to this plan
and those who will use it and improve upon it in
the future. We all look forward to a bright future
for gastroenterology. This article appeared previously in Gastroenterology (2015;148:1053–4). The
author discloses no conficts.
[email protected]
18
LIVER DISEASES
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
New hepatitis treatments cost effective for some
BY KARI OAKES
Frontline Medical News
F
or individuals infected with hepatitis C virus (HCV), new regimens
are highly efective, but also very
expensive, at approximately $28,000
for 4 weeks of treatment. However,
the treatment is cost efective for HCV
patients with cirrhosis and for those
without cirrhosis who have failed other
treatments, according to a new study.
In an analysis of the cost efectiveness of sofosbuvir-based treatments
for patients with HCV genotypes 2
and 3, Dr. Benjamin Linas of Boston
Medical Center reported that when
compared with pegylated interferon
and ribavirin therapy, treatment regimens based on the new direct-acting
antiviral are only cost efective for
select groups (Ann. Intern Med. 2015
[doi:10.7326/M15-0674]).
Cure rates with sofosbuvir are
higher than rates with the previous
standard of care, and sustained virologic response (SVR) “is associated
with a greatly reduced lifetime risk for
AGA Resources
Review the AGA Hepatitis C
Clinical Service Line to learn
more about managing the disease
at www.gastro.org/practice/
clinical-service-line/hcv-clinicalservice-line
liver-related morbidity and mortality,”
noted Dr. Linas and his colleagues.
Using sophisticated statistical modeling to compare HCV treatment
with pegylated interferon and ribavirin – the previous standard of care
– to the newly Food and Drug Administration–approved sofosbuvir-ribavirin regimen, Dr. Linas explored
clinical outcomes and costs for several diferent patient groups, including
treatment-naive and treatment-experienced HCV genotype 2 and 3 patients with and without cirrhosis.
Clinical outcomes, modeled from
clinical trial and observational cohort
data, were expressed as life expectancy in quality-adjusted life-years
(QALYs) and lifetime medical costs.
Investigators then calculated the
incremental cost-efectiveness ratio
(ICER) for each treatment strategy,
dividing any additional cost for a
more expensive treatment by the QALYs gained from this regimen.
Using the commonly accepted
ICER threshold of $100,000 per QALY,
Dr. Linas and colleagues concluded
that sofosbuvir-based HCV therapy
for treatment-naive patients without
cirrhosis was not cost efective, with
ICERs of $238,000-$266,000. Interferon-based treatments, they noted, still
achieve an approximately 80% rate of
cure in this population.
In the constrained resources of the
real world, Dr. Linas and his associates noted that this analysis is import-
ant. “Treatment strategies that do
not use limited resources where they
are likely to have the greatest impact
may result in unequal access to interferon-free regimens, thereby limiting
the population-level benefts of new
HCV treatments,” they said.
The National Institute on Drug
Abuse and the National Institute of
Allergy and Infectious Disease provided
funding. Dr. Milton Weinstein reported
compensation from OptumInsight; Dr.
Arthur Kim received grants and compensation from Gilead, AbbVie, and
Bristol-Myers Squibb. The other authors reported no relevant disclosures.
[email protected]
PERSPECTIVE
HCV cost-effectiveness analysis raises
tough questions for payers
I
n an editorial accompanying Dr.
Linas’ study, Dr. Etzion and Dr.
Ghany placed this analysis of the
cost-efectiveness of sofosbuvir in
the context of payer and clinician
priorities. They noted that “from
the patient and physician perspective, the benefts of new treatment
are evident.” For payers, however,
resources are constrained and tough
decisions will have to be made.
This cost-efectiveness analysis
is needed to inform resource allocation decisions, since the cost
of using direct-acting antivirals to
treat all those infected in the United States alone would exceed $300
billion. In that context, the editorial noted, quality-of-life assessments
become important. HCV infection
causes relatively little diminution
of quality of life until the stage of
cirrhosis is reached; in this analysis,
therefore, interferon-based regimens are still a reasonable choice
for treatment-naive HCV patients
without cirrhosis.
Though Dr. Linas’ study also
models incremental cost-efectiveness ratios for various lower price
points for sofosbuvir, the editorial
authors point out that the price point
for the public’s willingness to eradicate HCV has not been established.
Dr. Ohad Etzion and Dr. Marc G.
Ghany are at the National Institute
of Diabetes and Digestive and Kidney Diseases, National Institutes of
Health, Bethesda, Md. Dr. Ghany
reported nonfnancial support from
Bristol-Meyers Squibb.
Novel HCV therapies found cost effective, with caveats
BY MARY ANN MOON
Frontline Medical News
T
wo diferent statistical models found that novel
therapies for chronic HCV infection, particularly the combination of sofosbuvir and ledipasvir,
are cost efective in most patients, according to
separate reports published online in Annals of Internal Medicine.
The novel therapies, which typically contain sofosbuvir in combination with ledipasvir, simeprevir,
or daclatasvir, substantially reduce the length of
treatment, achieve much higher rates of sustained
viral response (SVR), and ofer interferon-free alter-
natives for patients who can’t tolerate or don’t respond to standard interferon-based treatments. Both
statistical models were developed to examine this
issue, but from diferent perspectives.
In one study, investigators constructed a model that
simulated 120 possible clinical courses of HCV-infectContinued on page 20
PERSPECTIVE
Is the price of treatment too high? To whom?
T
he development and widespread use of highly
efcacious direct-acting antiviral agents (DAAs)
represent a paradigm shift in which the retail cost
of treatment is now the most signifcant barrier
to hepatitis C virus (HCV) eradication. We have
begun to learn the medical value of curing HCV
in the context of the staggering burden of chronic
liver disease, but less is known about the economic
value of the cost of therapy. There has been public
outcry over the $1,000 per pill price tag of sofosbuvir, but demand for the medications remains
high as nearly all HCV-infected patients are now
treatment eligible. These studies collectively
demonstrate a favorable incremental cost-efectiveness ratio per adjusted life-year relative to interferon-containing regimens in most patients with
HCV: genotype 1, treatment experienced, and
cirrhotic.
And these studies illustrate the paradox at
the crux of the issue: How can the novel HCV
therapies be both cost efective for most HCV
patients but simultaneously unafordable for payers? Although the price of achieving a sustained
virologic response is reduced with the DAA reg-
imens, the cost of treating all infected patients in
the U.S. could exceed $300 billion, which greatly
outweighs the short-term cost of the annual
HCV-related burden (about $6.5 billion [Hepatology 2013;57:2164-70]). Treatment of other chronic
illnesses such as HIV may incur greater costs but
they are distributed over a lifetime. Ultimately, value depends on perspective; payers may balk at the
price for the same cure that our patients consider
invaluable.
Dr. J.P. Norvell is assistant professor of medicine, Emory University, Atlanta. He has been a consultant to
Gilead Sciences.
Hepatic Encephalopathy (HE)
EPISODES CAUSE COGNITIVE DYSFUNCTIONS.
by 2014
SOME MAY BE IRREVERSIBLE Supported
AASLD/EASL HE guidelines
1
Xifaxan® (rifaximin) 550 mg tablets are indicated for reduction in risk of overt hepatic
encephalopathy (HE) recurrence in patients ≥ 18 years of age.
Manage HE patients continuously with a Xifaxan 550 mg tablet twice daily
The most common adverse reactions occurring in ≥10% of patients and at a higher incidence than placebo in
the clinical study were peripheral edema (15%), nausea (14%), dizziness (13%), fatigue (12%), and ascites (11%).
Important Safety Information about XIFAXAN 550 mg
XIFAXAN® (rifaximin) 550 mg tablets are contraindicated
in patients with a hypersensitivity to rifaximin, any of
the rifamycin antimicrobial agents, or any of the
components in XIFAXAN. Hypersensitivity reactions have
included exfoliative dermatitis, angioneurotic edema,
and anaphylaxis.
Clostridium difficile-associated diarrhea (CDAD) has
been reported with use of nearly all antibacterial agents,
including XIFAXAN, and may range in severity from mild
diarrhea to fatal colitis. Treatment with antibacterial
agents alters the normal flora of the colon which may
lead to overgrowth of C. difficile. If CDAD is suspected
or confirmed, ongoing antibiotic use not directed against
C. difficile may need to be discontinued.
There is increased systemic exposure in patients with more
severe hepatic dysfunction. The clinical trials were limited
to patients with MELD scores < 25. Therefore, caution
should be exercised when administering XIFAXAN to patients
with severe hepatic impairment (Child-Pugh C).
Xifaxan 550 mg is licensed by Alfa Wassermann S.p.A.
to Salix Pharmaceuticals, Inc.
Concomitant administration of drugs that are P-glycoprotein
(P-gp) inhibitors with XIFAXAN can substantially increase
the systemic exposure to XIFAXAN. Caution should be
exercised when concomitant use of XIFAXAN and a P-gp
inhibitor such as cyclosporine is needed. In patients with
hepatic impairment, a potential additive effect of reduced
metabolism and concomitant P-gp inhibitors may further
increase the systemic exposure to XIFAXAN.
Based on animal data, XIFAXAN may cause fetal harm.
Discontinue in nursing mothers after taking into account
the importance of the drug to the mother.
The most common adverse reactions occurring in ≥10%
of patients and at a higher incidence than placebo in
the clinical study were peripheral edema (15%), nausea
(14%), dizziness (13%), fatigue (12%), and ascites (11%).
Please see brief summary on reverse.
Web site: www.salix.com
8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597)
©2015 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. XIFH-US-0073-v1
GIHEP_19.indd 1
References: 1. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic
encephalopathy in chronic liver disease: 2014 practice guideline
by the American Association for the Study of Liver Diseases and
the European Association for the Study of the Liver. Hepatology.
2014; 60(2):715-735. 2. Xifaxan [prescribing information]. Raleigh,
NC: Salix Pharmaceuticals, Inc; 2014.
*Over a 6-month period in a double-blind, placebo-controlled clinical
trial; P<0.0001 vs placebo.2
Prescribe. Protect. Repeat.
3/23/2015 10:28:44 AM
20
LIVER DISEASES
Continued from page 18
ed adults of diferent ages and sexes,
treatment histories, HCV genotypes,
fbrosis scores, and interferon tolerances. For each of these patient profles,
they ran simulations in which patients
received either “the old standard of
care” (peginterferon and ribavirin, with
The following is a brief summary only. See complete Prescribing
Information on www.Xifaxan550.com or request complete prescribing
information by calling 1-800-508-0024.
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
or without boceprevir and telaprevir)
or sofosbuvir plus ledipasvir.
The per-patient cost of standard
care ranged from $15,000 to $71,000,
depending on the patient profle; that
of sofosbuvir-ledipasvir ranged from
$66,000 to $154,000, said Jagpreet
Chhatwal, Ph.D., of the University of
Texas MD Anderson Cancer Center,
Table 1: Adverse Reactions Occurring in ≥ 5% of Patients
Receiving XIFAXAN and at a Higher Incidence Than Placebo
Number (%) of Patients
INDICATIONS AND USAGE
To reduce the development of drug-resistant bacteria and maintain the
effectiveness of XIFAXAN and other antibacterial drugs, XIFAXAN when
used to treat infection should be used only to treat or prevent infections
that are proven or strongly suspected to be caused by susceptible
bacteria. When culture and susceptibility information are available, they
should be considered in selecting or modifying antibacterial therapy. In
the absence of such data, local epidemiology and susceptibility
patterns may contribute to the empiric selection of therapy.
Hepatic Encephalopathy
XIFAXAN 550 mg is indicated for reduction in risk of overt hepatic
encephalopathy (HE) recurrence in patients ≥ 18 years of age.
In the trials of XIFAXAN for HE, 91% of the patients were using
lactulose concomitantly. Differences in the treatment effect of those
patients not using lactulose concomitantly could not be assessed.
XIFAXAN has not been studied in patients with MELD (Model for EndStage Liver Disease) scores > 25, and only 8.6% of patients in the
controlled trial had MELD scores over 19. There is increased systemic
exposure in patients with more severe hepatic dysfunction.
CONTRAINDICATIONS
MedDRA Preferred Term
XIFAXAN Tablets
550 mg TWICE DAILY
N = 140
Placebo
N = 159
Edema peripheral
Nausea
21 (15%)
20 (14%)
13 (8%)
21 (13%)
Dizziness
18 (13%)
13 (8%)
Fatigue
17 (12%)
18 (11%)
Ascites
16 (11%)
15 (9%)
Muscle spasms
13 (9%)
11 (7%)
Pruritus
13 (9%)
10 (6%)
Abdominal pain
12 (9%)
13 (8%)
12 (8%)
Abdominal distension
11 (8%)
Anemia
11 (8%)
6 (4%)
Cough
10 (7%)
11 (7%)
Depression
10 (7%)
8 (5%)
Insomnia
10 (7%)
11 (7%)
Nasopharyngitis
10 (7%)
10 (6%)
Abdominal pain upper
9 (6%)
8 (5%)
Arthralgia
9 (6%)
4 (3%)
Back pain
9 (6%)
10 (6%)
Constipation
9 (6%)
10 (6%)
WARNINGS AND PRECAUTIONS
Dyspnea
9 (6%)
7 (4%)
Travelers’ Diarrhea Not Caused by Escherichia coli
Pyrexia
Rash
9 (6%)
7 (5%)
5 (3%)
6 (4%)
Hypersensitivity
XIFAXAN is contraindicated in patients with a hypersensitivity to
rifaximin, any of the rifamycin antimicrobial agents, or any of the
components in XIFAXAN. Hypersensitivity reactions have included
exfoliative dermatitis, angioneurotic edema, and anaphylaxis.
XIFAXAN was not found to be effective in patients with diarrhea
complicated by fever and/or blood in the stool or diarrhea due to
pathogens other than Escherichia coli.
Discontinue XIFAXAN if diarrhea symptoms get worse or persist
more than 24-48 hours and alternative antibiotic therapy should
be considered.
XIFAXAN is not effective in cases of travelers’ diarrhea due to
Campylobacter jejuni. The effectiveness of XIFAXAN in travelers’ diarrhea
caused by Shigella spp. and Salmonella spp. has not been proven. XIFAXAN
should not be used in patients where Campylobacter jejuni, Shigella spp.,
or Salmonella spp. may be suspected as causative pathogens.
Clostridium diffcile-Associated Diarrhea
Clostridium diffcile-associated diarrhea (CDAD) has been reported with
use of nearly all antibacterial agents, including XIFAXAN, and may range
in severity from mild diarrhea to fatal colitis. Treatment with antibacterial
agents alters the normal fora of the colon which may lead to overgrowth
of C. diffcile.
C. diffcile produces toxins A and B which contribute to the development
of CDAD. Hypertoxin producing strains of C. diffcile cause increased
morbidity and mortality, as these infections can be refractory to antimicrobial
therapy and may require colectomy. CDAD must be considered in all
patients who present with diarrhea following antibiotic use. Careful
medical history is necessary since CDAD has been reported to occur over
two months after the administration of antibacterial agents.
If CDAD is suspected or confrmed, ongoing antibiotic use not directed
against C. diffcile may need to be discontinued. Appropriate fuid
and electrolyte management, protein supplementation, antibiotic
treatment of C. diffcile, and surgical evaluation should be instituted as
clinically indicated.
Development of Drug Resistant Bacteria
Prescribing XIFAXAN for travelers’ diarrhea in the absence of a proven or
strongly suspected bacterial infection or a prophylactic indication is
unlikely to provide beneft to the patient and increases the risk of the
development of drug-resistant bacteria.
Severe (Child-Pugh C) Hepatic Impairment
There is increased systemic exposure in patients with severe hepatic
impairment. Animal toxicity studies did not achieve systemic exposures
that were seen in patients with severe hepatic impairment. The clinical
trials were limited to patients with MELD scores <25. Therefore, caution
should be exercised when administering XIFAXAN to patients with
severe hepatic impairment (Child-Pugh C).
Concomitant Use With P-glycoprotein Inhibitors
The following adverse reactions, presented by body system, have also
been reported in the placebo-controlled clinical trial in greater than 2%
but less than 5% of patients taking XIFAXAN 550 mg taken orally two
times a day for hepatic encephalopathy. The following includes adverse
events occurring at a greater incidence than placebo, regardless of causal
relationship to drug exposure.
Ear and Labyrinth Disorders: Vertigo
Gastrointestinal Disorders: Abdominal pain lower, abdominal tenderness,
dry mouth, esophageal variceal bleed, stomach discomfort
General Disorders and Administration Site Conditions: Chest pain,
generalized edema, infuenza like illness, pain NOS
Infections and Infestations: Cellulitis, pneumonia, rhinitis, upper respiratory
tract infection NOS
Injury, Poisoning and Procedural Complications: Contusion, fall, procedural pain
Investigations: Weight increased
Metabolic and Nutritional Disorders: Anorexia, dehydration,
hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia
Musculoskeletal, Connective Tissue, and Bone Disorders: Myalgia,
pain in extremity
Nervous System Disorders: Amnesia, disturbance in attention,
hypoesthesia, memory impairment, tremor
Psychiatric Disorders: Confusional state
Respiratory, Thoracic, and Mediastinal Disorders: Epistaxis
Vascular Disorders: Hypotension
Postmarketing Experience
The following adverse reactions have been identifed during post
approval use of XIFAXAN. Because these reactions are reported
voluntarily from a population of unknown size, estimates of frequency
cannot be made. These reactions have been chosen for inclusion due
to either their seriousness, frequency of reporting or causal connection
to XIFAXAN.
Infections and Infestations
Cases of C. diffcile-associated colitis have been reported.
General
Hypersensitivity reactions, including exfoliative dermatitis, rash,
angioneurotic edema (swelling of face and tongue and diffculty swallowing),
urticaria, fushing, pruritus and anaphylaxis have been reported. These
events occurred as early as within 15 minutes of drug administration.
DRUG INTERACTIONS
Effects of Rifaximin on Cytochrome P450 Enzymes
ADVERSE REACTIONS
In vitro studies have shown that rifaximin did not inhibit cytochrome
P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 at
concentrations ranging from 2 to 200 ng/mL. Rifaximin is not expected
to inhibit these enzymes in clinical use.
An in vitro study has suggested that rifaximin induces CYP3A4. However,
in patients with normal liver function, rifaximin at the recommended dosing
regimen is not expected to induce CYP3A4. It is unknown whether
rifaximin can have a signifcant effect on the pharmacokinetics of
concomitant CYP3A4 substrates in patients with reduced liver function
who have elevated rifaximin concentrations.
Clinical Studies Experience
Concomitant P-glycoprotein Inhibitors
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 refect the rates observed in practice.
An in vitro study suggested that rifaximin is a substrate of P-glycoprotein.
Co-administration of cyclosporine, a potent P-glycoprotein inhibitor, with
rifaximin resulted in 83-fold and 124-fold increases in rifaximin mean Cmax
and AUC∞ in healthy subjects. The clinical signifcance of this increase in
systemic exposure is unknown.
Concomitant administration of drugs that are P-glycoprotein inhibitors
with rifaximin can substantially increase the systemic exposure to
rifaximin. Caution should be exercised when concomitant use of rifaximin
and a P-glycoprotein inhibitor such as cyclosporine is needed. In patients
with hepatic impairment, a potential additive effect of reduced metabolism
and concomitant P-glycoprotein inhibitors may further increase the
systemic exposure to rifaximin.
Hepatic Encephalopathy
The data described below refect exposure to XIFAXAN 550 mg in 348
patients, including 265 exposed for 6 months and 202 exposed for more
than a year (mean exposure was 364 days). The safety of XIFAXAN 550
mg taken two times a day for reducing the risk of overt hepatic
encephalopathy recurrence in adult patients was evaluated in a 6-month
placebo-controlled clinical trial (n = 140) and in a long term follow-up
study (n = 280). The population studied had a mean age of 56.26 (range:
21-82) years; approximately 20% of the patients were ≥ 65 years old,
61% were male, 86% were White, and 4% were Black. Ninety-one
percent of patients in the trial were taking lactulose concomitantly. All
adverse reactions that occurred at an incidence ≥ 5% and at a higher
incidence in XIFAXAN 550 mg-treated subjects than in the placebo
group in the 6-month trial are provided in Table 1. (These include
adverse events that may be attributable to the underlying disease).
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are no adequate and well controlled studies in pregnant women.
Rifaximin has been shown to be teratogenic in rats and rabbits at doses
that caused maternal toxicity. XIFAXAN tablets should be used during
pregnancy only if the potential beneft justifes the potential risk to
the fetus.
Administration of rifaximin to pregnant rats and rabbits at dose levels
that caused reduced body weight gain resulted in eye malformations in
both rat and rabbit fetuses. Additional malformations were observed in
fetal rabbits that included cleft palate, lumbar scoliosis, brachygnathia,
interventricular septal defect, and large atrium.
Houston, and his associates.
Compared with standard care,
treating 10,000 patients with sofosbuvir-ledipasvir was projected to
prevent 600 cases of decompensated
cirrhosis, 310 cases of hepatocellular
carcinoma (HCC), 60 liver transplantations, and 550 liver-related deaths.
Compared with standard care, the in-
The fetal rat malformations were observed in a study of pregnant rats
administered a high dose that resulted in 16 times the therapeutic dose
to diarrheic patients or 1 times the therapeutic dose to patients with
hepatic encephalopathy (based upon plasma AUC comparisons). Fetal
rabbit malformations were observed from pregnant rabbits administered
mid and high doses that resulted in 1 or 2 times the therapeutic dose to
diarrheic patients or less than 0.1 times the dose in patients with hepatic
encephalopathy, based upon plasma AUC comparisons.
Post-natal developmental effects were not observed in rat pups from
pregnant/lactating female rats dosed during the period from gestation
to Day 20 post-partum at the highest dose which resulted in
approximately 16 times the human therapeutic dose for travelers’
diarrhea (based upon AUCs) or approximately 1 times the AUCs derived
from therapeutic doses to patients with hepatic encephalopathy.
Nursing Mothers
It is not known whether rifaximin is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential for
adverse reactions in nursing infants from XIFAXAN, a decision should be
made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of XIFAXAN 200 mg in pediatric
patients with travelers’ diarrhea less than 12 years of age have not
been established.
The safety and effectiveness of XIFAXAN 550 mg for HE have not
been established in patients < 18 years of age.
Geriatric Use
Clinical studies with rifaximin 200 mg for travelers’ diarrhea did not
include suffcient numbers of patients aged 65 and over to determine
whether they respond differently than younger subjects.
In the controlled trial with XIFAXAN 550 mg for hepatic encephalopathy,
19.4% were 65 and over, while 2.3% were 75 and over. No overall
differences in safety or effectiveness were observed between these
subjects and younger subjects, and other reported clinical experience has
not identifed differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be
ruled out.
Renal Impairment
The pharmacokinetics of rifaximin in patients with impaired renal
function has not been studied.
Hepatic Impairment
Following administration of XIFAXAN 550 mg twice daily to patients with
a history of hepatic encephalopathy, the systemic exposure
(i.e., AUCt) of rifaximin was about 10-, 13-, and 20-fold higher in those
patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe
(Child-Pugh C) hepatic impairment, respectively, compared to that in
healthy volunteers. No dosage adjustment is recommended because
rifaximin is presumably acting locally. Nonetheless, caution should be
exercised when XIFAXAN is administered to patients with severe
hepatic impairment.
PATIENT COUNSELING INFORMATION
Persistent Diarrhea
For those patients being treated for travelers’ diarrhea, discontinue XIFAXAN
if diarrhea persists more than 24-48 hours or worsens. Advise the patient to
seek medical care for fever and/or blood in the stool.
Clostridium diffcile-Associated Diarrhea
Clostridium diffcile-associated diarrhea (CDAD) has been reported with
use of nearly all antibacterial agents, including XIFAXAN, and may range
in severity from mild diarrhea to fatal colitis. Treatment with antibiotics
alters the normal fora of the colon which may lead to C. diffcile. Patients
can develop watery and bloody stools (with or without stomach cramps
and fever) even as late as two or more months after having taken the last
dose of the antibiotic. If diarrhea occurs after therapy or does not improve
or worsens during therapy, advise patients to contact a physician as soon
as possible.
Administration With Food
Inform patients that XIFAXAN may be taken with or without food.
Antibacterial Resistance
Counsel patients that antibacterial drugs including XIFAXAN should only
be used to treat bacterial infections. They do not treat viral infections
(e.g., the common cold). When XIFAXAN is prescribed to treat a
bacterial infection, patients should be told that although it is common to
feel better early in the course of therapy, the medication should be taken
exactly as directed. Skipping doses or not completing the full course of
therapy may (1) decrease the effectiveness of the immediate treatment
and (2) increase the likelihood that bacteria will develop resistance and
will not be treatable by XIFAXAN or other antibacterial drugs in
the future.
Severe Hepatic Impairment
Patients should be informed that in patients with severe hepatic impairment
(Child-Pugh C) there is an increase in systemic exposure to XIFAXAN.
You are encouraged to report negative side effects of prescription
drugs to the FDA. Visit http://www.fda.gov/medwatch or call
1-800-FDA-1088.
To report adverse events, a product complaint, or for additional information,
call: 1-800-508-0024.
Manufactured for:
Salix Pharmaceuticals, Inc.
8510 Colonnade Center Drive, Raleigh, NC 27615
http://www.salix.com
XIFAXAN® is a trademark of Alfa Wassermann S.p.A., used under
license by Salix Pharmaceuticals, Inc.
Copyright © Salix Pharmaceuticals, Inc.
cremental cost-efectiveness ratio of
sofosbuvir-ledipasvir was $55,400 per
additional quality-of-life-year (QALY)
gained, which falls well within the accepted range (Ann. Intern. Med. 2015
[doi:10.7326/M14-1336]).
But there was an important caveat:
More patients are eligible because the
novel therapies are much more easily
tolerated. Compared with standard
care, giving these novel HCV therapies to all eligible patients “would cost
an additional $65 billion in the next 5
years,” which would not be counterbalanced by the estimated $16 billion
saved by preventing cirrhosis, HCC, and
transplantations.
Therefore, “despite the cost-efectiveness of [novel] HCV treatments, our
analysis shows that it is unafordable at
the current price,” Dr. Chhatwal and
his associates said.
In the other study, researchers developed a discrete-event simulation
model of the progression of liver
disease in treatment-naive patients,
categorized by whether they were
infected with HCV genotype 1, 2, or
3. Several treatment regimens were
considered for each genotype, and
the SVR rates they were projected
to attain were derived from those
reported in clinical trials, said Mehdi
Najafzadeh, Ph.D., of the division of
pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical
School, Boston, and his associates.
“The newly approved PEG-free
regimen of sofosbuvir-ledipasvir for
12 weeks could be very cost-efective
relative to usual care (costing $12,825/
QALY gained) for patients with HCV
genotype 1.” This treatment proved to
be the optimal strategy in the greatest
number of simulations involving genotype 1. For genotype 3, sofosbuvir-ledipasvir plus ribavirin for 12 weeks cost
$73,000/QALY gained, compared with
usual care. This represents “relatively
good value.” However, for genotype 2
the most cost-efective novel therapy,
sofosbuvir-ribavirin, was $110,168/
QALY gained, which is not considered
cost efective, Dr. Najafzadeh and his
associates said (Ann. Intern. Med. 2015
[doi:10.7326;M14-1152]).
Dr. Chhatwal’s study was supported
by the National Center for Advancing
Translational Sciences and the VA
Health Services Research and Development Center for Innovations in
Quality, Efectiveness, and Safety. Dr.
Najafzadeh’s study was supported by
an unrestricted grant from CVS Health
to Brigham and Women’s Hospital and
by a Canadian Institutes of Health Research fellowship. Both groups’ disclosures are available at www.annals.org.
[email protected]
Know the difference.
Make a difference.
a potent probiotic medical food
VSL#3 provides clinically proven benefts in the dietary management of UC and an ileal pouch.Recognized by the ACG
Practice Parameter Committee1 and the Cochrane Library2 as an effective tool for the management of pouchitis. VSL#3 adds
billions of bacteria to the microbial barrier restoring balance and diversity in the GI tract.3
The research of the Human Microbiome Project [http://hmpdacc.org/] is investigating key links between human health and
the balance of specifc microbes in the human gut.
Knowing the difference makes all the difference when it comes to probiotic health.
References:
1. Kornblut A, et al. Am J Gastroenterol. 2004;99(7):1371-1385.
2. Holubar SD, et al. The Cochrane Library. 2010, Issue 6.
3. Gionchetti P, et al. Gastroenterology, 2000;119(2):305-309.
VSL#3 is a high potency probiotic medical food that must be used under medical supervision.
www.vsl3.com
Made in U.S.A. Distributed by Sigma-Tau Pharmaceuticals, Inc. Gaithersburg, M.D. ©2014 Sigma-Tau Pharmaceuticals. All rights reserved V1166 03/15
GIHEP_21.indd 1
3/24/2015 1:47:56 PM
22
LIVER DISEASES
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
Obeticholic acid for NASH improves markers, fbrosis
BY KARI OAKES
Frontline Medical News
F
or patients with nonalcoholic steatohepatitis
(NASH), a bile acid derivative that acts on a
nuclear receptor reduced liver fat and fbrosis,
but patients taking the drug also had worsening in
serum lipid values and increased insulin resistance.
The lipophilic bile acid obeticholic acid showed
promise in the FLINT trial (Farnesoid X Receptor
Ligand Obeticholic Acid in NASH Treatment) for
NASH patients whose liver disease improved but
did not resolve.
Dr. Brent Neuschwander-Tetri of Saint Louis
University, and coinvestigators in the National
Institute of Diabetes and Digestive and Kidney
Diseases’ NASH Clinical Research Network, conducted the multicenter, randomized, placebo-controlled study. The fndings were published in the
Lancet.
Obeticholic acid, a farnesoid X nuclear receptor
agonist, works at a site whose activation promotes
increased insulin sensitivity and decreased serum
triglycerides. Serum lipids may also be improved
by increased peripheral clearance of VLDL, increased reverse cholesterol transport, and reduced
lipid synthesis in the liver. Currently, the only
other treatments for NASH, aside from diet and
lifestyle modifcations, are thiazolidinediones and
vitamin E. Long-term safety and efcacy of these
medications are unknown, especially in NASH
patients with diabetes (Lancet 2015;385:956-65
[doi:10.1016/S0140-6736(14)61933-4]).
Study participants were adults with biopsy-con-
VITALS
Key clinical point: The farnesoid X nuclear receptor
agonist obeticholic acid improved clinical markers
of nonalcoholic steatohepatitis (NASH) but increased serum cholesterol.
Major fnding: Of patients assigned to receive liver
biopsies, 50/110 (45%) receiving obeticholic acid
showed improvement in liver histology compared
with 23/109 (21%) in the placebo group (P =
.0002).
Data source: The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) study, a
72-week multicenter, double-blind, placebo-controlled trial of obeticholic acid for treatment of 283
patients with noncirrhotic NASH.
Disclosures: Dr. Neuschwander-Tetri disclosed
ties with Genentech/Roche, Nimbus Discovery,
Boehringer Ingelheim, and Bristol-Myers Squibb.
Several coinvestigators disclosed ties with various
companies, including Intercept Pharmaceuticals,
which provided partial funding for the trial under
a Collaborative Research and Development Agreement with the National Institute of Diabetes and
Digestive and Kidney Diseases.
frmed NASH or borderline NASH with histologic
steatosis, ballooning, and lobular infammation,
but without cirrhosis. The study excluded heavy
consumers of alcohol. Baseline and fnal assessments included liver biopsy and demographic and
anthropometric information, as well as metabolic
and lipid markers and liver enzymes.
FLINT’s primary outcome measure was improved liver histology, defned as a decrease of two
or more points on a nonalcoholic fatty liver disease
Correction
In the January 2015 issue (page 1, “Screen baby boomers, treat all hepatitis C”), Dr. Zobair Younossi’s conficts of interest were noted incorrectly. He is a consultant to AbbVie, BMS, Gilead, GSK, and Intercept.
None of the other study authors had any relevant conficts of interest.
The study was not supported by any pharmaceutical company.
(NAFLD) pathology scoring system, without a
worsening of liver fbrosis. Resolution of NASH
was a secondary outcome, as were changes in liver
enzymes, body measurements, and homeostasis
model of assessment of insulin resistance (HOMA-IR) levels.
The study’s Data Safety Monitoring Board recommended stopping biopsies after about half the
patients had received biopsies and the primary
histologic outcome measure was met, in order to
avoid unnecessary patient risk.
An intention-to-treat analysis found that 50
(45%) of 110 patients receiving obeticholic acid
had improved liver histology, compared with 23
(21%) of 109 patients receiving placebo (relative
risk 1.9, 95% CI: 1.3-2.8, P = .0002). This diference did not change with prespecifed subgroup
analyses. Serum AST and ALT measures decreased
signifcantly for the treatment group. The medication was generally well tolerated, though pruritis
developed in 33 (23%) of 141 patients in the intervention group and 9 (6%) of the placebo group.
Total serum cholesterol and LDL cholesterol,
however, increased for the obeticholic acid group,
while HDL cholesterol decreased. Insulin resistance as measured by HOMA-IR increased slightly
for the treatment group, an unexpected efect.
Study authors noted that this class of medication’s
efect on cholesterol transport is complex. “Future
studies of farnesoid X nuclear receptor agonists,”
they noted, “will need to address the consequences
of these changes on cardiovascular outcomes.”
[email protected]
Quick Quiz
Q1: As compared to patients who
acquire C. difcile infection in the
hospital setting, individuals with
community-associated C. difcile
infection are more likely to have
which of the following characteristics:
A. Male sex
B. Older age
C. On PPI therapy
D. Cancer patients
E. Recent antibiotic exposure
Q2: A 29-year-old man with a
history of moderate ulcerative
colitis diagnosed at the age of 22
has been in remission while on
6-mercaptopurine and sulfasalazine for approximately 3 years.
He was started on sulfasalazine at
diagnosis with improvement of his
symptoms. At the age of 26 he required multiple courses of steroids
for UC fares. As a result, 6-mer-
captopurine was added at a dose
of 1.5 mg/kg. Three months after
initiation of 6-mercaptopurine he
was in remission with one formed
bowel movement daily. He got
married about 2 years ago but he
and his wife have been unable to
have children despite unprotected
intercourse. As his gastroenterologist, what would you suggest?
A. Stop the 6-mercaptopurine and
the sulfasalazine.
B. Continue the 6-mercaptopurine
and the sulfasalazine.
C. Continue the 6-mercaptopurine. Switch the sulfasalazine to
Asacol® (mesalamine).
D. Continue sulfasalazine. Switch
the 6-mercaptopurine to infiximab.
E. Ask him to consult an in vitro
fertilization specialist.
The answers are on page 47.
Now, less is an option.
l
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prep and is now available as a value-branded generic. GaviLyte-H is part of our complete family
of generic PEG-3350 products, and is just one more example of how GAVIS Pharmaceuticals
is listening – and delivering – what patients, physicians and pharmacists want: a choice.
Learn more at gavilyte.com.
*HalfLytely is a registered trademark of Braintree Laboratories, Inc.
GIHEP_23.indd 1
4/14/2015 4:46:44 PM
24
GI ONCOLOGY
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
BUN and Khorana score predict pancreatic ca death
BY JENNIFER KELLY SHEPPHIRD
Frontline Medical News
U
sing parameters routinely collected in patients with pancreatic cancer, the Khorana
score and the blood urea nitrogen (BUN) level were signifcantly associated with early mortality
in patients with pancreatic cancer who underwent
surgical resection, according to a report published
in the journal Cancer.
VITALS
Key clinical point: High Khorana score and elevated blood urea nitrogen predicted early mortality
in patients after surgical resection for pancreatic
cancer.
Major fnding: For patients with elevated blood urea
nitrogen, the early mortality hazard ratio was 4.34
(95% CI, 1.84-10.25), and for high-risk Khorana
scores, this was 2.32 (1.04-5.13).
Data source: The retrospective cohort study used
medical chart data from 334 consecutive patients
who underwent surgical resection at the Cleveland
Clinic from 2006 to 2013.
Disclosures: Dr. Sohal reported having no disclosures. Dr. Khorana has received fees from several
industry sources for work outside of the current
study.
Dr. Davendra P.S. Sohal, an oncologist at
Cleveland Clinic, and his colleagues stated that
by identifying patients with resectable pancreatic adenocarcinoma who are at high risk of early
mortality, the parameters “may be used to stratify
patients, and ultimately may be used to select
high-risk patients for more aggressive therapies in
prospective studies” (Cancer 2015 [doi:10.1002/
cncr.29298]).
Multivariate analysis showed the risk for early
mortality (before 6 months) increased with highrisk Khorana score (hazard ratio, 2.32; 95% confdence interval, 1.04-5.13; P = .039) and elevated
blood urea nitrogen (HR, 4.34; 95% CI, 1.84-10.25;
P < .001). The authors noted that other key variables, such as TNM classifcation of malignant
tumor staging, were not associated with early
mortality.
The study evaluated 334 patients, median age 67
years, who underwent surgical resection of pancreatic adenocarcinoma during 2006-2013 at the
Cleveland Clinic. With a median follow-up time
of 39.4 months, there were 205 deaths (61%), and
median overall survival was 21.3 months. Within
30 days after surgery, 3 (0.9%) deaths occurred,
and within 6 months of surgery, 29 (8.7%) deaths
occurred. Most tumors were located in the head
of the pancreas (73%); most pathologic stages
were T3 (67%) and N1 (63%); median Khorana
score was 2; 47% of patients had a score ≥ 3; 59%
had comorbidities. Some of the patients received
preoperative anticancer therapy, making the study
population heterogeneous in that respect.
The Khorana score, a measure of venous thromboembolism risk, combines fve items: cancer site,
platelet count > 350/nL, white blood cell count
> 11/nL, hemoglobin <100 g/L, and body mass
index (BMI) ≥ 35 kg/m2; Khorana scores of 3 or
greater indicate high risk.
A novel fnding in patients with pancreatic cancer, elevated BUN levels have been previously
linked to poorer prognosis for patients with non–
small cell lung cancer and advanced malignancies
Variants near pathogenesis genes
Colon cancer from page 1
VITALS
Key clinical point: The protective effect
of aspirin and NSAIDs against colon
cancer was linked to three genetic
variants on chromosomes 12 and 15.
Major fnding: The prevalence of colon cancer was 28% among regular
users of aspirin/NSAIDs, compared
with 38% among nonusers, for an
odds ratio of 0.69.
Data source: A genome-wide analysis
of gene and environment interactions
using data from 17,187 participants
in 10 case-control studies conducted
over a 40-year period in Australia,
Canada, Germany, and the United
States.
Disclosures: The National Cancer Institute and the National Institutes of
Health supported the study. Dr. Nan
reported having no fnancial disclosures. One of her associates reported
holding a patent for aspirin as a colorectal chemopreventive agent and
two others reported ties to Arctic Dx,
Bayer Healthcare, Pfzer, and Pozen.
study, the investigators pooled data
from 10 observational studies conducted between 1976 and 2003 in
Australia, Canada, Germany, and the
United States, which enrolled 8,634
colon cancer case subjects and 8,553
control subjects matched for age,
sex, and race/ethnicity. Regular use
was defned for the pooled studies
and all of the study subjects were of
European descent.
Compared with nonuse of aspirin,
NSAIDs, or both, regular use was associated with a lower risk of colorectal cancer: The overall prevalence of
the disease was 28% among regular
users, compared with 38% among
nonusers, for an odds ratio of 0.69.
The regular use of aspirin alone also
was associated with a lower risk of
colorectal cancer: The prevalence
was 24% among regular users and
31% among nonusers, for an odds
ratio of 0.71.
This protective efect, however, and thus an NSAID user’s risk
who were receiving palliative care. Elevated BUN
levels may indicate subclinical renal dysfunction or
other comorbidities that infuence survival.
Univariate analysis in the current study did not
fnd an association between early mortality and
BMI, which may be due to the timing of the mea-
The parameters ‘may be used to
stratify patients, and ultimately
may be used to select highrisk patients for more aggressive
therapies in prospective studies.’
surement. Patients may experience cancer-induced
weight loss that renders BMI measures falsely low.
The association between BMI and decreased survival after pancreatic cancer diagnosis was found
previously to be strongest when BMI was taken 1820 years prior to diagnosis.
The authors note that although perioperative
mortality has improved considerably in recent
years, there exists a subgroup of patients who experience early recurrence.
“These patients may not beneft from the current standard of care but to our knowledge, little
is known regarding how best to identify such patients at high risk of early mortality,” wrote Dr.
Sohal and his associates. The current study identifes a simple set of baseline parameters that may
allow for “easy targeting of high-risk patients for
specifc interventions aimed at improving clinical
outcomes.”
for colorectal cancer, varied by
whether patients carried the genetic variants and how many copies
of the risk alleles they carried, Dr.
Nan and her associates said ( JAMA
2015;313:1133-42).
All three genetic variants are
located near genes known to be involved in the pathogenesis of colon
cancer, including genes that regulate
[email protected]
the production of proinfammatory prostaglandins and interleukins,
particularly within the gut. This
proximity supports the idea that
aspirin and NSAIDs exert their
gut-protective efects through these
infammatory mediators, the investigators said.
[email protected]
PERSPECTIVE
Aspirin/NSAIDs to prevent colon cancer
T
hese fndings add complexity to, but do not answer, the
longstanding clinical question of
whether healthy adults should take
aspirin regularly to reduce their
risk of colon cancer.
In the not-too-distant future, it
will become afordable and practical to conduct genetic testing
routinely in healthy people. At
that time, primary care clinicians
will need to understand genetic risks and to have informed,
clear, literacy-adjusted, culturally
competent discussions with their
patients about how to use this information.
Dr. Richard C. Wender is with the
American Cancer Society, Atlanta,
and the department of family and
community medicine at Thomas
Jeferson University, Philadelphia.
He reported having no fnancial
disclosures. Dr. Wender made these
remarks in an editorial accompanying Dr. Nan’s report (JAMA
2015;313:1111-2).
Albert Einstein used with permission of the HUJ/GreenLight.
INDICATION
HARVONI is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults.
Please see Brief Summary of full Prescribing Information adjacent to this ad.
GIHEP_25.indd 1
4/14/2015 4:51:18 PM
HARVONI is the only HCV treatment offering an 8-week course
of therapy1
% SVR12 among treatment-naïve HCV GT 1 subjects without
cirrhosis who had baseline HCV RNA <6 million IU/mL1
100
90
Percent (%) Subjects
80
97%
70
60
50
40
30
20
10
0
n=119/123
HARVONI 8 weeks
ION-3
• Overall SVR12 was 94% (n=202/215) in subjects receiving HARVONI for 8 weeks1,a
• In treatment-naïve subjects taking HARVONI for 12 weeks, 96% (n=208/216) achieved SVR12
in the ION-3 trial and 99% (n=210/213) achieved SVR12 in the ION-1 trial1,a
• The recommended treatment duration for treatment-naïve patients is 12 weeks1
• HARVONI for 8 weeks can be considered in treatment-naïve patients without cirrhosis who
have pre-treatment HCV RNA <6 million IU/mL1
Study Designs
ION-11: a randomized, open-label trial evaluating HARVONI with or without ribavirin (RBV) in GT 1 treatment-naïve subjects (N=865) with
or without cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + RBV for 12 weeks, HARVONI
for 24 weeks, or HARVONI + RBV for 24 weeks, and stratified by presence or absence of cirrhosis and HCV genotype (1a vs 1b).
ION-31: a randomized, open-label trial in GT 1 treatment-naïve subjects (N=647) without cirrhosis. Subjects were randomized in a 1:1:1 ratio
to receive HARVONI for 8 weeks, HARVONI + RBV for 8 weeks, or HARVONI for 12 weeks, and stratified by HCV genotype (1a vs 1b).
a
SVR12 was the primary endpoint and was defined as HCV RNA <25 IU/mL at 12 weeks after the end of treatment.1 Achieving SVR is
considered a virologic cure.2
RBV was not shown to increase the response rates observed with HARVONI in ION-1 or ION-3. Therefore, the HARVONI + RBV arms are
not presented.1
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
• Risk of Serious Symptomatic Bradycardia when Coadministered with Amiodarone:
Amiodarone is not recommended for use with HARVONI due to the risk of symptomatic
bradycardia, particularly in patients also taking beta blockers or with underlying cardiac
comorbidities and/or with advanced liver disease. In patients without alternative, viable
treatment options, cardiac monitoring is recommended. Patients should seek immediate
medical evaluation if they develop signs or symptoms of bradycardia.
• Risk of Reduced Therapeutic Effect of HARVONI Due to P-gp Inducers: Rifampin and
St. John’s wort are not recommended for use with HARVONI as they may significantly
decrease ledipasvir and sofosbuvir plasma concentrations.
• Related Products Not Recommended: HARVONI is not recommended for use with other
products containing sofosbuvir (SOVALDI®).
GIHEP_26&27.indd 2
4/14/2015 4:55:53 PM
HARVONI is the only once-daily single-tablet regimen for HCV
GT 1 patients1
Recommended treatment duration1
1
HARVONI
TABLET
ONCE DAILY
WITH OR
WITHOUT FOOD
Can be considered in treatmentnaïve patients without cirrhosis
who have pre-treatment
HCV RNA <6 million IU/mL
8
weeks
Treatment-naïve patients with or without cirrhosis
Treatment-experienced patientsb without cirrhosis
12
weeks
12
weeks
Treatment-experienced patientsb with cirrhosis
24
weeks
Treatment-experienced patients who failed treatment with either peginterferon (Peg-IFN) alfa + ribavirin (RBV) or an HCV protease inhibitor + Peg-IFN + RBV.1
b
• HARVONI is interferon- and RBV-free for GT 1 treatment-naïve and treatment-experienced
patients with or without cirrhosis, regardless of GT 1a or 1b subtype1
• Each HARVONI tablet contains 90 mg of ledipasvir and 400 mg of sofosbuvir1
• Relapse rates are affected by baseline host and viral factors and differ between treatment
durations for certain subgroups1
• No dose adjustments are required based on advanced age, mild or moderate renal impairment,
or mild, moderate, or severe hepatic impairment. The safety and efficacy of HARVONI have
not been established in patients with decompensated cirrhosis1
• No dose recommendations can be given for patients with severe renal impairment (estimated
glomerular filtration rate [eGFR] <30 mL/min/1.73m2) or with end stage renal disease (ESRD)
due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite1
IMPORTANT SAFETY INFORMATION
ADVERSE REACTIONS
Most common (≥10%, all grades) adverse reactions were fatigue and headache.
DRUG INTERACTIONS
• In addition to rifampin and St. John’s wort, coadministration of HARVONI is also not
recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin,
rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the
concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of HARVONI.
• Coadministration of HARVONI is not recommended with simeprevir due to increased
concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with
rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil
fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively.
Consult the full Prescribing Information for HARVONI
for more information on potentially significant drug
interactions, including clinical comments.
Please see Brief Summary of full Prescribing Information
on the following pages.
Visit harvoni.com/hcp
GIHEP_26&27.indd 3
4/14/2015 4:56:31 PM
HARVONI® (ledipasvir 90 mg and sofosbuvir 400 mg)
tablets, for oral use
Brief Summary of full Prescribing Information. See full
Prescribing Information. Rx Only.
INDICATIONS AND USAGE: HARVONI is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults.
CONTRAINDICATIONS: None
WARNINGS AND PRECAUTIONS:
Serious Symptomatic Bradycardia When Coadministered
with Amiodarone: Postmarketing cases of symptomatic
bradycardia, as well as fatal cardiac arrest and cases requiring
pacemaker intervention, have been reported when amiodarone is
coadministered with HARVONI. Bradycardia has generally occurred
within hours to days, but cases have been observed up to 2
weeks after initiating HCV treatment. Patients also taking beta
blockers, or those with underlying cardiac comorbidities and/or
advanced liver disease may be at increased risk for symptomatic
bradycardia with coadministration of amiodarone. Bradycardia
generally resolved after discontinuation of HCV treatment. The
mechanism for this effect is unknown. Coadministration of
amiodarone with HARVONI is not recommended. For patients
taking amiodarone who will be coadministered HARVONI and
patients taking HARVONI who need to start amiodarone, who
have no other alternative, viable treatment options; and due to
amiodarone’s long half-life for patients discontinuing amiodarone
just prior to starting HARVONI: Counsel patients about the risk
of serious symptomatic bradycardia; and cardiac monitoring in
an in-patient setting for the frst 48 hours of coadministration is
recommended, after which outpatient or self-monitoring of the
heart rate should occur on a daily basis through at least the frst
2 weeks of treatment. Patients who develop signs or symptoms
of bradycardia should seek medical evaluation immediately.
Symptoms may include near-fainting or fainting, dizziness or
lightheadedness, malaise, weakness, excessive tiredness,
shortness of breath, chest pains, confusion or memory problems.
Risk of Reduced Therapeutic Effect Due to P-gp Inducers:
Concomitant use may signifcantly decrease ledipasvir and
sofosbuvir concentrations and may lead to a reduced HARVONI
effect. Use of HARVONI with P-gp inducers (e.g., rifampin or St.
John’s wort) is not recommended.
Related Products Not Recommended: Use of HARVONI with
products containing sofosbuvir (SOVALDI®) is not recommended.
ADVERSE REACTIONS:
The safety assessment of HARVONI was based on pooled data
from three Phase 3 clinical trials in subjects with genotype 1 CHC
with compensated liver disease (with and without cirrhosis) who
received HARVONI for 8 (N=215), 12 (N=539) and 24 (N=326)
weeks. Adverse events led to permanent treatment discontinuation
in 0%, <1% and 1% of subjects receiving HARVONI for 8, 12 and
24 weeks, respectively.
Adverse Reactions (adverse events assessed as causally
related by the investigator): The most common adverse reactions
(≥10%; all grades) were fatigue and headache. Adverse reactions
(all grades; majority Grade 1) observed in ≥5% of subjects by
treatment duration were:
GIHEP_28.indd 1
• HARVONI for 8 weeks: fatigue (16%); headache (11%); nausea
(6%); diarrhea (4%); and insomnia (3%)
• HARVONI for 12 weeks: fatigue (13%); headache (14%); nausea
(7%); diarrhea (3%); and insomnia (5%)
• HARVONI for 24 weeks: fatigue (18%); headache (17%); nausea
(9%); diarrhea (7%); and insomnia (6%)
Direct comparison across trials should not be made due to
differing trial designs.
Laboratory Abnormalities: Bilirubin Elevations: Bilirubin
elevations of greater than 1.5x ULN were observed in 3%, <1%
and 2% of subjects treated with HARVONI for 8, 12 and 24 weeks,
respectively. Lipase Elevations: Transient, asymptomatic lipase
elevations of greater than 3x ULN were observed in <1%, 2% and
3% of subjects treated with HARVONI for 8, 12 and 24 weeks,
respectively. Creatine Kinase: Creatine kinase was not assessed
in Phase 3 trials of HARVONI. Isolated, asymptomatic creatine
kinase elevations (Grade 3 or 4) have been previously reported in
subjects treated with sofosbuvir in combination with ribavirin or
peginterferon/ribavirin in other clinical trials.
Postmarketing Experience
Cardiac Disorders: Serious symptomatic bradycardia has been
reported in patients taking amiodarone who initiate treatment
with HARVONI during post approval use of HARVONI. Because
postmarketing 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.
DRUG INTERACTIONS:
Ledipasvir is an inhibitor of the drug transporters P-gp and breast
cancer resistance protein (BCRP) and may increase intestinal
absorption of coadministered substrates for these transporters.
Ledipasvir and sofosbuvir are substrates of P-gp and BCRP
while the inactive sofosbuvir metabolite GS-331007 is not. P-gp
inducers (e.g. rifampin or St. John’s wort) may decrease ledipasvir
and sofosbuvir concentrations leading to reduced HARVONI
effect; use of HARVONI with P-gp inducers is not recommended.
Established and Potentially Signifcant Drug Interactions:
The drug interactions described are based on studies conducted
in healthy adults with either HARVONI, the components of
HARVONI as individual agents, or are predicted drug interactions
that may occur with HARVONI. This list includes potentially
signifcant interactions but is not all inclusive. An alteration in
dose or regimen may be recommended for the following
drugs when coadministered with HARVONI:
• Acid Reducing Agents: Ledipasvir solubility decreases
as pH increases. Drugs that increase gastric pH are
expected to decrease ledipasvir concentration.
• Antacids: Separate HARVONI and antacid administration by
4 hours.
• H2-receptor antagonists: Doses comparable to famotidine
40 mg twice daily or lower may be administered simultaneously
with or 12 hours apart from HARVONI.
• Proton-pump inhibitors: Doses comparable to omeprazole
20 mg or lower can be administered simultaneously with
HARVONI under fasted conditions.
4/14/2015 5:00:10 PM
Brief Summary (cont.)
USE IN SPECIFIC POPULATIONS:
• Antiarrhythmics
(amiodarone;
digoxin)
Amiodarone:
Coadministration of amiodarone with HARVONI may result in
serious symptomatic bradycardia and is not recommended.
Mechanism of effect is unknown. If coadministration is required,
cardiac monitoring is recommended. Digoxin: Increased digoxin
concentration. Monitor digoxin therapeutic concentration during
coadministration with HARVONI.
Pregnancy: HARVONI is Pregnancy Category B; there are
no adequate and well-controlled studies in pregnant women.
HARVONI should be used during pregnancy only if the potential
beneft justifes the potential risk to the fetus.
• Anticonvulsants
(carbamazepine;
phenytoin;
phenobarbital; oxcarbazepine): Decreased ledipasvir and
sofosbuvir concentrations leading to reduced HARVONI effect.
Coadministration is not recommended.
• Antimycobacterials (rifabutin; rifampin; rifapentine):
Decreased ledipasvir and sofosbuvir concentrations leading to
reduced HARVONI effect. Coadministration is not recommended.
• HIV Antiretrovirals
• Regimens containing tenofovir disoproxil fumarate (DF) and
an HIV protease inhibitor/ritonavir (emtricitabine/tenofovir
DF plus atazanavir/ritonavir, darunavir/ritonavir or lopinavir/
ritonavir): The safety of increased tenofovir concentrations has
not been established. Consider alternative HCV or antiretroviral
therapy. If coadministration is necessary, monitor for tenofovirassociated adverse reactions. Refer to VIREAD or TRUVADA
prescribing information for renal monitoring recommendations.
• Efavirenz/emtricitabine/tenofovir DF: Monitor for tenofovirassociated adverse reactions. Refer to VIREAD, TRUVADA
or ATRIPLA prescribing information for renal monitoring
recommendations.
• Elvitegravir/cobicistat/emtricitabine/tenofovir DF: The safety of
increased tenofovir concentrations has not been established.
Coadministration is not recommended.
• Tipranavir/ritonavir: Decreased ledipasvir and sofosbuvir
concentrations leading to reduced HARVONI effect. Coadministration is not recommended.
Nursing Mothers: Studies in rats have demonstrated that
ledipasvir and GS-331007 are secreted in milk but had no effect
on nursing pups. It is not known if HARVONI and its metabolites
are secreted in human breast milk. The developmental and health
benefts of breastfeeding should be considered along with the
mother’s clinical need for HARVONI and any potential adverse
effects on the nursing child from the drug or from the underlying
maternal condition.
Pediatric Use: Safety and effectiveness of HARVONI have not
been established in pediatric patients.
Geriatric Use: Clinical trials of HARVONI included 117 subjects
aged 65 and over. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and
other reported clinical experience has not identifed differences in
responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out. No
dosage adjustment of HARVONI is warranted in geriatric patients.
Renal Impairment: No dosage adjustment of HARVONI is required
for patients with mild or moderate renal impairment. The safety
and effcacy of HARVONI have not been established in patients
with severe renal impairment (eGFR <30 mL/min/1.73m2) or end
stage renal disease (ESRD) requiring hemodialysis. No dosage
recommendation can be given for patients with severe renal
impairment or ESRD.
Hepatic Impairment: No dosage adjustment of HARVONI is
required for patients with mild, moderate or severe hepatic
impairment (Child-Pugh Class A, B or C). Safety and effcacy
of HARVONI have not been established in patients with
decompensated cirrhosis.
• HCV Products (simeprevir): Increased ledipasvir and simeprevir
concentrations. Coadministration is not recommended.
• Herbal Supplements (St. John’s wort): Decreased
ledipasvir and sofosbuvir concentrations. Coadministration is not
recommended.
• HMG-CoA Reductase Inhibitors (rosuvastatin): Signifcant
increase in rosuvastatin concentrations and risk of rosuvastatin
associated myopathy, including rhabdomyolysis. Coadministration is not recommended.
Drugs without Clinically Signifcant Interactions with
HARVONI: Based on drug interaction studies conducted
with HARVONI or its components, no clinically signifcant drug
interactions have been observed or are expected when used
with the following drugs individually: abacavir, atazanavir/ritonavir,
cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, lamivudine,
methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine,
tacrolimus, tenofovir DF or verapamil.
Consult the full Prescribing Information prior to and during
treatment with HARVONI for potential drug interactions;
this list is not all inclusive.
GIHEP_29.indd 1
References: 1. HARVONI US full Prescribing Information.
Gilead Sciences, Inc. Foster City, CA. March 2015.
2. US Department of Health and Human Services, Center for
Drug Evaluation and Research. Draft Guidance for Industry.
Chronic Hepatitis C Virus Infection: Developing Direct-Acting
Antiviral Drugs for Treatment. October 2013.
HARVONI, the HARVONI logo, SOVALDI, TRUVADA, VIREAD, GILEAD
and the GILEAD logo are trademarks of Gilead Sciences, Inc., or its
related companies. ATRIPLA is a trademark of Bristol-Myers Squibb &
Gilead Sciences, LLC.
©2015 Gilead Sciences, Inc. All rights reserved. HVNP0241 04/15
4/14/2015 5:02:04 PM
30
IBD AND INTESTINAL DISORDERS
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
Stem cells may relieve Crohn’s fstula
BY DOUG BRUNK
Frontline Medical News
T
hree-quarters of Crohn’s fstula patients who
were treated with one or two doses of autologous mesenchymal stem cells derived from
adipose tissue achieved complete closure at 2 years
of follow-up, a retrospective analysis showed.
“Crohn’s fstula is one of the most distressing
diseases because it decreases patient’s quality of
life and frequently recurs,” South Korean researchers led by Dr. Yong Beom Cho wrote in a study
published online March 31, 2015, in Stem Cells
Translational Medicine. “It has been reported to
occur in 13%-38% of patients with Crohn’s disease and a proctectomy is required in 10%-18% of
Crohn’s patients over the course of the disease.”
To date, they continued, treatment with antibiotics
and biological agents remain unsatisfactory “because they fail to achieve complete closure, lower
recurrence, and limit adverse efects.”
Over the past several years, researchers have
been evaluating the efcacy of stem cell therapy
for treating Crohn’s fstula, including those derived
from bone marrow and adipose tissue. An earlier
phase II trial conducted by Dr. Cho of the de-
partment of surgery at Samsung Medical Center,
Seoul, South Korea, and associates found that using mesenchymal stem cells derived from adipose
tissue (ASCs) resulted in favorable efcacy and
complete healing in 82% of 43 patients at 1 year
(Stem Cells Trans. Med. 2013;31:2575-81). The purpose of the current trial was to evaluate the outcome of this approach by following the patients
for an additional year.
For the current phase II trial, the researchers
followed 41 of the 43 patients from the initial trial,
which took place at fve hospitals in South Korea
from January 2010 to August 2012 and involved
one or two injections of ASCs into the tract of
fstulae associated with Crohn’s disease (Stem
Cells Trans. Med. 2015 March 31 [doi:10.5966/
sctm.2014-0199]). At baseline the mean age of
patients was 26 years, 68% were male, the mean
fstula length was 4.6 cm, and the average duration of Crohn’s disease was 58 months. Modifed
intention-to-treat (mITT) and modifed per protocol (mPP) analysis were used to assess efcacy.
Patients who received other surgical procedures
or operations involving the injection site were
excluded from the mPP analysis, while the mITT
analysis included patients who received ASC treat-
Whose metabolism is it?
Microbiome from page 1
of these communities, however, has
changed over the last 30 years, diverging along a path that mirrors global
spikes in obesity, diabetes, and allergic
and infammatory disorders.
“We have seen dramatic increases worldwide in these disorders,”
Dr. Ratner said. “We’ve also seen
decreased diversity of the microbiome, with a progressive change in
density from Bacteroidetes to Firmicutes. These are associations – not
causations – but I think the time has
come to ask ‘What are we doing to
change these bacteria?’ ”
The use of antibiotics is the frst
place suspicion falls – and it’s no wonder, since the epidemiologic changes
Dr. Ratner described began to appear
shortly after World War II. Antibiotics
could exert their fora-changing efects
in a couple of ways, he noted.
They directly alter the composition
of communities in the person who
consumes the drug, even if just in the
short term. There is some evidence
that early-life antibiotics, though changing the microbiome only temporarily,
can change fat metabolism for the entire lifespan (Cell 2014;158:705-21).
The association between an altered
gut microbiome and long-term health
is unproven. But a picture does seem
to emerge when viewed in light of the
exponential increases in obesity and its
attendant rise in diabetes.
The Type 1 Diabetes Prediction
and Prevention Project (DIPP) is an
efort to predict and search for means
to delay or prevent type 1 diabetes.
Launched in 1994, it’s following a cohort of children who had genetic risk
factors for type 1 diabetes. Data have
consistently shown that those who
develop the disease have signifcantly
lower diversity in their gut fora, Dr.
Ratner said. Certain species of Bacteroides increased the risk of autoimmunity by up to 20 times.
ment and had efcacy data at month 24.
At 24 months, complete fstula healing was
observed in 81% of patients in the mPP analysis
and 75% of patients in the mITT analysis. Furthermore, 83% of patients who showed complete
closure at week 8 after ASC injection still showed
complete closure at 24 months. No adverse events
related to the administration of ASCs were observed.
“ASCs represent a novel therapeutic option for
Crohn’s fstulae with a high risk of recurrence,
showing durable efcacy with low recurrence,
even in cases in which healing cannot be achieved
with biologics or in which conventional surgical
procedures cannot be performed,” the researchers
concluded. “Such refractory patients should be
referred to tertiary centers where optimal therapy,
including stem cell implants, can be ofered.”
The work was supported by the National Institutes of Health Clinical Trials. Two of the study
authors are employees of Anterogen Co. The remaining researchers reported having no relevant
fnancial conficts.
York University show for the frst time
that a specifc bacterium, Ralstonia,
can cause diabetes, and removing
it cures the disease. The bacterium
is a gram-negative pathogen that
contaminates drinking water. Mice
engineered for prediabetes gained
much more weight when they consumed live Ralstonia than when they
got a heat-inactivated version. They
also developed insulin resistance and
hyperglycemia with the live version.
But when the same mice were given
a Ralstonia antibody, they lost weight
and their glycemic profle normalized.
“This is the frst direct evidence we
have of causality,” Dr. Ratner said.
Mice engineered
as prediabetic
gained much
more weight
when they
consumed live
Ralstonia.
Benefcial
Firmicutes
increased in mice
that underwent
vertical sleeve
gastrectomy.
DR. BLASER
DR. SEELEY
“It does now appear that our microbes are actually controlling our
metabolism,” he said. “Some of these
species liberate lipopolysaccharides,
which function as endotoxins. These
cross the mucosal barrier in the intestine, enter the interstitial space, and
set up an infammation that impacts
the liver and adipocytes, potentially decreasing insulin sensitivity.”
Unpublished data from the laboratory of Dr. Martin J. Blaser at New
Strong evidence of causation is also
emerging in the surgical realm. Rouxen-Y gastric bypass seems to change
the microbiome in a way that facilitates
weight loss, beyond caloric intake.
Randy Seeley, Ph.D., of the University of Michigan, Ann Arbor, theorizes
that the physical manipulation of the
gut induces what he calls “enteroplasticity” – a fuid adaptation of both
the gut’s structure and its bacterial
communities to the altered physical
[email protected]
On Twitter @dougbrunk
and chemical environment. “There’s
more going on during postsurgical
weight loss than just food restriction
and malabsorption,” Dr. Seeley said in
an interview. “It’s logical to think that
when you do this kind of surgery, the
microbes in the intestine will change.”
Roseburia intestinalis is a Firmicute
that typically increases after bariatric
surgery. It’s also defcient in people
who have diabetes. Dr. Seeley coauthored an article showing that Roseburia and other benefcial Firmicutes
increased signifcantly in mice that
underwent vertical sleeve gastrectomy
(Nature 2014;509:183-8). These mice
lost weight after surgery, as would be
expected, but then showed a preference for the high-protein and carbohydrate-rich foods that Firmicutes need.
Their microbiome also showed decreases in fat-loving Bacteroides species.
But weight loss and microbiome
improvement happened only in mice
that had a normal bile acid–signaling
system. Immediately after surgery,
mice engineered to lack bile acid receptors did eat less and lose weight.
But a week later, their appetites
came back full force, and they actually seemed driven to eat fat. They
returned to their presurgical weight
and their microbiome didn’t show
the same improvement as their cousins with normal signaling pathways.
Dr. Seeley disclosed receiving
fnancial support from Johnson &
Johnson, Novo Nordisk, and Eisai.
[email protected]
IBD AND INTESTINAL DISORDERS
GIHEP NEW S. COM • M AY 2015
31
Colonoscopy follow-up varied after positive FOBT
BY SHARON WORCESTER
Frontline Medical News
BIRMINGHAM, ALA. – The time
to colonoscopy after a positive fecal
occult blood test varied widely between health systems and also varied
based on age and comorbidity score,
in a study of more than 62,000 patients from four health systems.
Both individuallevel factors as
well as health
care system were
associated with
follow-up.
DR. CHUBAK
The median time to colonoscopy
after a positive fecal occult blood test
(FOBT) in 62,384 patients in the Population-based Research Optimizing
Screening through Personalized Regimens (PROSPR) Network ranged
from 41 to 174 days. Most of those
who received a follow-up colonoscopy did so within 3-6 months of their
positive FOBT.
The percentage of patients fol-
lowed up with colonoscopy within 12
months ranged from 58.1% to 83.8%,
with lowest percentages occurring
in the two systems with the longest
median time to follow-up, Jessica
Chubak, Ph.D., of Group Health
Research Institute and her colleagues
reported in a poster at the American
Society of Preventive Oncology annual meeting.
The rate of colonoscopy follow-up
within 12 months also decreased
with advancing age and increasing
Charlson comorbidity score. For
those aged 55-59 years, 60-64 years,
65-69 years, or 70-75 years, the hazard ratios for follow-up were 1.02,
0.98, 0.98, and 0.90, respectively,
compared with the youngest age
group (50-54 years). But for those
patients aged 76-84 years or 85-89
years, the hazard ratios were 0.65
and 0.34, respectively.
For those with a Charlson comorbidity score of 1, 2, or 3 or more,
the adjusted hazard ratios for follow-up were 0.93, 0.87, and 0.70,
respectively, compared with those
with a score of 0, the investigators
said.
No signifcant diferences in follow-up were seen based on gender,
body mass index, or race/ethnicity.
The investigators used administrative and clinical data to estimate the
VITALS
Key clinical point: Increasing age
and comorbidities reduce the likelihood of colonoscopy follow-up for a
positive fecal occult blood test.
Major fnding: The percentage of
patients followed up with colonoscopy within 12 months ranged from
58.1% to 83.8%.
Data source: An analysis of administrative and clinical data from
four health systems with more than
62,000 patients in the PROSPR
Network.
Disclosures: The National Cancer
Institute funded the study.
time to follow-up and probability of
follow-up for all persons with a positive FOBT in 2011 and 2012.
The fndings have implications for
future research on improving follow-up in older patients and those
with comorbidities, the study authors said.
The diferences between health
care systems may be due to varying
practices. The two organizations
with the best time to colonoscopy
follow-up in the network are health
maintenance organizations with
targets for time to colonoscopy and
monitored appointment supply.
In contrast, the organization with
the second longest time to follow-up
was an HMO that contracted with
external providers for about 60% of
colonoscopies. The organization with
the longest time to follow-up was a
safety-net system with limited colonoscopy capacity that served socioeconomically disadvantaged patients
who may have faced more barriers to
colonoscopy completion.
Colorectal cancer is the fourth
most common cancer in the United
States, and FOBT is an important
screening strategy that relies on
follow-up in the event of a positive
fnding.
“Our fndings that both individual-level factors as well as health care
system were associated with follow-up strengthens the rationale for
investigating multilevel interventions
to improve follow-up after abnormal
screening tests,” the researchers concluded.
[email protected]
GIHEP_32.indd
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GIHEP_33.indd
  
BRIEF SUMMARY: Consult the Full Prescribing Information for complete
product information.
LIALDA® (mesalamine) Delayed Release Tablets
Rx only
INDICATIONS AND USAGE
LIALDA is indicated for the induction of remission in patients with
active, mild to moderate ulcerative colitis and for the maintenance of
remission of ulcerative colitis.
CONTRAINDICATIONS
LIALDA is contraindicated in patients with known hypersensitivity to
salicylates or aminosalicylates or to any of the ingredients of LIALDA .
WARNINGS AND PRECAUTIONS
Renal Impairment
Renal impairment, including minimal change nephropathy, acute and
chronic interstitial nephritis, and, rarely, renal failure, has been reported
in patients given products such as LIALDA that contain mesalamine or
are converted to mesalamine.
It is recommended that patients have an evaluation of renal function
prior to initiation of LIALDA therapy and periodically while on therapy.
Exercise caution when using LIALDA in patients with known renal
dysfunction or a history of renal disease.
In animal studies, the kidney was the principal organ for toxicity.
Mesalamine-Induced Acute Intolerance Syndrome
Mesalamine has been associated with an acute intolerance syndrome that
may be difficult to distinguish from an exacerbation of ulcerative colitis.
Although the exact frequency of occurrence has not been determined, it
has occurred in 3% of patients in controlled clinical trials of mesalamine
or sulfasalazine. Symptoms include cramping, acute abdominal pain and
bloody diarrhea, and sometimes fever, headache, and rash. Observe
patients closely for worsening of these symptoms while on treatment. If
acute intolerance syndrome is suspected, promptly discontinue treatment
with LIALDA.
Hypersensitivity Reactions
Some patients who have experienced a hypersensitivity reaction to
sulfasalazine may have a similar reaction to LIALDA tablets or to other
compounds that contain or are converted to mesalamine.
Mesalamine-induced cardiac hypersensitivity reactions (myocarditis
and pericarditis) have been reported with LIALDA and other
mesalamine medications. Caution should be taken in prescribing this
medicine to patients with conditions predisposing them to the
development of myocarditis or pericarditis.
Hepatic Impairment
There have been reports of hepatic failure in patients with preexisting
liver disease who have been administered mesalamine. Caution should
be exercised when administering LIALDA to patients with liver disease.
Upper GI Tract Obstruction
Pyloric stenosis or other organic or functional obstruction in the upper
gastrointestinal tract may cause prolonged gastric retention of LIALDA
which would delay mesalamine release in the colon.
Interference With Laboratory Tests
Use of mesalamine may lead to spuriously elevated test results when
measuring urinary normetanephrine by liquid chromatography with
electrochemical detection because of the similarity in the
chromatograms of normetanephrine and mesalamine’s main
metabolite, N-acetylaminosalicylic acid (N-Ac-5-ASA). An alternative,
selective assay for normetanephrine should be considered.
ADVERSE REACTIONS
The most serious adverse reactions seen in Lialda clinical trials or with
other products that contain or are metabolized to mesalamine are:
• Renal impairment, including renal failure
• Mesalamine-induced acute intolerance syndrome
• Hypersensitivity reactions
• Hepatic impairment, including hepatic failure
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.
LIALDA has been evaluated in 1368 ulcerative colitis patients in
controlled and open-label trials.
Induction of Remission
In two 8-week placebo-controlled clinical trials involving 535 ulcerative
colitis patients, 356 received 2.4 g/day or 4.8 g/day LIALDA tablets and
179 received placebo. The most frequent adverse reaction leading to
discontinuation from LIALDA therapy was exacerbation of ulcerative
colitis (0.8%). Pancreatitis occurred in less than 1% of patients during
clinical trials and resulted in discontinuation of therapy with LIALDA in
patients experiencing this event.
Adverse reactions occurring in LIALDA or placebo groups at a
frequency of at least 1% in two 8-week, double blind, placebocontrolled trials are listed in Table 1. The most common adverse
reactions with LIALDA 2.4 g/day and 4.8 g/day were headache (5.6%
and 3.4%, respectively) and flatulence (4% and 2.8%, respectively).
GIHEP_34.indd
Table 1: Adverse Reactions in Two Eight-Week Placebo-Controlled
Trials Experienced by at Least 1% of the LIALDA Group and at a Rate
Greater than Placeboa
LIALDA
2.4 g/day
(n = 177)
10 (5.6%)
7 (4%)
LIALDA
4.8 g/day
(n = 179)
6 (3.4%)
5 (2.8%)
Placebo
Adverse Reaction
(n = 179)
Headache
1 (0.6%)
Flatulence
5 (2.8%)
Liver Function Test
Abnormal
1 (0.6%)
4 (2.2%)
2 (1.1%)
Alopecia
0
2 (1.1%)
0
Pruritus
1 (0.6%)
2 (1.1%)
2 (1.1%)
a: Adverse reactions for which the placebo rate equalled or exceeded the
rate for at least one of the LIALDA treatment groups were abdominal pain,
dizziness, dyspepsia, and nausea.
The following adverse reactions, presented by body system, were
reported infrequently (less than 1%) by LIALDA-treated ulcerative
colitis patients in the two controlled trials.
Cardiac Disorder: tachycardia
Vascular Disorders: hypertension, hypotension
Skin and Subcutaneous Tissue Disorders: acne, prurigo, rash, urticaria
Gastrointestinal Disorders: abdominal distention, colitis, diarrhea,
pancreatitis, rectal polyp, vomiting
Investigations: decreased platelet count
Musculoskeletal and Connective Tissue Disorders: arthralgia, back pain
Nervous System Disorders: somnolence, tremor
Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain
General Disorders and Administrative Site Disorders: asthenia, face
edema, fatigue, pyrexia
Ear and Labyrinth Disorders: ear pain
Maintenance of Remission of Ulcerative Colitis
The dose evaluated in three studies of LIALDA given for the maintenance
of remission in patients with ulcerative colitis was 1.2 g twice daily or
2.4 g once daily. One of these studies was a 6-month double-blind
comparator study while two were 12- to 14-month open-label studies.
The most common adverse reactions with LIALDA in the maintenance
arms of long-term trials were colitis ulcerative (5.8%), headache
(2.9%), liver function test abnormal (2.3%), and abdominal pain
(2.2%). Of the 1082 subjects in the all maintenance studies pooled,
1.9% had severe adverse reactions. The most common severe adverse
reactions were gastrointestinal disorders; these were mainly symptoms
associated with ulcerative colitis.
Table 2: Adverse Reactions in Three Maintenance Trials Experienced
by at Least 1% of the LIALDA Group (maintenance phases of trials)
All LIALDA
(n=1082)
Adverse Reaction
Colitis ulcerative
Headache
Liver function test abnormal
Abdominal pain
Diarrhea
Abdominal distension
Abdominal pain upper
Dyspepsia
Back pain
Rash
Arthralgia
Fatigue
Hypertension
n
63
31
25
24
18
14
13
13
13
13
12
11
10
%
(5.8%)
(2.9%)
(2.3%)
(2.2%)
(1.7%)
(1.3%)
(1.2%)
(1.2%)
(1.2%)
(1.2%)
(1.1%)
(1.0%)
(1.0%)
The following adverse reactions, presented by body system, were
reported infrequently (less than 1%) by LIALDA-treated ulcerative
colitis patients in the three long-term maintenance trials (maintenance
phases of these trials):
Cardiac Disorder: tachycardia
Skin and Subcutaneous Tissue Disorders: acne, alopecia, pruritus,
urticaria
Gastrointestinal Disorders: colitis, flatulence, nausea, pancreatitis, rectal
polyp, vomiting
Nervous System Disorders: dizziness
Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain
General Disorders and Administrative Site Disorders: asthenia, pyrexia
Ear and Labyrinth Disorders: ear pain
Postmarketing Experience
In addition to the adverse reactions reported above in clinical trials
involving LIALDA, the adverse reactions listed below have been identified
during post-approval use of LIALDA and other mesalamine-containing
products. 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.
Body as a Whole: lupus-like syndrome, drug fever
Cardiac Disorders: pericarditis, pericardial effusion, myocarditis
Gastrointestinal: pancreatitis, cholecystitis, gastritis, gastroenteritis,
gastrointestinal bleeding, perforated peptic ulcer
Hepatic: jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver
failure, Kawasaki-like syndrome including changes in liver enzymes
Hematologic: agranulocytosis, aplastic anemia
Immune System Disorders: anaphylactic reaction, angioedema,
Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and
systemic symptoms (DRESS)
Musculoskeletal and Connective Tissue Disorders: myalgia
Neurological/Psychiatric: peripheral neuropathy, Guillain-Barre
syndrome, transverse myelitis
Renal Disorders: interstitial nephritis
Respiratory, Thoracic and Mediastinal Disorders: hypersensitivity
pneumonitis (including interstitial pneumonitis, allergic alveolitis,
eosinophilic pneumonitis)
Skin: psoriasis, pyoderma gangrenosum, erythema nodosum
Urogenital: reversible oligospermia
DRUG INTERACTIONS
No investigations of interaction between LIALDA and other drugs
except for certain antibiotics have been performed. However, the
following drug-drug interactions have been reported for products
containing mesalamine:
Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs
The concurrent use of mesalamine with known nephrotoxic agents,
including non-steroidal anti-inflammatory drugs (NSAIDs) may
increase the risk of renal reactions.
Azathioprine or 6-mercaptopurine
The concurrent use of mesalamine with azathioprine or 6-mercaptopurine
may increase the risk for blood disorders.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B. Reproduction studies with mesalamine have
been performed in rats at doses up to 1000 mg/kg/day (1.8 times the
maximum recommended human dose based on a body surface area
comparison) and rabbits at doses up to 800 mg/kg/day (2.9 times the
maximum recommended human dose based on a body surface area
comparison) and have revealed no evidence of impaired fertility or
harm to the fetus due to mesalamine. There are, however, no adequate
and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, this
drug should be used during pregnancy only if clearly needed.
Mesalamine is known to cross the placental barrier.
Nursing Mothers
Low concentrations of mesalamine and higher concentrations of its
N-acetyl metabolite have been detected in human breast milk. The
clinical significance of this has not been determined and there is limited
experience of nursing women using mesalamine. Caution should be
exercised if LIALDA is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of LIALDA in pediatric patients have not been
established.
Geriatric Use
Reports from uncontrolled clinical studies and postmarketing reporting
systems suggested a higher incidence of blood dyscrasias, i.e.,
neutropenia and pancytopenia in patients who were 65 years or older
who were taking mesalamine-containing products such as LIALDA.
Caution should be taken to closely monitor blood cell counts during
mesalamine therapy.
Clinical trials of LIALDA did not include sufficient numbers of patients
aged 65 and over to determine whether they respond differently from
younger patients. Other reported clinical experience has not identified
differences in responses between the elderly and younger patients.
Systemic exposures are increased in elderly subjects. In general, dose
selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concurrent
disease or other drug therapy in elderly patients.
OVERDOSAGE
LIALDA is an aminosalicylate, and symptoms of salicylate toxicity may
include tinnitus, vertigo, headache, confusion, drowsiness, sweating,
seizures, hyperventilation, dyspnea, vomiting, and diarrhea. Severe
intoxication may lead to disruption of electrolyte balance and blood-pH,
hyperthermia, dehydration, and end organ damage.
There is no specific known antidote for mesalamine overdose; however,
conventional therapy for salicylate toxicity may be beneficial in the event
of acute overdosage. Fluid and electrolyte imbalance should be
corrected by the administration of appropriate intravenous therapy.
Adequate renal function should be maintained.
DOSAGE AND ADMINISTRATION
The recommended dosage for the induction of remission in adult patients
with active, mild to moderate ulcerative colitis is two to four 1.2 g tablets
taken once daily with a meal for a total daily dose of 2.4 g or 4.8 g. The
recommended dosage for the maintenance of remission is two 1.2 g
tablets taken once daily with a meal for a total daily dose of 2.4 g.
Store at room temperature 15°C to 25°C (59°F to 77°F); excursions
permitted to 30°C (86°F).
Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA
19087, USA by Cosmo S.p.A., Milan, Italy. By license of Nogra Pharma
Limited, Dublin, Ireland.
U.S. Patent No. 6,773,720.
© 2014 Shire US Inc.
Rev. 06/2014 S03025
  
GIHEP NEW S. COM • M AY 2015
IBD AND INTESTINAL DISORDERS
35
Alternatives to colonoscopy are ‘works in progress’
BY DOUG BRUNK
Frontline Medical News
SAN FRANCISCO – Colonoscopy may be the
most commonly used technique to screen for colorectal cancer in the United States, but it’s far from
perfect, according to Dr. David A. Lieberman,
AGAF.
For one thing, serious complications occur in 3-5 per
1,000 procedures at 30 days of
follow-up, “and if you look at
individuals over 65, the rates
almost double in terms of serious complications,” Dr. Lieberman, chief of the division of
gastroenterology and hepatology at Oregon Health and Science University, said at the 2015 AGA Tech Summit,
which was sponsored by the AGA Center for GI Innovation and Technology. “The rate of perforation
over age 65 is about 1 per 1,000,” he said.
Colonoscopy is invasive, “and it would never be
conceived of as the ideal test for population-based
screening,” he added. “It’s expensive, and [clinicians] in many countries simply do not have the
resources and expertise to do it.”
Compared with current screening rates in the
United States for cervical and breast cancer, a
“screening gap” exists in the percentage of adults
who are up to date in tests for colorectal cancer,
he said. “If you look at what’s been accomplished
with cervical cancer screening and mammography,
we see that there’s a ways to go for colonoscopy,”
he said.
The ideal screening test for colorectal cancer
would accurately identify individuals at risk for colon cancer at an early, preventable stage, Dr. Lieberman said. That prevention element “really averts
the downstream colon cancer care costs, which
would be very attractive in a single-payer health
care system,” he said. “If we had a system that took
care of us for life, that system would be very invested in trying to prevent colon cancer, because [it
would] be worried about those downstream costs.”
One potential alternative to colonoscopy is fecal
immunochemical testing (FIT). A recent meta-analysis suggested that FIT detected cancer with a 79%
sensitivity (Ann. Intern. Med. 2014;160:171-81),
and a separate, recent prospective study found a
74% sensitivity rate in detecting cancer, but a 24%
sensitivity rate in detecting advanced adenoma (N.
Engl. J. Med. 2014;370:1287-97). “So in terms of
early detection, FIT is pretty good,” Dr. Lieberman
said. “In terms of cancer prevention? Maybe not
so good. There are also issues around the testing
program, which requires adherence to both positive
and negative tests. Some of these behavioral factors
play a major role in the actual efectiveness. So you
can have a great test, but if it’s not getting done
properly then there’s going to be an issue. There is
some potential for CRC prevention, but it’s going
to be less than for some others.”
What about stool DNA? A landmark study
found that stool DNA detected cancer with a
sensitivity of 92%, compared with FIT at 74%
(N. Engl. J. Med. 2014;370:1287-97). However,
the sensitivity for detecting adenomas was rela-
per second before it reaches the small bowel,” Dr.
tively low for both methods (42% for stool DNA,
Ladabaum said.
compared with 24% for FIT). Stool DNA testing
In an early study of the second-generation sys“appears to be an efective screening test [but] the
tem, the device achieved a sensitivity of 89% and a
appropriate interval for testing is still uncertain,”
specifcity of 76% in detecting polyps of 6 mm in
Dr. Lieberman said. “The recommendation is a
size or larger and a sensitivity of 88% and a speci3-year interval.”
fcity of 89% in detecting polyps 10 mm in size or
He characterized serum testing as the “holy
grail” of screening for colorec- larger (Endoscopy 2009;41:1026-31).
More recently, researchers examined consecutive
tal cancer, “because it would
‘Colonoscopy
patients who had incomplete colonoscopy and
be ideal to have a noninvasive
would never be
compared a follow-up with either second-generatest. You’d come in, get a
conceived of as
tion CCE or CT colonography (Gut 2015;64:272blood draw, and get risk stratthe ideal test for
81). The diagnostic yield of CCE and CT
ifed. There are a number of
population-based
colonography was 25% and 12%, respectively, for
diferent possible pathways,
screening.’
one looking at specifc genetic polyps 6 mm or larger and 5% vs. 3% for polyps 10
mm or larger.
markers, others looking at
DR. LIEBERMAN
In a larger, multisite study, researchers examined
genetic fngerprinting: in oththe efcacy of the second-generation PillCam as
er words, seeing a pattern of
a primary screening tool (Gastroenterology 2015
genes that are associated with colon cancer versus
patients who do not have colon cancer. Proteomics [doi:10.1053/j.gastro.2015.01.025). Of 884 subjects
is another fngerprinting technique, as is metabolo- enrolled, 85 were excluded from the analysis for a
variety of reasons. Of these, 12 were excluded bemics: looking at a variety of metabolites that may
cause the capsule did not reach the colon within 12
be altered by the presence of having neoplasia.
hours and 8 were excluded because the capsule did
This is an intriguing area but so far there hasn’t
not pass the cecum within 12 hours. “So if used in
been a lot of data.”
practice, we’ll see this – [incomplete capsule studTo date, the most progress involved in this area
ies],” Dr. Ladabaum said.
involves molecular tests of DNA or proteins.
In addition, 77 were excluded for inadequate
“These studies are all relatively small and somecleansing and capsule transit time through the
what promising in terms of cancer sensitivity, but
colon in less than 40 minutes. “Maybe that’s due
not so great for adenoma sensitivity,” he said. “It’s
to the booster regifair to say that this is
men,” he said. “There
still a work in progTo date, the most progress involved in this
are still some things to
ress.”
area involves molecular tests of DNA or
work out in the bowel
Dr. Lieberman reportprep. Overall, there
ed having served on the proteins. ‘These studies are all relatively
were a good number of
scientifc advisory board small and somewhat promising in terms
people [in this study]
of Exact Sciences.
of cancer sensitivity, but not so great
who didn’t really have
In a separate prethe exam [completed
sentation, Dr. Uri
for adenoma sensitivity.... It’s fair to say
as intended]. Is that
Ladabaum updated atgoing to pan out as a
tendees on the status of that this is still a work in progress.’
big problem in clinical
PillCam, also known as
practice? That remains to be seen.”
colon capsule endoscopy (CCE), for detecting coThe study found that the second-generation
lon cancer. The PillCam is cleared by the Food and
Drug Administration for detection of colon polyps PillCam achieved a sensitivity of 87% and a specin patients after an incomplete optical colonoscopy ifcity of 94% in detecting polyps 6 mm or larger
with adequate preparation, or if a complete evalu- and a sensitivity of 85% and a specifcity of 97%
in detecting polyps 10 mm in size or larger. “Is this
ation of the colon was not technically possible. In
good enough for this kind of technology?” Dr.
a large meta-analysis, the frst-generation PillCam
Ladabaum asked. “There’s lots of room for debate
achieved a sensitivity of 71% and a specifcity of
here. Interestingly, the numbers for sessile serrated
75% in detecting polyps of any size and a sensipolyps didn’t look that good” (a sensitivity of 29%
tivity of 68% and a specifcity of 82% in detecting
polyps 6 mm in size or larger (Clin. Gastroenterol. for polyps 6 mm in size or greater and 33% for polyps 10 mm in size or greater).
Hepatol. 2010;8:515-22). “The results were someDr. Ladabaum disclosed that he has served as a
what disappointing for a test like this, not hitting
consultant for Given Imaging and Exact Sciences.
the bar that we would want,” said Dr. Ladabaum,
He has also served on the advisory board for Mauprofessor of medicine in the division of gastroenna Kea Technologies.
terology and hepatology at Stanford (Calif.) UniIn conclusion, according to Dr. Lieberman, there
versity.
are several feasible alternatives to colonoscopy for
The second-generation PillCam features an imprimary colon cancer screening in average-risk
proved angle of the imagers, from 156 degrees to
individuals. Each has advantages and limitations
172 degrees, “so you get a bigger view all the way
and ofers a less invasive approach to screening.
around,” he said. Another new feature is an adapThe bar for screening has been raised from early
tive imaging rate. The frst-generation device captured 4 images per second regardless of where the cancer detection alone to both early detection and
prevention.
capsule was moving. The new system “goes at 4
images per second when stationary, goes as fast as
[email protected]
35 images per second while moving, and 14 images
INTRODUCING
A New Face of
*
Cure in HCV
For the treatment of chronic
genotype 1 (GT1) hepatitis C
virus (HCV) infection—an all-oral,
interferon-free regimen with
3 distinct direct-acting antivirals
*Cure (virologic cure): sustained virologic response (SVR12); HCV ribonucleic acid (RNA) below the lower limit of quantifcation (<25 IU/mL)
12 weeks after the end of treatment.
INDICATION1
VIEKIRA PAK™, with or without ribavirin (RBV), is indicated for the
treatment of adult patients with genotype 1 chronic hepatitis C virus
infection, including those with compensated cirrhosis.
Limitation of Use:
VIEKIRA PAK is not recommended for use in patients with
decompensated liver disease.
IMPORTANT SAFETY INFORMATION
for which elevated plasma levels are associated with serious and/
or life-threatening events; strong inducers of CYP3A or CYP2C8,
which may lead to reduced effcacy of VIEKIRA PAK; and strong
CYP2C8 inhibitors, which may increase dasabuvir levels and the
risk of QT prolongation.
• with the following drugs: alfuzosin HCL; carbamazepine, phenytoin,
phenobarbital; gemfbrozil; rifampin; ergotamine, dihydroergotamine,
ergonovine, methylergonovine; ethinyl estradiol-containing
medicines, such as many oral contraceptives; St. John’s wort (Hypericum
perforatum); lovastatin, simvastatin; pimozide; efavirenz; sildenafl
(when dosed as Revatio‡ for pulmonary arterial hypertension);
triazolam and oral midazolam.
Risks Associated with RBV Combination Treatment
If VIEKIRA PAK is administered with RBV, the contraindications,
warnings and precautions (particularly pregnancy avoidance), and
adverse reactions for RBV also apply to this combination regimen.
Refer to the RBV prescribing information.
• in patients with known hypersensitivity (e.g., toxic epidermal
necrolysis or Stevens-Johnson syndrome) to ritonavir.
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
VIEKIRA PAK is contraindicated:
• in patients with severe hepatic impairment due to risk of
potential toxicity.
• with drugs that are highly dependent on CYP3A for clearance and
Increased Risk of ALT Elevations
• Elevations of ALT to >5x the ULN occurred in 1% of all subjects in
clinical trials and were signifcantly more frequent in females using
ethinyl estradiol-containing medications. In female patients,
GIHEP_36.indd 2
2/20/2015 5:13:11 PM
VIEKIRA PAK +/- ribavirin (RBV) cured* chronic HCV in
multiple GT1 patient types, including compensated cirrhotics
VIEKIRA PAK +/- RBV was studied in 6 phase III clinical trials that included >2300 adult
patients with chronic GT1 HCV1
Across patient populations, pooled by recommended treatment regimen† (n=1084),
VIEKIRA PAK +/- RBV delivered consistently high cure* rates ranging from 95%–100%1,2
SVR12 rates
Overall GT1
Patients Cured1,2*
(n=1053/1084)
VIEKIRA PAK /
RBV
(12 OR 24 WEEKS)
Learn more at
viekiraHCP.com
†
Recommended regimen=ombitasvir, paritaprevir, ritonavir (25/150/100 mg QD) and dasabuvir (250 mg BID) +/- ribavirin (1000 or 1200 mg
determined by body weight; divided BID).1
discontinue ethinyl estradiol-containing medications prior to starting
therapy and use alternative methods of contraception during therapy
(e.g., progestin only or non-hormonal contraception). Use caution
when co-administering VIEKIRA PAK with estrogens other than ethinyl
estradiol, such as estradiol and conjugated estrogens.
• Perform hepatic lab testing on all patients during the frst 4 weeks of
treatment and as clinically indicated thereafter. If ALT is elevated above
baseline levels, repeat testing and monitor closely. Patients should be
instructed to consult their doctor without delay if they have onset of
fatigue, weakness, lack of appetite, nausea and vomiting, jaundice,
or discolored feces. Consider discontinuing VIEKIRA PAK if ALT levels
remain persistently >10x the ULN. Discontinue VIEKIRA PAK if ALT
elevation is accompanied by signs or symptoms of liver infammation
or increasing conjugated bilirubin, alkaline phosphatase, or INR.
Risk of Adverse Reactions or Reduced Therapeutic Effect Due to
Drug Interactions
• The concomitant use of VIEKIRA PAK and certain other drugs may
result in known or potentially signifcant drug interactions, some
of which may lead to loss of therapeutic effect of VIEKIRA PAK and
possible development of resistance, or adverse reactions from greater
exposures of concomitant drugs or components of VIEKIRA PAK.
GIHEP_37.indd 3
HCV/HIV-1 Co-infected Patients: Risk of HIV-1 Protease Inhibitor
Drug Resistance
• The ritonavir component of VIEKIRA PAK is an HIV-1 protease
inhibitor and can select for HIV-1 protease inhibitor resistance. To
reduce this risk, HCV/HIV-1 co-infected patients should also be on a
suppressive antiretroviral drug regimen.
ADVERSE REACTIONS
• In subjects receiving VIEKIRA PAK with RBV, the most commonly
reported adverse reactions (>10% of subjects) were fatigue,
nausea, pruritus, other skin reactions, insomnia, and asthenia. In
subjects receiving VIEKIRA PAK without RBV, the most commonly
reported adverse reactions (≥5% of subjects) were nausea,
pruritus, and insomnia.
‡
Revatio® is a trademark of its respective owner and not a trademark of AbbVie Inc. The
makers of this brand are not affiliated with and do not endorse AbbVie Inc. or its products.
References: 1. VIEKIRA PAK [package insert]. North Chicago, IL. AbbVie Inc.
2. Data on file. AbbVie Inc.
Please see Brief Summary of Prescribing Information on the adjacent page(s).
©2014 AbbVie Inc. North Chicago, IL 046-1574501
December 2014 Printed in U.S.A.
2/20/2015 5:14:00 PM
PROFESSIONAL BRIEF SUMMARY
CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
VIEKIRA PAKTM (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets)
INDICATIONS AND USAGE
VIEKIRA PAK with or without ribavirin is indicated for the treatment of patients with genotype 1 chronic hepatitis
C virus (HCV) infection including those with compensated cirrhosis.
Limitation of Use:
VIEKIRA PAK is not recommended for use in patients with decompensated liver disease [see Use in Specifc
Populations].
CONTRAINDICATIONS
• If VIEKIRA PAK is administered with ribavirin, the contraindications to ribavirin also apply to this combination
regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin.
• VIEKIRA PAK is contraindicated in patients with severe hepatic impairment due to risk of potential toxicity [see
Use in Specifc Populations].
• VIEKIRA PAK is contraindicated with:
° Drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations
are associated with serious and/or life-threatening events.
° Drugs that are strong inducers of CYP3A and CYP2C8 and may lead to reduced effcacy of VIEKIRA PAK.
° Drugs that are strong inhibitors of CYP2C8 and may increase dasabuvir plasma concentrations and the
risk of QT prolongation.
Table 1 lists drugs that are contraindicated with VIEKIRA PAK [see Drug Interactions].
Table 1. Drugs that are Contraindicated with VIEKIRA PAK
Drug Class
Alpha1adrenoreceptor
antagonist
Anticonvulsants
Drug(s) within Class
that are Contraindicated
Alfuzosin HCL
Clinical Comments
Potential for hypotension.
Carbamazepine, phenytoin,
phenobarbital
Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures
may decrease leading to a potential loss of therapeutic activity
of VIEKIRA PAK.
Antihyperlipidemic Gemfbrozil
Increase in dasabuvir exposures by 10-fold which may increase
agent
the risk of QT prolongation.
Antimycobacterial
Rifampin
Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures
may decrease leading to a potential loss of therapeutic activity
of VIEKIRA PAK.
Ergot derivatives
Ergotamine,
Acute ergot toxicity characterized by vasospasm and tissue
dihydroergotamine,
ischemia has been associated with co-administration of
ergonovine, methylergonovine ritonavir and ergonovine, ergotamine, dihydroergotamine, or
methylergonovine.
Ethinyl estradiolEthinyl estradiol-containing
Potential for ALT elevations
containing products medications such as combined [see Warnings and Precautions].
oral contraceptives
Herbal Product
St. John’s Wort (Hypericum
Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures
perforatum)
may decrease leading to a potential loss of therapeutic activity
of VIEKIRA PAK.
HMG-CoA Reductase Lovastatin, simvastatin
Potential for myopathy including rhabdomyolysis.
Inhibitors
Neuroleptics
Pimozide
Potential for cardiac arrhythmias.
Non-nucleoside
Efavirenz
Co-administration of efavirenz based regimens with
paritaprevir, ritonavir plus dasabuvir was poorly tolerated and
reverse transcriptase
inhibitor
resulted in liver enzyme elevations.
There is increased potential for sildenafl-associated adverse
Phosphodiesterase-5 Sildenafl when dosed as
(PDE5) inhibitor
REVATIO for the treatment
events such as visual disturbances, hypotension, priapism,
and syncope.
of pulmonary arterial
hypertension (PAH)
Sedatives/hypnotics Triazolam
Triazolam and orally administered midazolam are extensively
Orally administered midazolam metabolized by CYP3A4. Coadministration of triazolam or orally
administered midazolam with VIEKIRA PAK may cause large
increases in the concentration of these benzodiazepines. The
potential exists for serious and/or life threatening events such
as prolonged or increased sedation or respiratory depression.
• VIEKIRA PAK is contraindicated in patients with known hypersensitivity (e.g. toxic epidermal necrolysis (TEN)
or Stevens-Johnson syndrome) to ritonavir.
WARNINGS AND PRECAUTIONS
Increased Risk of ALT Elevations
During clinical trials with VIEKIRA PAK with or without ribavirin, elevations of ALT to greater than 5 times
the upper limit of normal (ULN) occurred in approximately 1% of all subjects [see Adverse Reactions]. ALT
elevations were typically asymptomatic, occurred during the frst 4 weeks of treatment, and declined within
two to eight weeks of onset with continued dosing of VIEKIRA PAK with or without ribavirin.
These ALT elevations were signifcantly more frequent in female subjects who were using ethinyl estradiolcontaining medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal
rings. Ethinyl estradiol-containing medications must be discontinued prior to starting therapy with VIEKIRA
PAK [see Contraindications]. Alternative methods of contraception (e.g, progestin only contraception or nonhormonal methods) are recommended during VIEKIRA PAK therapy. Ethinyl estradiol-containing medications
can be restarted approximately 2 weeks following completion of treatment with VIEKIRA PAK.
Women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in
hormone replacement therapy had a rate of ALT elevation similar to those not receiving any estrogens;
however, due to the limited number of subjects taking these other estrogens, caution is warranted for coadministration with VIEKIRA PAK [see Adverse Reactions].
Hepatic laboratory testing should be performed during the frst 4 weeks of starting treatment and as clinically
indicated thereafter. If ALT is found to be elevated above baseline levels, it should be repeated and monitored
closely:
• Patients should be instructed to consult their health care professional without delay if they have onset of
fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.
• Consider discontinuing VIEKIRA PAK if ALT levels remain persistently greater than 10 times the ULN.
• Discontinue VIEKIRA PAK if ALT elevation is accompanied by signs or symptoms of liver infammation or
increasing conjugated bilirubin, alkaline phosphatase, or INR.
Risks Associated With Ribavirin Combination Treatment
If VIEKIRA PAK is administered with ribavirin, the warnings and precautions for ribavirin, in particular the
pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information
for a full list of the warnings and precautions for ribavirin.
Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions
The concomitant use of VIEKIRA PAK and certain other drugs may result in known or potentially signifcant drug
interactions, some of which may lead to:
• Loss of therapeutic effect of VIEKIRA PAK and possible development of resistance
• Possible clinically signifcant adverse reactions from greater exposures
of concomitant drugs or components of VIEKIRA PAK.
See Table 4 for steps to prevent or manage these possible and known signifcant drug interactions, including
dosing recommendations [see Drug Interactions]. Consider the potential for drug interactions prior to and
during VIEKIRA PAK therapy; review concomitant medications during VIEKIRA PAK therapy; and monitor for the
adverse reactions associated with the concomitant drugs [see Contraindications and Drug Interactions].
Risk of HIV-1 Protease Inhibitor Drug Resistance in HCV/HIV-1 Co-infected Patients
The ritonavir component of VIEKIRA PAK is also an HIV-1 protease inhibitor and can select for HIV-1 protease
inhibitor resistance-associated substitutions. Any HCV/HIV-1 co-infected patients treated with VIEKIRA PAK
should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug
resistance.
ADVERSE REACTIONS
If VIEKIRA PAK is administered with ribavirin (RBV), refer to the prescribing information for ribavirin for a list of
ribavirin-associated adverse reactions.
The following adverse reaction is described below and elsewhere in the labeling:
• Increased Risk of ALT Elevations [see Warnings and Precautions]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
clinical trials of VIEKIRA PAK cannot be directly compared to rates in the clinical trials of another drug and may
not refect the rates observed in practice.
The safety assessment was based on data from six Phase 3 clinical trials in more than 2,000 subjects who
received VIEKIRA PAK with or without ribavirin for 12 or 24 weeks.
VIEKIRA PAK with Ribavirin in Placebo-Controlled Trials
The safety of VIEKIRA PAK in combination with ribavirin was assessed in 770 subjects with chronic HCV
infection in two placebo-controlled trials (SAPPHIRE-I and -II). Adverse reactions that occurred more often in
subjects treated with VIEKIRA PAK in combination with ribavirin compared to placebo were fatigue, nausea,
pruritus, other skin reactions, insomnia, and asthenia (see Table 2). The majority of the adverse reactions were
mild in severity. Two percent of subjects experienced a serious adverse event (SAE). The proportion of subjects
who permanently discontinued treatment due to adverse reactions was less than 1%.
GIHEP_38.indd 103-B026 Viekira Pak PB 10.5x13 (1.25).indd 1
Table 2. Adverse Reactions with ≥5% Greater Frequency Reported in Subjects with Chronic HCV GT1
Infection Treated with VIEKIRA PAK in Combination with Ribavirin Compared to Placebo for
12 Weeks
SAPPHIRE-I and -II
VIEKIRA PAK + RBV
Placebo
12 Weeks
12 Weeks
N = 770
N = 255
%
%
Fatigue
34
26
Nausea
22
15
Pruritus*
18
7
16
9
Skin reactions$
Insomnia
14
8
Asthenia
14
7
*Grouped term ‘pruritus’ included the preferred terms pruritus and pruritus generalized.
$Grouped terms: rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular,
skin exfoliation, rash pruritic, rash erythematous, rash generalized, dermatitis allergic, dermatitis contact,
exfoliative rash, dermatitis, photosensitivity reaction, psoriasis, skin reaction, ulcer, urticaria.
VIEKIRA PAK with and without Ribavirin in Regimen-Controlled Trials
VIEKIRA PAK with and without ribavirin was assessed in 401 and 509 subjects with chronic HCV infection,
respectively, in three clinical trials (PEARL-II, PEARL-III and PEARL-IV). Pruritus, nausea, insomnia, and asthenia
were identifed as adverse events occurring more often in subjects treated with VIEKIRA PAK in combination
with ribavirin (see Table 3). The majority of adverse events were mild to moderate in severity. The proportion
of subjects who permanently discontinued treatment due to adverse events was less than 1% for both VIEKIRA
PAK in combination with ribavirin and VIEKIRA PAK alone.
Table 3. Adverse Events with ≥5% Greater Frequency Reported in Subjects with Chronic HCV GT1
Infection Treated with VIEKIRA PAK in Combination with Ribavirin Compared to VIEKIRA PAK
for 12 Weeks
PEARL-II, -III and -IV
VIEKIRA PAK + RBV
VIEKIRA PAK
12 Weeks
12 Weeks
N = 401
N = 509
%
%
Nausea
16
8
Pruritus*
13
7
Insomnia
12
5
Asthenia
9
4
*Grouped term ‘pruritus’ included the preferred terms pruritus and pruritus generalized.
VIEKIRA PAK with Ribavirin in Subjects with Compensated Cirrhosis
VIEKIRA PAK with ribavirin was assessed in 380 subjects with compensated cirrhosis who were treated for 12
(n=208) or 24 (n=172) weeks duration (TURQUOISE-II). The type and severity of adverse events in subjects
with compensated cirrhosis was comparable to non-cirrhotic subjects in other phase 3 trials. Fatigue, skin
reactions and dyspnea occurred at least 5% more often in subjects treated for 24 weeks. The majority of
adverse events occurred during the frst 12 weeks of dosing in both treatment arms. Most of the adverse
events were mild to moderate in severity. The proportion of subjects treated with VIEKIRA PAK for 12 and 24
weeks with SAEs was 6% and 5%, respectively and 2% of subjects permanently discontinued treatment due to
adverse events in each treatment arm.
Skin Reactions
In PEARL-II, -III and -IV, 7% of subjects receiving VIEKIRA PAK alone and 10% of subjects receiving VIEKIRA
PAK with ribavirin reported rash-related events. In SAPPHIRE-I and -II 16% of subjects receiving VIEKIRA PAK
with ribavirin and 9% of subjects receiving placebo reported skin reactions. In TURQUOISE-II, 18% and 24%
of subjects receiving VIEKIRA PAK with ribavirin for 12 or 24 weeks reported skin reactions. The majority of
events were graded as mild in severity. There were no serious events or severe cutaneous reactions, such as
Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme (EM) or drug rash
with eosinophilia and systemic symptoms (DRESS).
Laboratory Abnormalities
Serum ALT Elevations
Approximately 1% of subjects treated with VIEKIRA PAK experienced post-baseline serum ALT levels greater
than 5 times the upper limit of normal (ULN) after starting treatment. The incidence increased to 25% (4/16)
among women taking a concomitant ethinyl estradiol containing medication [see Contraindications and
Warnings and Precautions]. The incidence of clinically relevant ALT elevations among women using estrogens
other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy
was 3% (2/59).
ALT elevations were typically asymptomatic, generally occurred during the frst 4 weeks of treatment (mean
time 20 days, range 8-57 days) and most resolved with ongoing therapy. The majority of these ALT elevations
were assessed as drug-related liver injury. Elevations in ALT were generally not associated with bilirubin
elevations. Cirrhosis was not a risk factor for elevated ALT [see Warnings and Precautions].
Serum Bilirubin Elevations
Post-baseline elevations in bilirubin at least 2 x ULN were observed in 15% of subjects receiving VIEKIRA
PAK with ribavirin compared to 2% in those receiving VIEKIRA PAK alone. These bilirubin increases were
predominately indirect and related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir
and ribavirin-induced hemolysis. Bilirubin elevations occurred after initiation of treatment, peaked by study
Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associated with serum ALT
elevations.
Anemia/Decreased Hemoglobin
Across all Phase 3 studies, the mean change from baseline in hemoglobin levels in subjects treated with
VIEKIRA PAK in combination with ribavirin was -2.4 g/dL and the mean change in subjects treated with VIEKIRA
PAK alone was -0.5 g/dL. Decreases in hemoglobin levels occurred early in treatment (Week 1-2) with further
reductions through Week 3. Hemoglobin values remained low during the remainder of treatment and returned
towards baseline levels by post-treatment Week 4. Less than 1% of subjects treated with VIEKIRA PAK with
ribavirin had hemoglobin levels decrease to less than 8.0 g/dL during treatment. Seven percent of subjects
treated with VIEKIRA PAK in combination with ribavirin underwent a ribavirin dose reduction due to a decrease
in hemoglobin levels; three subjects received a blood transfusion and fve required erythropoietin. One patient
discontinued therapy due to anemia. No subjects treated with VIEKIRA PAK alone had a hemoglobin level less
than 10 g/dL.
VIEKIRA PAK in HCV/HIV-1 Co-infected Subjects
VIEKIRA PAK with ribavirin was assessed in 63 subjects with HCV/HIV-1 co-infection who were on stable
antiretroviral therapy. The most common adverse events occurring in at least 10% of subjects were fatigue
(48%), insomnia (19%), nausea (17%), headache (16%), pruritus (13%), cough (11%), irritability (10%), and
ocular icterus (10%).
Elevations in total bilirubin greater than 2 x ULN (mostly indirect) occurred in 34 (54%) subjects. Fifteen of
these subjects were also receiving atazanavir at the time of bilirubin elevation and nine also had adverse
events of ocular icterus, jaundice or hyperbilirubinemia. None of the subjects with hyperbilirubinemia had
concomitant elevations of aminotransferases [see Warnings and Precautions and Adverse Reactions]. No
subject experienced a grade 3 ALT elevation.
Seven subjects (11%) had at least one post-baseline hemoglobin value of less than 10 g/dL, and six of these
subjects had a ribavirin dose modifcation; no subject in this small cohort required a blood transfusion or
erythropoietin.
Median declines in CD4+ T-cell counts of 47 cells/mm3 and 62 cells/mm3 were observed at the end of 12 and
24 weeks of treatment, respectively, and most returned to baseline levels post-treatment. Two subjects had
CD4+ T-cell counts decrease to less than 200 cells/mm3 during treatment without a decrease in CD4%. No
subject experienced an AIDS-related opportunistic infection.
VIEKIRA PAK in Selected Liver Transplant Recipients
VIEKIRA PAK with ribavirin was assessed in 34 post-liver transplant subjects with recurrent HCV infection.
Adverse events occurring in more than 20% of subjects included fatigue 50%, headache 44%, cough 32%,
diarrhea 26%, insomnia 26%, asthenia 24%, nausea 24%, muscle spasms 21% and rash 21%. Ten subjects
(29%) had at least one post-baseline hemoglobin value of less than 10 g/dL. Ten subjects underwent a
ribavirin dose modifcation due to decrease in hemoglobin and 3% (1/34) had an interruption of ribavirin. Five
subjects received erythropoietin, all of whom initiated ribavirin at the starting dose of 1000 to 1200 mg daily.
No subject received a blood transfusion.
DRUG INTERACTIONS
See also Contraindications and Warnings and Precautions.
Potential for VIEKIRA PAK to Affect Other Drugs
Ombitasvir, paritaprevir, and dasabuvir are inhibitors of UGT1A1, and ritonavir is an inhibitor of CYP3A4.
Paritaprevir is an inhibitor of OATP1B1 and OATP1B3 and paritaprevir, ritonavir and dasabuvir are inhibitors of
BCRP. Co-administration of VIEKIRA PAK with drugs that are substrates of CYP3A, UGT1A1, BCRP, OATP1B1 or
OATP1B3 may result in increased plasma concentrations of such drugs.
Potential for Other Drugs to Affect One or More Components of VIEKIRA PAK
Paritaprevir and ritonavir are primarily metabolized by CYP3A enzymes.
Co-administration of VIEKIRA PAK with strong inhibitors of CYP3A may increase paritaprevir and ritonavir
concentrations. Dasabuvir is primarily metabolized by CYP2C8 enzymes. Co-administration of VIEKIRA PAK with
drugs that inhibit CYP2C8 may increase dasabuvir plasma concentrations. Ombitasvir is primarily metabolized
via amide hydrolysis while CYP enzymes play a minor role in its metabolism. Ombitasvir, paritaprevir, dasabuvir
and ritonavir are substrates of P-gp. Ombitasvir, paritaprevir and dasabuvir are substrates of BCRP. Paritaprevir
is a substrate of OATP1B1 and OATP1B3. Inhibition of P-gp, BCRP, OATP1B1 or OATP1B3 may increase the
plasma concentrations of the various components of VIEKIRA PAK.
Established and Other Potential Drug Interactions
If dose adjustments of concomitant medications are made due to treatment with VIEKIRA PAK, doses should be
re-adjusted after administration of VIEKIRA PAK is completed. Dose adjustment is not required for VIEKIRA PAK.
Table 4 provides the effect of co-administration of VIEKIRA PAK on concentrations of concomitant drugs and
the effect of concomitant drugs on the various components of VIEKIRA PAK. See Contraindications for drugs
that are contraindicated with VIEKIRA PAK. Refer to the ritonavir prescribing information for other potentially
signifcant drug interactions with ritonavir.
Table 4. Established Drug Interactions Based on Drug Interaction Trials
Concomitant Drug Class:
Drug Name
ANTIARRHYTHMICS
amiodarone,
bepridil,
disopyramide,
fecainide,
lidocaine (systemic),
mexiletine,
propafenone,
quinidine
ANTIFUNGALS
ketoconazole
Effect on
Concentration
↑ antiarrhythmics
Caution is warranted and therapeutic concentration monitoring
(if available) is recommended for antiarrhythmics when coadministered with VIEKIRA PAK.
↑ ketoconazole
voriconazole
↓ voriconazole
When VIEKIRA PAK is co-administered with ketoconazole, the
maximum daily dose of ketoconazole should be limited to
200 mg per day.
Co-administration of VIEKIRA PAK with voriconazole is not
recommended unless an assessment of the beneft-to-risk
ratio justifes the use of voriconazole.
CALCIUM CHANNEL BLOCKERS
amlodipine
↑ amlodipine
CORTICOSTEROIDS (INHALED/NASAL)
futicasone
↑ futicasone
DIURETICS
furosemide
↑ furosemide (Cmax)
HIV-ANTIVIRAL AGENTS
atazanavir/ritonavir once daily
↑ paritaprevir
Clinical Comments
Consider dose reduction for amlodipine. Clinical monitoring
is recommended.
Concomitant use of VIEKIRA PAK with inhaled or nasal
futicasone may reduce serum cortisol concentrations.
Alternative corticosteroids should be considered, particularly
for long term use.
Clinical monitoring of patients is recommended and therapy
should be individualized based on patient’s response.
When coadministered with VIEKIRA PAK, atazanavir 300 mg
(without ritonavir) should only be given in the morning.
darunavir/ritonavir
↓ darunavir (Ctrough) Co-administration of VIEKIRA PAK with darunavir/ritonavir is
not recommended.
lopinavir/ritonavir
↑ paritaprevir
Co-administration of VIEKIRA PAK with lopinavir/ritonavir is
not recommended.
rilpivirine
↑ rilpivirine
Co-administration of VIEKIRA PAK with rilpivirine once daily is
not recommended due to potential for QT interval prolongation
with higher concentrations of rilpivirine.
HMG CoA REDUCTASE INHIBITORS
rosuvastatin
↑ rosuvastatin
When VIEKIRA PAK is co-administered with rosuvastatin, the
dose of rosuvastatin should not exceed 10 mg per day.
pravastatin
↑ pravastatin
When VIEKIRA PAK is co-administered with pravastatin, the
dose of pravastatin should not exceed 40 mg per day.
IMMUNOSUPPRESSANTS
↑ cyclosporine
When initiating therapy with VIEKIRA PAK, reduce cyclosporine
cyclosporine
dose to 1/5th of the patient’s current cyclosporine dose.
Measure cyclosporine blood concentrations to determine
subsequent dose modifcations. Upon completion of VIEKIRA
PAK therapy, the appropriate time to resume pre-VIEKIRA
PAK dose of cyclosporine should be guided by assessment
of cyclosporine blood concentrations. Frequent assessment
of renal function and cyclosporine-related side effects is
recommended.
tacrolimus
↑ tacrolimus
When initiating therapy with VIEKIRA PAK, the dose of
tacrolimus needs to be reduced. Do not administer tacrolimus
on the day VIEKIRA PAK is initiated. Beginning the day after
VIEKIRA PAK is initiated; reinitiate tacrolimus at a reduced dose
based on tacrolimus blood concentrations. Typical tacrolimus
dosing is 0.5 mg every 7 days.
Measure tacrolimus blood concentrations and adjust dose or
dosing frequency to determine subsequent dose modifcations.
Upon completion of VIEKIRA PAK therapy, the appropriate
time to resume pre-VIEKIRA PAK dose of tacrolimus should
be guided by assessment of tacrolimus blood concentrations.
Frequent assessment of renal function and tacrolimus related
side effects is recommended.
LONG ACTING BETA-ADRENOCEPTOR AGONIST
salmeterol
↑ salmeterol
Concurrent administration of VIEKIRA PAK and salmeterol is not
recommended. The combination may result in increased risk
of cardiovascular adverse events associated with salmeterol,
including QT prolongation, palpitations and sinus tachycardia.
NARCOTIC ANALGESICS
buprenorphine/naloxone
↑ buprenorphine
↑ norbuprenorphine
No dose adjustment of buprenorphine/naloxone is required
upon co-administration with VIEKIRA PAK. Patients should be
closely monitored for sedation and cognitive effects.
PROTON PUMP INHIBITORS
omeprazole
↓ omeprazole
Monitor patients for decreased effcacy of omeprazole.
Consider increasing the omeprazole dose in patients whose
symptoms are not well controlled; avoid use of more than
40 mg per day of omeprazole.
SEDATIVES/HYPNOTICS
alprazolam
↑ alprazolam
Clinical monitoring of patients is recommended. A decrease in
alprazolam dose can be considered based on clinical response.
The direction of the arrow indicates the direction of the change in exposures (Cmax and AUC) (↑ = increase of more than
20%, ↓ = decrease of more than 20%, ↔ = no change or change less than 20%).
Drugs without Clinically Signifcant Interactions with VIEKIRA PAK
No dose adjustments are recommended when VIEKIRA PAK is co-administered with the following medications:
digoxin, duloxetine, emtricitabine/tenofovir disoproxil fumarate, escitalopram, methadone, progestin only
contraceptives, raltegravir, warfarin and zolpidem.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
Pregnancy Exposure Registry
There is an Antiretroviral Pregnancy Registry that monitors pregnancy outcomes in women who are HCV/HIV-1
co-infected and taking concomitant antiretrovirals. Physicians are encouraged to register patients by calling
1-800-258-4263.
Risk Summary
Adequate and well controlled studies with VIEKIRA PAK have not been conducted in pregnant women. In animal
reproduction studies, no evidence of teratogenicity was observed with the administration of ombitasvir (mice
and rabbits), paritaprevir, ritonavir (mice and rats), or dasabuvir (rats and rabbits) at exposures higher than
the recommended clinical dose [see Data]. Because animal reproduction studies are not always predictive of
human response, VIEKIRA PAK should be used during pregnancy only if clearly needed.
If VIEKIRA PAK is administered with ribavirin, the combination regimen is contraindicated in pregnant women
and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more
information on use in pregnancy.
Data
Animal data
In animal reproduction studies, there was no evidence of teratogenicity in offspring born to animals treated
throughout pregnancy with ombitasvir and its major inactive human metabolites (M29, M36), paritaprevir,
ritonavir, or dasabuvir. For ombitasvir, the highest dose tested produced exposures approximately 28-fold
2/17/2015 12:23:33 PM
(mouse) or 4-fold (rabbit) the exposures in humans at the recommended clinical dose. The highest doses of the
major, inactive human metabolites similarly tested produced exposures approximately 26-fold the exposures
in humans at the recommended clinical dose. For paritaprevir, ritonavir, the highest doses tested produced
exposures approximately 98-fold (mouse) or 8-fold (rat) the exposures in humans at the recommended clinical
dose. For dasabuvir, the highest dose tested produced exposures approximately 48-fold (rat) or 12-fold (rabbit)
the exposures in humans at the recommended clinical dose.
Nursing Mothers
It is not known whether any of the components of VIEKIRA PAK or their metabolites are present in human
milk. Unchanged ombitasvir, paritaprevir and its hydrolysis product M13, and dasabuvir were the predominant
components observed in the milk of lactating rats, without effect on nursing pups.
The developmental and health benefts of breastfeeding should be considered along with the mother’s clinical
need for VIEKIRA PAK and any potential adverse effects on the breastfed child from VIEKIRA PAK or from the
underlying maternal condition.
If VIEKIRA PAK is administered with ribavirin, the nursing mothers information for ribavirin also applies to this
combination regimen (see prescribing information for ribavirin).
Pediatric Use
Safety and effectiveness of VIEKIRA PAK in pediatric patients less than
18 years of age have not been established.
Geriatric Use
No dosage adjustment of VIEKIRA PAK is warranted in geriatric patients. Of the total number of subjects
in clinical studies of VIEKIRA PAK, 8.5% (174/2053) were 65 and over. No overall differences in safety or
effectiveness were observed between these subjects and younger subjects, and other reported clinical
experience has not identifed differences in responses between the elderly and younger subjects, but greater
sensitivity of some older individuals cannot be ruled out.
Hepatic Impairment
No dosage adjustment of VIEKIRA PAK is required in patients with mild hepatic impairment (Child-Pugh
A). VIEKIRA PAK is not recommended in HCV-infected patients with moderate hepatic impairment (ChildPugh B). VIEKIRA PAK is contraindicated in patients with severe (Child-Pugh C) hepatic impairment [see
Contraindications].
GIHEP_39.indd 03-B026 Viekira Pak PB 10.5x13 (1.25).indd 2
Renal Impairment
No dosage adjustment of VIEKIRA PAK is required in patients with mild, moderate or severe renal impairment. VIEKIRA
PAK has not been studied in patients on dialysis. For patients that require ribavirin, refer to the ribavirin prescribing
information for information regarding use in patients with renal impairment.
Other HCV Genotypes
The safety and effcacy of VIEKIRA PAK has not been established in patients with HCV genotypes other than
genotype 1.
OVERDOSAGE
In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse
reactions and appropriate symptomatic treatment instituted immediately.
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients to review the Medication Guide for ribavirin [see Warnings and Precautions].
Risk of ALT Elevations
Inform patients to watch for early warning signs of liver infammation, such as fatigue, weakness, lack of
appetite, nausea and vomiting, as well as later signs such as jaundice and discolored feces, and to consult
their health care professional without delay if such symptoms occur [see Warnings and Precautions and
Adverse Reactions].
Pregnancy
Advise patients to avoid pregnancy during treatment with VIEKIRA PAK with ribavirin. Inform patients to notify
their health care provider immediately in the event of a pregnancy. Inform pregnant patients that there is an
Antiretroviral Pregnancy Registry that monitors pregnancy outcomes in women who are HCV/HIV-1 co-infected
and taking concomitant antiretrovirals [see Use in Specifc Populations].
Drug Interactions
Inform patients that VIEKIRA PAK may interact with some drugs; therefore, patients should be advised to report
to their healthcare provider the use of any prescription, non-prescription medication or herbal products [see
Contraindications, Warnings and Precautions, and Drug Interactions].
Inform patients that contraceptives containing ethinyl estradiol are contraindicated with VIEKIRA PAK [see
Contraindications and Warnings and Precautions].
Hepatitis C Virus Transmission
Inform patients that the effect of treatment of hepatitis C virus infection on transmission is not known, and that
appropriate precautions to prevent transmission of the hepatitis C virus during treatment should be taken.
Missed Dose
Inform patients that in case a dose of ombitasvir, paritaprevir, ritonavir is missed, the prescribed dose can be
taken within 12 hours.
In case a dose of dasabuvir is missed, the prescribed dose can be taken within 6 hours.
If more than 12 hours has passed since ombitasvir, paritaprevir, ritonavir is usually taken or more than 6 hours
has passed since dasabuvir is usually taken, the missed dose should NOT be taken and the patient should take
the next dose as per the usual dosing schedule.
Instruct patients not to take more than their prescribed dose of VIEKIRA PAK to make up for a missed dose.
Manufactured by AbbVie Inc., North Chicago, IL 60064.
VIEKIRA PAK and NORVIR are trademarks of AbbVie Inc. All other brands listed are trademarks of their
respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affliated with
and do not endorse AbbVie Inc. or its products.
Ref: 03-B026-R2-Revised December, 2014
046-1658504 MASTER
046-1574501
2/18/2015 4:43:02 PM
40
UPPER GI TRACT
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
CLINICAL CHALLENGES AND IMAGES
Answer to “What’s your diagnosis?” on page
2: Retrograde jejunogastric intussusception
etrograde jejunogastric intussusception ( JGI)
is a rare complication of gastric surgery with
an unknown mechanism; the lapse of time between surgery and occurrence has been reported
as being from 2 days to 30 years.1 There are three
anatomic types of JGI that have been previously
described by Shackman:2 Type I, aferent loop
intussusception; type II, eferent loop intussusception; and type III, a combined form. In this
case, type II JGI was present; this form has been
reported most commonly (80%).
The presence of a tender mass with vomiting
and pain in a patient with a history of prior gastric
surgery is the typical presentation. However, most
reported cases have not been diagnosed preoperatively. The current state-of-the-art CT allows for the
detection of the characteristic target-shaped soft-tissue mass with adjacent mesenteric vessels within
the stomach; this is pathognomonic for JGI.3
The treatment of acute retrograde JGI is
prompt surgery with reduction and resection of
the gangrenous bowel and revision of the anastomosis, depending on the patient’s condition
during the operation. In this case, contrast-enhanced CT scan showed retrograde jejunojejunal
(Figure B, black arrow) and jejunogastric intussusception (Figure B, white arrow) via the gastrojejunostomy anastomosis (Figure B, dashed arrow).
An emergency exploratory laparotomy showed
AGA InstItute
R
an eferent loop jejunum of 25 cm long herniating into the stomach leading to the retrograde
intussusception (Figure C). The intussuscepted
loop had gangrenous changes and was resected;
an end-to-end jejunojejunal anastomosis was performed. The postoperative recovery was uneventful, and the patient was discharged after 22 days
of hospitalization. The pathology report showed
hemorrhagic necrosis of the resected bowel, but
no malignant changes were found.
References
1. Conklin E.F., Markowitz A.M. Intussusception, a complication of gastric surgery. Surgery
1965;57:480-8.
2. Shackman R. Jejunogastric intussusception.
Br. J. Surg. 1940;27:475-80.
3. Azar T., Berger D.L. Adult intussusception.
Ann. Surg. 1997;226:134-8.
[email protected]
PRACTICE ECONOMICS
GIHEP NEW S. COM • M AY 2015
41
Value-based payment: Time to start getting ready
BY WHITNEY McKNIGHT
Frontline Medical News
WASHINGTON – Are physicians ready for the
shift toward value-based compensation?
A report from the American Medical Association
and the RAND Corp. aims to get physicians thinking
about what investments they should expect to make
and what obstacles they may encounter as they prepare for the federal government’s switch from fee-forservice to value-based medicine in 2018.
“There is a lot of enthusiasm for change,” Dr.
Mark W. Friedberg, senior natural scientist at RAND
in Boston and lead researcher on the report, said in
an interview. “There is a lot of
hope this will result in better patient care and physician success.
It’s a matter of the details.”
The report is based on survey
data from 34 practices across the
country, all of which have some
form of alternative payment
structure in place, whether it
be accountable care or bundled
services. Practices were located
in rural and urban settings ranging from hospital- to
physician-owned or corporately managed, all with
varying sizes of patient panels.
The top concern that practice managers faced
was matching the appropriate alternative payment
model to their particular patient population, researchers found. Other concerns included how
best to use incentives without adversely afecting
patient care and how to avoid physician burn-out.
These concerns, Dr. Friedberg said, point to
a need for payers to ofer guidance about what
makes sense when and why. “We got the message
that more communication between payers and
physician practices tends to be a good thing.”
Many of the coming changes will require updated
technology. Finding the money for such an overhaul
is a universal preoccupation of many practice man-
agers, and another reason some
practices have yet to switch.
“Some of the time, practices
can get a loan, or have the reserves to do it on their own, but
sometimes they don’t and they
need to partner with a large
organization like a hospital or
a large physician group,” Dr.
Friedberg said.
Payers are not likely to help foot the bill, according to Susan DeVore, president and chief executive
ofcer of Premier Health, a performance improvement alliance of hospitals and other providers.
“It would be wonderful
if the health plans would
‘There is a lot
spend hundreds of millions
of hope this will
of dollars for the technology
result in better
enablement of the physician
patient care
practices and the health sysand physician
tems,” Ms. DeVore said at the
success.’
press conference. “The truth
is, health systems and physiDR. FRIEDBERG
cians are [already] spending
the billions to build these technology infrastructures, and
they need to do that together.”
She called for more systemwide transparent collaboration
in how cost is determined and
in how quality and outcomes
are measured. “It’s not fair
to say we need a coordinated
system of care, but then we
can’t do it for lots of regulatory
reasons,” she said, noting that
ultimately, she believed such information sharing
would be determined by Congress.
Payers should make sure that physicians and other
providers have a seat at the table when performance
metrics are determined, Dr. Friedberg said.
“Some of the concerns we heard were that, in
Value-based transition
SGR repeal from page 1
Act of 2015 (MACRA). “Anytime a
complex bill as helpful as this one
is passed, there are implementation
problems that sometimes arise, so
one of the areas that we will be
strongly attentive to at the AMA is
keeping our fnger on the pulse of
the implementation and working
with the federal government to make
sure that this tracks in a correct way.”
President Obama signed the bill
into law on April 16.
The new law repeals the Medicare
Sustainable Growth Rate formula,
negating the 21% physician fee cut
that was to go into efect April 1. In
its place, the law provides a 0.5% pay
increase yearly for 5 years as the Medicare program makes the transition
away from fee-for-service and to val-
ue-based payment.
To help get to a point of value over
volume, the bill consolidates existing
quality programs – including those
addition to the number of
measures, was also whether individual measures are clinically
valid, and do they really refect
true diferences in the quality
of the patient care. Is it possible
that the measure isn’t really
reliable and not adequately risk
MS. DEVORE
adjusted, and therefore might
not be ready for prime time in
a payment contract?”
Although the report did not ofer specifc time
frames practice managers could expect before a
new structure would take hold, Ms. DeVore said
she was aware of some practices that realized
more than a third more profts within 3 years of
switching to value-based care models.
Chet Burrell, president and CEO of CareFirst
BlueCross BlueShield, said his group’s experience
was that overall, physicians were not ready for the
change to value-based care. This, despite the insurer’s announcement that $1 in every $5 it spends on
reimbursement is now tied to quality care.
For physicians who are ready to make the shift
to value-based payment, Mr. Burrell said an average of 5 years was necessary
to fully integrate. “Each
practice is its own ecosystem.
Some physicians catch on very
‘Some physicians quickly, but some are hostile.”
catch on very
Through our Roadmap to
quickly, but some the Future of GI Practice, AGA
are hostile.’
has been developing resources
to prepare you for value-based
MR. BURRELL
reimbursement systems. If you
haven’t started to demonstrate
and measure quality, it’s more important than ever
to put processes in place. Learn more at www.gastro.
org/roadmap-to-the-future-of-gi.
Systemwide
collaboration
is needed in
how cost is
determined
and quality is
measured.
and our House of Delegates, and
the conclusion was that this was not
just an improvement, but a signifcant improvement, over the current
set of measurements,” Dr. Madara
said. The new law also incentivizes
physicians to use alternate payment
models that focus on care coordina-
This is a
signifcant
improvement over
the current set of
measurements.
The bill ‘ensures
that these federal
rules are not
misused for
purposes for
which they were
never intended.’
DR. MADARA
MR. ATCHINSON
regarding the meaningful use of electronic health records – into a single
value-based performance program.
“We studied that, along with some
of the other physician organizations
tion and preventive care with a 5%
payment bonus. It pushes for more
transparency of Medicare data for
physicians, providers, and patients.
MACRA also includes funding to
[email protected]
On Twitter @whitneymcknight
help smaller practices participate in
alternative payment models or the
streamlined quality measurement program, as well as funding to help in the
development of quality measures.
“The provisions that allow for continued funding of the quality measurement enterprise in H.R. 2 are a
key building block of this important
transition and will also facilitate work
to continue advancing measurement
science,” the National Quality Forum
said in a statement. “Ultimately, these
eforts will not only help people get
better healthcare, but also will reduce
costs that strain patients, purchasers,
and the system overall.”
Other important provisions in the
new law include the reauthorization of several key programs. CHIP
(the Children’s Health Insurance
Program), the Community Health
Center program, the National Health
Continued on following page
42
PRACTICE ECONOMICS
Continued from previous page
Service Corps, and the Teaching
Health Centers program were all reauthorized for 2 years; they had been
scheduled to expire later this year.
Additionally, the law continues a partial delay of the Medicare two-midnights rule until Sept. 30.
Physicians also cheered provisions
of the new law that allay malpractice
concerns. The law specifes that the development, recognition, or implementation of any federal health care guideline
or standard does not establish a duty of
care in medical malpractice claims.
The provision helps distinguish
government quality guidelines and
payment rules from medical liability standards, according to Brian K.
Atchinson, president and CEO of
PIAA, a national trade association for
medical malpractice liability insurers.
“None of these rules or guidelines
were created with the intent to establish a legal standard for negligence,
and so it makes sense for Congress
to clarify that fact,” Mr. Atchinson
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
said in an interview. “The standard of
care provision in the SGR fx bill does
just that, and nothing more. It does
not shift the playing feld to either
plaintifs or defendants. Instead, it ensures that these federal rules are not
misused for purposes for which they
were never intended.”
H.R. 2 ran into some trouble in the
Senate because it does not have a dedicated funding mechanism to cover its
full cost. The Congressional Budget
Ofce estimated that enactment of
the law will increase the defcit by
$141 billion over 10 years. The CBO’s
score also found that the legislation
would save money, compared with the
price of continued patches.
A total of $73 billion of the $214
billion cost of the package is ofset
through spending reductions and
revenue increases included in the
bill, the CBO found. These include
income-related premium adjustments
for Medicare Parts B and D, Medigap
reforms, an increase of levy authority
on payments to Medicare providers
with delinquent tax debt, adjustments to inpatient hospital payment
rates, a delay of Medicaid Disproportionate Share Hospital changes until
2018, and a 1% market basket update
for postacute care providers.
Enactment of the law also looked a
bit shaky when the Ofce of the Actuary for CMS released a report April
9 that suggested physicians would see
future payment cuts under the law.
“Physician payment rates under H.R.
The provisions that allow for
continued funding of the quality
measurement enterprise in
H.R. 2 are a key building block
of this important transition
and will also facilitate
work to continue advancing
measurement science.
GICareerSearch com
Looking for a new
career or a new
staff member?
Job Seekers: Search jobs, fnd career
advice and post your resume.
Employers: Access qualifed candidates
in the GI feld.
Start your search today at GICareerSearch.com.
2 would be lower than scheduled under the current SGR formula by 2048
and would continue to worsen thereafter,” according to the report. “Absent
a change in the method or level of
update by subsequent legislation, we
expect access to Medicare-participating
physicians to become a signifcant issue
in the long term under H.R. 2.”
However, the AMA’s Dr. Madara
said that he was not concerned about
the projections because the report
assumes no changes in coming years.
“One does not make linear trajectories
over a period of decades or more and
assume that that’s where we are going
to end up because that assumption is
that nothing happens in the interim
and, as we all know, that’s just simply
not the way life works,” he said.
AMA President Robert Wah noted
that the report “fails to take into account the long-range impact such a
drastic payment cut [due to the SGR]
would have on quality and access for
Medicare benefciaries, or the many
options H.R. 2 will make available
to physicians for avoiding onerous
penalties under current law and the
signifcant positive updates that high
performers can earn.”
525-500COM_14-4
[email protected]
PRACTICE ECONOMICS
GIHEP NEW S. COM • M AY 2015
43
PRACTICE MANAGEMENT TOOLBOX:
ACOs can be an opportunity for gastroenterologists
BY G. ANTON DECKER, MBBCH,
MRCP, FACG, CPE, MHA
This month’s article comes from Dr. G.
Anton Decker. Dr. Decker is one of the
few board-certifed gastroenterologists
who is in a leadership position of a
functioning accountable care organization (ACO). As such, his insights into
ACO workings and funds fow are especially important. As we continue to
note health system consolidation and
changes in the formulas by which reimbursements are distributed, gastroenterology has a lot at stake. We are
fortunate to have several gastroenterologists in leadership positions within
large integrated delivery networks.
John I. Allen, M.D., MBA, AGAF,
Special Section Editor
A
s a practicing gastroenterologist
and chief medical ofcer of
a large medical group participating in the Pioneer Accountable
Care Organization (ACO) program, I
have an encouraging view of health
care transformation. Banner Medical
Group (BMG), Banner Health’s employed medical group, has a presence
in six states and employs more than
1,000 physicians. BMG is part of Banner Health Network (BHN), Banner
Health’s ACO. Banner Health chose to
form an ACO to maintain its competitive advantage and improve patient
health and experience by providing
coordinated and cost-efective care.
My journey from a clinical gastroenterologist to a chief medical ofcer
immersed in the challenges and opportunities of health care reform has
been exciting and educational.
From gastroenterologist to
chief medical offcer
I enjoyed clinical gastroenterology
but became equally fascinated by
more global health care challenges;
the United States spends an unsustainable $8,402 per capita on health
care,1 far higher than any other developed country, and yet it does not
achieve superior outcomes or life
expectancies. To obtain a seat at the
table where health care delivery decisions are made, I sought out oppor-
tunities to expand my knowledge and
credibility in the science of health
care delivery: I volunteered for committees such as Quality, Electronic
Medical Record, and Practice Operations. I read books and journals on
health care economics, business,
leadership, and
management.
Finally, I pursued a master’s
degree in health
administration
and became a
certifed physiDR. DECKER
cian executive
through the
American College of Physician Executives Program. Although a radical
career move, the position of chief
medical ofcer of BMG provided me
the opportunity to be on the forefront of health care reform. Before
my arrival, BHN received approval
from the Centers for Medicare &
Medicaid Services (CMS) to be a
Pioneer ACO, 1 of 32 such ACOs in
the country. I had to rapidly learn
the rules of CMS ACOs and position
the medical group to succeed as a
component of BHN. A failed attempt at reading through the Patient
Protection and Afordable Care Act
(ACA)2 led me to search for articles
and books on ACOs; however, most
were outdated and based on 1990s
managed care programs. My most
useful sources of information were
the administrative leaders of health
plans and BHN, who had frsthand
knowledge of and literature on the
“rule book” because they had communicated directly with CMS during
the application and formation of
Banner’s Pioneer ACO. My eyes were
opened to the true costs of health
care and the complexity of an uncoordinated health care system riddled
with stakeholders.
Accountable care organizations
A common misconception is that an
ACO is a government invention or designation. An ACO is simply a group of
providers who agree to be accountable
for the quality, cost, and overall care
Continued on page 46
44
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
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we are only a four (4) hour drive to San Francisco. We ofer an attractive
compensation and beneft package to our new associate physicians, plus the
opportunity for practice and ancillary service ownership. Candidates must be
board eligible or board certifed in gastroenterology.
Gundersen Health System in La Crosse, Wisconsin
is seeking a BC/BE Gastroenterologist to join its
established medical team.
Practice in our state-of-the-art Endoscopy Center
and modern outpatient clinic. Outreach services are
provided at our satellite clinics located within an
easy drive from La Crosse. In addition, you will have
opportunities for clinical research and will be
actively involved in teaching our Surgical,
Transitional, and Internal Medicine residents.
You’ll join a physician-led, not-for-proft health
system with a top-ranked teaching hospital and
one of the largest multi-specialty group practices
with about 700 physicians and associate medical
staf. Visit gundersenhealth.org/MedCareers
Send CV to Kalah Haug
Medical Staf Recruitment
Gundersen Health System
[email protected]
or call (608)775-1005.
DIRECT CONTACT INFORMATION
If you are interested in joining our team, please contact our Chief Operating
Ofcer, Mr. Tomas Klim at 775-284-4620 or send your CV directly by fax to
775-327-8868 or email at [email protected]. To learn more about our
organization, please refer to our website at www.giconsultants.com
GASTROENTEROLOGY
OPPORTUNITY
Cape Fear Center for Digestive
Diseases growing Gastroenterology
practice in Fayetteville, NC, is seeking
a full-time BC/BE Gastroenterologist. Join a busy practice with
5 physicians and four mid-level providers that offer outpatient
care at our practice owned endoscopy center, Digestive Health
Endoscopy Center. Inpatient care is provided at Cape Fear Valley
Health System, the 9th largest health system in the state with 765
patient beds, serving more than 935,000 patients annually.
ABOUT THE PRACTICE
• Practice established since 1984
• Full range of endoscopy including ERCP and
capsule endoscopy
• Practice owned endoscopy center
ABOUT THE POSITION
• ERCP/EUS experience necessary
• Desirable call arrangement with one hospital
• Partnership track with strong, reputable group
• State of the art infrastructure
• Outstanding quality of life in a family oriented community,
with excellent schools and low cost of living.
• Easy access to beach and mountains
For more information about this great opportunity contact:
Rita Graves, Practice Administrator
[email protected]
(910) 323-2477
EEO/AA/Veterans/Disabilities
FIND YOUR NEXT JOB AT
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45
GIHEP NEWS. COM • M AY 2015
CLASSIFIEDS
Also available at MedJobNetwork.com
PROFESSIONAL OPPORTUNITIES
If contributing to a team with an expectation for excellence and creating a
balanced and fulfilling life are important to you, St. Vincent Healthcare in
Billings, Montana has the opportunity and community for you!
St. Vincent Healthcare in Billings, Montana seeks U.S. trained BE/BC certified
physicians for our Gastroenterologist Clinic
•
•
•
•
•
•
•
•
•
•
•
•
Full time employed position
Physician will practice the full scope of general gastroenterology
Skills in ERCP and/or EUS would be a plus.
State of the art GI Diagnostic Center:
Call responsibilities are 1:3
Hospital is staffed for 220 beds and is a Level II Trauma Center
SVH is a regional destination hospital with a full complement of medical
specialties available.
Thriving medical community in a family-oriented suburban location
Excellent School Systems
Abundant recreational activities year round – hiking, skiing, fishing,
biking and camping
Competitive salaries with productivity incentives
Start date bonus, Moving Allowances and CME reimbursement
For more information, please contact
Therese Teske, Physician Recruiter at (406) 237-4017
[email protected] or visit our website at www.svh-mt.org
************
Billings, Montana listed 4th in cities with highest satisfaction – Business Insider, Gallup 2014
Additional Gastroenterologist
Wanted for Established Group
Full or Part-Time
Our Gastroenterology group of 4 Board Certified GIs, located in Palos
Heights, IL, just 25 miles from downtown Chicago is seeking a full or part
time BE/BC gastroenterologist. This well respected practice has enjoyed
an excellent reputation in the community for many years and maintains a
close relationship with our local hospital—Palos Community Hospital. The
group also performs GI procedures at two ambulatory surgical centers in
the area.
The demand for GI services has remained strong in our area and we
anticipate an industrious physician will be immediately able to fill an
office schedule, a surgical schedule as share in weekend call among 3
other gastroenterologists.
Our salary and benefits package are very competitive, and the
opportunity exists to own shares in a surgical center.
Send CV to Maura O’Reilly at
[email protected]
or call (708) 361-4089
PRESBYTERIAN HEALTHCARE SERVICES
Albuquerque, NM
Presbyterian Healthcare Services is seeking Board Certified Gastroenterology trained
physicians to join our established practice of 11 physicians, 2 Gastroenterology
Hospitalists and 7 midlevels. Our medical group employs more than 600 primary
care and specialty providers and is the fastest growing employed physician group
in New Mexico. Presbyterian Healthcare Services is a locally owned, not-for-profit
organization based in Albuquerque. Our integrated healthcare system includes eight
hospitals in seven New Mexico cities, a medical group, multispecialty clinics and a
health plan (over 400,000 members). We have been proudly providing care to New
Mexicans for 105 years.
In addition to a guaranteed base salary we also offer a sign on bonus, incentive
bonus, malpractice, relocation, house hunting trip, health, dental, vision, 403(b) w/
contribution from PHS 457(b), short & long term disability, CME allowance, etc.
Albuquerque thrives as New Mexico’s largest metropolitan center with a population
of 700,000. Albuquerque has been listed as one of the best places to live in the
United States by Newsweek, U.S. News & World Report, Money and Entrepreneur
Magazines! Albuquerque is considered a destination city for most types of outdoor
activities with 310 days of sunshine. A truly diverse and multicultural city, Albuquerque
offers you and your family a great variety of activities and entertainment including
national theater productions, sporting events, golf courses ranked among the
best in the country, the largest hot air balloon festival in the US, American Indian
Cultural activities and much more.
For more information, e-mail Kelly Herrera at [email protected]
or call 1-505-923-5662. Visit our website at www.phs.org
EOE
EXCELLENT OPPORTUNITY
Well established, successful hospital owned GI group in Cincinnati, Ohio is seeking a
gastroenterologist due to growth and expansion. Our twenty one member physician
group needs a general gastroenterologist to work in Northern Cincinnati, beautiful
Oxford, Ohio, home to Miami University. Candidates should be board certifed or
board eligible, able to work in a team atmosphere, possess an excellent bed-side
manner, goal oriented with strong clinical endoscopic skills.
Our practice ofers expertise in the clinical realm through performing diagnostic and
therapeutic endoscopy, ERCP, EUS and dedicated Hepatologists. Within our system we
also are doing research and training of primary care residents. Despite being a large
group, we still maintain small group camaraderie.
We ofer a very competitive starting salary with benefts and opportunities for
performance bonuses, retirement plans, group insurance plans (health, dental,
malpractice, disability), and an equal voice from the beginning. The group has a very
favorable call schedule which means working only 14-15 weekends a year. Our ideal
candidates will have outpatient and inpatient clinical responsibilities.
If you are looking to join a reputable, fnancially stable and
well-established practice, please give us a call. Please contact:
Greg Bush via email at [email protected]
or by phone at 513-569-6661 or
Dr. Allan Peck via email at [email protected]
or by phone at 513-853-9321.
46
PRACTICE ECONOMICS
Continued from page 43
of their benefciaries. An ACO may
have diferent ACO programs, which
generally fall into two categories: commercial ACO programs, initiated by
private payers; and government ACO
programs, initiated by CMS.
Government ACOs
After the passing of the ACA, CMS
initiated two ACO pilots: the Medicare
Shared Saving Program (MSSP), administered by CMS; and the Pioneer
ACO program, administered through
the Center for Medicare & Medicaid
Innovation, a CMS subsidiary.2
The goal for these ACO programs
is to achieve the Triple Aim, as defned by the Institute for Healthcare
Improvement: improving the patient
experience, improving the health of
populations, and reducing the per capita
cost of health care.3 Participation in
either of these programs is voluntary
and requires application to and approval
by CMS. The Pioneer program was
designed for organizations experienced
with taking fnancial risk for a population and capable of providing coordi-
MAY 2 0 1 5 • G I & HEPATO LO G Y NEW S
nated care. Thirty-two organizations
participated in the Pioneer program
beginning January 2012. Starting in year
3 of the initiative, those organizations
that have earned savings during the frst
2 years are eligible to move to a population-based payment arrangement and
full-risk arrangements that can continue
through optional years 4 and 5. Pioneer
ACOs are required to develop similar
outcomes-based payment arrangements with other private payers by the
end of the second year.
A Medicare benefciary (patient)
is aligned by CMS with an approved
ACO on the basis of the benefciary’s
pattern of utilization during a 3-year
alignment period. It is the ACO’s
decision on how to attribute the benefciary to a primary care provider.
After CMS aligns a benefciary with an
ACO, the ACO is required to notify the
benefciary of their participation. Benefciaries aligned with an ACO maintain
full benefts under the Medicare fee-forservice system and do not need a referral to see a specialist inside or outside
the ACO. One of the key features that
diferentiate these modern ACOs from
managed care programs in the 1990s is
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Disclaimer GI & HEPATOLOGY
NEWS assumes the statements made in
classified advertisements are accurate,
but cannot investigate the statements
and assumes no responsibility or
liability concerning their content. The
Publisher reserves the right to decline,
withdraw, or edit advertisements. Every
effort will be made to avoid mistakes,
but responsibility cannot be accepted
for clerical or printer errors.
For Deadlines and More information,
Contact: Linda Wilson
Tel: (973) 290-8243
Email: [email protected]
Moving?
Look to Classified Notices for
practices available in your area.
Take-away points:
1. Accountable care organizations
provide new opportunities for
gastroenterologists to be successful and to provide the best care
for their patients.
2. Gastroenterologists and their
practices should become leaders
of payment reform and accurate
quality reporting within their local health systems.
3. Gastroenterologists should seek
out opportunities for fnancial risk
sharing with payers so that they
are rewarded for taking the best
care of their patients.
that patient movement is not restricted.
Thus, a Pioneer ACO assumes responsibility for the total health care cost of
the benefciaries attributed to its providers, even though these patients may
choose to see providers outside of that
ACO. At frst glance this seems unjust;
however, it encourages the ACO to
build relationships of trust with their
patients on the basis of a strong primary care base and an integrated delivery
model. By default, CMS shares benefciary claims data with the ACO. The
ACO must give the benefciary written
notifcation and the option of opting
out of data sharing. Even when claims
data are not shared with the ACO, the
ACO is still responsible for that benefciary’s total spending and quality
outcomes.
In the Pioneer program, the percentage of fnancial savings (up to 75%)
shared with the ACO is dependent
on how the ACO performs against
benchmarks for each quality measure.
There are 33 quality measures in the
domains of patient experience, care
coordination and safety, preventative
health, and at-risk populations. Only
one measure, ACO 19, directly applies
to gastroenterology: the percentage of
patients aged 50-75 years who receive
appropriate colorectal cancer screening
(fecal occult blood test during the last
12 months, fexible sigmoidoscopy
during the reporting period or the 4
years prior, or colonoscopy during the
reporting period or 9 years prior). The
door opener for performance points
that contribute to a composite score
for all measures is the 30th percentile
(19.91%). After this, performance points
are awarded according to a sliding scale.
Reasons for exceptions, such as terminal illness, total colectomy, or colorectal
cancer, must be documented. Patient
noncompliance is not an acceptable exception. A percentage of CMS fnancial
savings for the benefciaries in the ACO,
with a predetermined cap, are distributed to the ACO. The ACO reimburses
itself for administrative overheads and
then distributes the remaining money
with the providers on the basis of any
prearranged agreement. CMS does not
prescribe how the ACO distributes the
savings to its providers. For example, an
ACO may choose to reinvest the savings in infrastructure or distribute the
savings with all its providers, or only the
primary care providers. In the Pioneer
model, the ACO is also at risk for fnancial loss up to a maximum of 15%.
Pioneer and Medicare shared
saving program ACO results to date
By the end of year 2, ACOs in the CMS
Pioneer ACO Model and MSSP generated over $372 million in program savings. In total, ACOs qualifed for shared
savings payments of $445 million.
Pioneer ACO year 1 and 2 results
have been published. In year 1 the
cost of care for Medicare benefciaries
aligned with Pioneer ACOs grew by
0.3% in 2012, compared with 0.8% for
non–Pioneer ACO–aligned benefciaries during the same period.4 Pioneer
ACO benefciaries outperformed the
control group in 15 clinical quality
measures for which comparable data
are available. At the end of year 1,
nine organizations chose to leave the
Pioneer Program, seven going over to
the MSSP and two leaving the ACO
programs entirely. During the second
performance year, Pioneer ACOs generated estimated total savings of over
$96 million and qualifed for shared savings payments of $68 million.5 The per
capita growth in spending for the Pioneer ACO program was 1.4%, which is
approximately 0.45% lower than traditional Medicare fee-for-service. At the
end of year 2, Pioneer ACOs showed
improvements in 28 of the 33 quality
measures and experienced average improvements of 14.8% across all quality
measures. BHN distributed Pioneer
ACO savings at the end of year 1 and 2
to the networks in the ACO.
The MSSP ACO results from year 1
only have been published. Fifty-three
MSSP ACOs reduced spending $652
million below their targets and
earned performance payments of
more than $300 million.
What do ACOs mean for
gastroenterologists?
Quality and payment data are becoming increasingly transparent not only
to patients but also between providers,
payers (including CMS), and health systems, which function like payers in an
ACO model. CMS, private payers, and
ACOs are highly motivated to meet the
Triple Aim to remain fnancially viable
and to attract new benefciaries.6,7,8
When viewed from the vantage point
of the ACO or payer, this undertaking
Continued on following page
PRACTICE ECONOMICS
GIHEP NEW S. COM • M AY 2015
Continued from previous page
is daunting, and limited attention can
be spent on each specialty because of
the lack of resources. This creates the
opportunity for gastroenterologists,
gastroenterology groups, and their
representative societies to be proactive
in setting quality standards and putting
forward bundled payment options.9
Quality measures
Gastroenterology quality measures
should be determined by gastroenterology societies. The appropriate
use of quality data is dependent on
the accuracy of the structured felds
in the electronic medical record
(EMR). Gastroenterologists must
take a leading role in ensuring that
the correct data are recorded in the
EMR where they practice and that
the data are recorded in a timely
manner. By using colorectal cancer
screening as an example, there are
logistical details that must be agreed
on: 1. Who is responsible for recording the performance of colon cancer
screening in the EMR, whether that
is the primary care doctor, the gastroenterologist, or someone else?
2. How and where is it documented
when the screening was performed
at another institution? 3. Is there an
automatic feed from the endoscopy
reporting software into the EMR
after the performance of the colonoscopy, or is this a manual process;
if so, by whom?
Content from this column was originally published in the “Practice Management: The
Road Ahead” section of Clinical Gastroenterology and Hepatology (2014;12:1769-72).
“Practice Management Toolbox” provides key information and resources necessary for facing the unique challenges of today’s clinical practices. Resources
for Practical Application: To view additional online resources about this topic
and to access our Coding Corner, visit www/cghjournal.org/content/practice_management.
Bundled payments
Bundled payments are appealing to
payers and ACOs not only because
they potentially lower expenses but,
more importantly, they make expenses predictable and improve ability to
manage fnancial risk and to share this
risk with providers. As an additional
beneft to the health care system and
patients, bundled payments require coordination of care. The American Gastroenterological Association convened
a physician work group in 2012 that
developed a framework for a colonoscopy bundled payment that includes
the preprocedure, procedure, and postprocedure periods. Specifc payment
for the bundle was not recommended
but left to the local physicians and payers to negotiate. A recent publication
in this journal by Minnesota Gastroenterology reports the deployment of
a colonoscopy bundle with three local
self-insured employers; however, specifcs of the fnancial arrangement and
outcomes are not presented.8 BHN is
presently working with AGA on colonoscopy and Crohn’s disease bundled
payment options.
Conclusion
Gastroenterology societies have
been successful lobbying for their
members’ and patients’ interests.
Individual gastroenterologists and
their practices should also become
leaders of payment reform and quality reporting within their local health
systems. If they do not, quality measures and payment methodologies
will be developed for gastroenterologists by payers who do not have the
same knowledge of what should be
measured and rewarded in the care
of patients with digestive diseases.
References
1. Centers for Disease Control and
Prevention. Healthcare Expenditure. 2010. Available at: www.cdc.
gov/nchs/fastats/hexpense.htm.
Accessed Nov. 11, 2013.
2. Patient Protection and Afordable
Care Act, 42 U.S.C. § 18001 et seq.
(2010). H.R. 3590 (2010).
3. Berwick, DM, Nolan, TW, and
Whittington, J. The triple aim:
care, health, and cost. Health Af.
(Millwood). 2008;27:759-69.
47
4. Centers for Medicare & Medicaid
Services. Pioneer Accountable
Care Organizations succeed in improving care, lowering costs. 2013.
Available at: www.cms.gov/Newsroom/MediaReleaseDatabase/
Press-Releases/2013-Press-Releases-Items/2013-07-16.html. Accessed
Nov. 11, 2013.
5. Centers for Medicare & Medicaid
Services. Medicare ACOs continue
to succeed in improving care, lowering cost growth. 2014. Available at:
www.cms.gov/Newsroom/MediaReleaseDatabase/Fact-sheets/2014Fact-sheets-items/2014-09-16.html.
Accessed Sept. 28, 2014.
6. Kislof, B. Accountable care organizations. Clin. Gastroenterol. Hepatol. 2012;10:442.
7. Rustgi, AK, Allen, JI. The house
of gastrointestinal medicine: how
academic medical centers can build
a sustainable economic clinical model. Clin. Gastroenterol. Hepatol.
2013;11:1370-3.
8. Taylor, IL. Clinchy, RM. The Affordable Care Act and academic
medical centers. Clin. Gastroenterol. Hepatol. 2012;10:828-30.
9. Ketover, SR. Bundled payment for
colonoscopy. Clin. Gastroenterol.
Hepatol. 2013;11:454-7.
Dr. Decker is president of Mercy Health
Physicians, Cincinnati. He has no relevant
conficts of interest.
[email protected]
Quick Quiz Answers
Q1: ANSWER: C
Critique
A recent Olmstead County, Minn., study was
undertaken to understand the epidemiology of
community-acquired C. difcile infections. In the
cohort of 385 proven C. difcile infections, 41%
were community acquired. Compared to cases
acquired in the hospital, community C. difcile
infections were observed in younger (B) females
(A) who had lower comorbidity scores and fewer chronic illnesses (D). Also, these outpatient
cases were less likely to have recent antibiotic
exposure (E) and fortunately had less severe clinical courses. A large population-based study and
several others have confrmed that the use of
gastric acid–suppressive agents such as PPIs (C)
increases the risk of C. difcile–associated disease
(adjusted risk ratio 2.9, 95% CI: 2.4-3.4).
References
1. Khanna S., Pardi D.S., Aronson S.L., et al. The
epidemiology of community-acquired Clostridium difcile infection: a population-based study.
Am. J. Gastroenterol. 2012;107:89-95.
2. Dial S., Delaney J.A., Barkun A.N., Suissa S.
Use of gastric acid–suppressive agents and the
risk of community-acquired Clostridium difcile-associated disease. JAMA 2005;294:2989.
Q2: ANSWER: C
Critique
Sulfasalazine can cause reversible azoospermia
and infertility. About 80% of patients taking
sulfasalazine have semen abnormalities and
72% have oligospermia. Only one case of azoospermia has been reported in patients taking
pure mesalamines. The sperm abnormalities are
thought to be caused by the sulfapyridine moiety in the sulfasalazine molecule. Therefore, a
switch from sulfasalazine to Asacol® or any other pure mesalamine is indicated. Sulfasalazine
inhibits dihydrofolate reductase and can cause
folate defciency. As a result, it should always
be given along with oral folic acid supplementation. There is no clear evidence that 6-mercaptopurine afects male fertility. Holding both
medications in a patient with UC would put
him at increased risk of recurrence and should
not be recommended. Withdrawal of an immunomodulatory agent such as 6-mercaptopurine
or azathioprine in patients who are in remission
can lead to rapid relapse in up to one-third of
patients in 1 year and two-thirds within 5 years.
Since 6-mercaptopurine is maintaining remission, there is no need for a switch to infiximab.
An in vitro fertilization specialist might be required if there is no conception despite sulfasalazine withdrawal.
References
1. Nielsen O.H., Munck L.K. Drug insight: aminosalicylates for the treatment of IBD. Nat. Clin.
Pract. Gastroenterol. Hepatol. 2007;4:160-70.
2. Cassinotti A., Actis G.C., Duca P., et al.
Maintenance treatment with azathioprine in ulcerative colitis: outcome and predictive factors
after drug withdrawal. Am. J. Gastroenterol.
2009;104:2760-7.
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