Gastroenterology and Endoscopy News Digital Edition - October 2012

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The Independent Monthly Newspaper for Gastroenterologists

Volume 63, Number 10 • October 2012 40th ANNIVERSARY 1972–201 2

H E PAT O L O G Y IN F O C U S

‘Astonishing’ Data on Metformin for HCC

By Christina Frangou San Diego—One of the most widely used diabetes drugs in the world appears to have an unexpected secondary benefit: reducing the risk for hepatocellular carcinoma (HCC) by more than 50%, according to two new studies. Results from an American case–control study and a see Metformin, page 26

First Guideline on NAFLD Published

By Christina Frangou Three leading American gastroenterology societies have published a new guideline on the diagnosis and management of non-alcoholic fatty liver disease (NAFLD).

Prompted by the fact that physicians are seeing a growing number of patients with the disease, this is the first time that any of these professional societies have developed

Studies Attempt To Define Patient Preferences for CRC Screening

By Caroline Helwick Despite its clear benefits, colorectal cancer (CRC) screening rates in the United States have stalled at around 50% of those eligible for screening.

Acceptance of screening recommendations might be enhanced if certain barriers could be overcome. Some believe that computed tomographic colonography (CTC) might be one way to improve adherence to screening recommendations.

This topic has been the aim of several recent clinical research surveys. What do these surveys reveal?

Are they accurate reflections of what patients truly desire? And why bother asking: Does patient preference really matter?

“The patient’s input and preferences have to be regarded as an absolutely central component of highquality care,” said David Weinberg, MD, MSc, chairman and professor of medicine at Fox Chase Cancer Center in Philadelphia, who spoke on the subject at

the 2012 Digestive Disease Week meeting in a lecture entitled, “What Will Be Competing with Colonoscopy in 5 years?”

“Clearly, patients who are well versed at an appropriate level, understand their treatment options and see Patient Preferences, page 7

see NAFLD Guideline, page 28

I N S I D E

GI Roundtable Round 2012

Gastroente enterologists Discuss Challenges, Changes, Future Fu of GI Health Care Compiled and written by Monica J. Smith Knoxville, Tenn.—The GI Roundtable conference evolved as a collaboration between Bergein Overholt, MD, of Gastrointestinal Associates in Knoxville, Tenn., and Klaus Mergener, MD, PhD, MBA, of Digestive Health Specialists in Tacoma,

EXPERT’S PICKS Best of Digestive Disease Week (DDW): Inflammatory Bowel Disease (IBD) Ellen J. Scherl, MD, provides an overview of IBD research presented at the DDW meeting Ellen J. Scherl, ............................................ page 10 MD Complications of Biologic Therapy for IBD Four IBD experts discuss common risks and complications associated with anti-TNF therapy for IBD ............................................ page 14

see GI Roundtable, page 50

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

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LETTER TO THE EDITOR

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Question: OC or CTC? Answer: Yes Re: “Patients Prefer Colonoscopy,� by David Wild. Gastroenterology & Endoscopy News June 2012;63:1,14-15.

When you ask the wrong question, you rarely get the right answer. Why, then, deliberate whether a wide and varied population prefers optical colonoscopy (OC) or virtual colonoscopy/computed tomographic colonography (CTC) for colorectal cancer (CRC) screening?

Asking this question misses the fundamental point that screening rates for CRC—the most preventable of the deadly cancers—continue to be far too low and are in desperate need of improvement. The better question is: How do we raise CRC screening rates so we can save more lives? The right answer to this question is clear: Offer an array of the best CRC screening tests and let patients choose which one is most acceptable to them. This array needs to include both OC and CTC. OC, the current and presumptive gold standard for CRC screening, undoubtedly is a highly effective screening test and has been accessible to insured patients for more than a decade. It is performed on, and well tolerated by, millions of Americans every year. Despite OC’s strong record, however, 40% to 50% of patients eligible for screening remain unscreened. Clearly, the “OC for everyone� strategy is inadequate and additional effective CRC screening options are needed.

With nearly 20 years of clinical study, including a large body of strongly positive clinical studies published in the past five years, CTC has emerged as a highly effective alternative to OC for CRC screening.

CTC’s rate of detection of significant polyps and cancers rivals or exceeds that of OC in recent studies. Furthermore, the practice of offering same-day colonoscopy for polyp removal when identified by CTC makes the CTC option as convenient and comprehensive as—and The Independent Monthly Newspaper for Gastroenterologists

4 0 th ANNIVERSARY

less expensive than—the “OC for everyone� screening strategy.

So which method—OC or CTC—do patients prefer?

Again, with 40% to 50% of the populattion remaining unscreened for CRC, it hardly matters. As long as a significant h percentage of patients would chose p tto be screened with CTC after refusiing OC, CTC should be offered as an aalternative screening option.

Several large studies of patient prefeerence with respect to CRC screeniing have now demonstrated that programs offering CTC get previously p unscreened patients off the “screenu iing sidelines.� A multicenter survey of more than 1,400 CTC patients, includm iing patients from our center, showed that nearly 30% of patients receiving CTC had previously refused to be screened with OC.1 Other studies have shown that the number of previously unscreened patients willing to be screened with CTC is close to 40%.2 Patients who had previously undergone OC were asked which test (OC or CTC) they preferred and which one they would like to receive for their next screening. In these studies, 75% to 90% responded that they preferred CTC to their previous OC. Furthermore, 90% of patients planned on receiving CTC for their next screening. Although these are clearly biased populations—patients who had already chosen to receive CTC—their post-test preference for CTC is impressive and undeniable.

If CTC does move previously unscreened people off the screening sidelines, we should see an increase in overall screening rates when CTC programs are initiated. A report soon to be published from the National Naval Medical Center—where President Obama gastroendonews.com

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Patients Prefer Colonoscopy

GI Quality Improvement Consortium Catching on Across the Country

BY DAVID WILD

Program a Win-Win-Win for Physicians, Patients, Payers

SAN DIEGO—Patients undergoing screening for colorectal cancer (CRC) experience less pain and have less anxiety with colonoscopy compared with patients undergoing computed tomographic colonography (CTC) screening, according to findings from a prospective questionnairebased study presented at the 2012 Digestive Disease see Colonoscopy, page 14

Fly and Flare

Air Travel Linked to IBD Flares

BY DAVID WILD

SAN DIEGO—Fly and flare. This was the link discovered by Swiss researchers who found that patients with inflammatory bowel disease (IBD) who embarked on high-altitude flights or journeys had higher relapse rates than those who stayed closer to the ground.

see Flares, page 15

BY MONICA J. SMITH

In an effort to facilitate the pursuit of quality in the evolving context of American merican health care, the American College of Gasttroenterology (ACG) and the American Society for Gastrointestinal Endoscopy (ASGE) launched the GI Quality Improvement Consortium (GIQuIC), a database of quality measurres in endoscopy thatt will allow participants to measure themselves against national benchmarks, satisfy demands for transparency, and possibly reap some financial rewards.

see GIQuIC, page 24

I N S I D E

EXPERT ROUNDTABLE

Physician n Rallie es Colleagues To Help Shape Fu uture off Health Care Reform

BY KATE O’ROURKE

“I think there is more and more emphasis from payers and CMS [the Centers for Medicare & Medicaid Services] for us to document that we are complying with quality measures,� said Karen L. Woods, MD M D, a gastroenterologist in Houston Houstoon. “This This is

HOUSTON—In the next five to 10 years, health care will change dramatically, and if physicians don’t lead the process of health care reform, the politicians will, Robert Pearl, MD, told physicians at the recent annual meeting of the Society of Critical Care Medicine. The prospect of politicians leading the way will not bode well

The Use of JCV Antibody Assay in Treating Patients With Crohn’s Disease .................. >}iÊ££

Stephen B. Hanauer, MD

Uma Mahadevan, MD

David T. Rubin, MD

see Health Care, page 38

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Time for Gastros To ‘Reclaim Our Profession’ Re: “CMS Unveils Major Changes for ASCs,� by Christina Frangou.

Gastroenterology & Endoscopy News May 2012;63:1,59.

Cuts in reimbursement annually relative to hospital outpatient department are unfair enough. But the cuts have come packaged with draconian requirements for documentation and reporting to CMS [Centers for Medicare & Medicaid Services]. The increased regulation has caused decreases in efficiency and increases in personnel costs, without discernible improvements in outcomes. It’s time to push back and reclaim our profession.

Web Comment

Ronald Feldman, MD Board-certiďŹ ed gastroenterologist Escondido, Calif.

Via Web site on August 18, 2012

William J. Sandborn, MD

Corey A. Siegel, MD, MS

received his screening CTC— shows that overall screening adherence rates increased by 15% with the addition of the dedicated Mark J. Baumel, CTC program.3 MD, MS Many commercial insurers in the United States already understand the logic of offering both tests and have added CTC to their covered CRC screening options. Elderly and disabled individuals in the United States, most of whom are subject to Medicare’s coverage policies, continue to have no coverage for screening CTC. Unfortunately and ironically, these types of patients are the very ones who would most benefit from a noninvasive screening option. There is little doubt that Medicare will be forced to correct this coverage deficiency on its next review.

If our primary goal is to save lives from this highly preventable cancer, then it is time to offer not one or the other, but both of these excellent CRC screening tests.â– Mark J. Baumel, MD, MS CEO, Colon Health Centers of America Mendenhall, Pennsylvania

References 1. Pooler BD, Baumel MJ, Cash BD, et al. Screening CT colonography: multicenter survey of patient experience, preference, and potential impact on adherence. AJR Am J Roentgenol. 2012;198:1361-1366.

2. Moawad FJ, Maydonovitch CL, Cullen PA, Barlow DS, Jenson DW, Cash BD. CT colonography may improve colorectal cancer screening compliance. AJR Am J Roentgenol. 2010;195:1118-1123.

3. Cash BD, Stamps K, McFarland EG, Spiegel AR, Wade SW. Clinical use of CT colonography for colorectal cancer screening in military training facilities and potential impact on HEDISÂŽ measures. J Am Coll Radiol. 2012. In press.

Patient With Obesity Expresses Hope gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

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Re: ‘New Drugs, Policy Changes Offer Gastros Ways To Help Patients Manage Obesity,’ by Christina Frangou.

Gastroenterology & Endoscopy News September 2012;63:1,20.

40th ANNIVER SARY 197 2 – 2012

Adenoma Detection Rate an ‘Imperfect’ Measure of Quality

BY CAROLINE HELWICK SAN DIEGO—Are adenoma detection rates (ADRs) the best way to measure the quality of colonoscopy? “The ADR is imperfect but better than some proposed replacements,� said Douglas K. Rex, MD, in a lecture at the 2012 Digestive Disease Week (DDW) see ADR, page 12

Novel Test IdentiďŹ es IBD Subtypes

BY DAVID WILD SAN DIEGO—A new diagnostic test incorporating 17 serologic, genetic and inflammatory markers is 87% accurate in identifying inflammatory bowel disease (IBD) and 93% accurate in differentiating ulcerative colitis (UC) from Crohn’s disease (CD), according to research presented at the 2012 Digestive Disease Week (DDW) meeting. see IBD Test, page 14

New Drugs, Policy Changes Offer Gastros Ways To Help Patients Manage Obesity

BY CHRISTINA FRANGOU After a series of national policy changes and drug approvals this summer, gastroenterologists have new w tools to help their patients who struggle with obesity.

In late June, the U.S. Preventive Services Task Force (USPSTF) recommended that all adults be screened for obesity during their checkups—a directive geared to primary care physicians, but all physicians are asked to heed the recommendations. The USPSTF also called on clinicians to refer patients with a body mass index (BMI) of 30 kg/ m2 or greater to intensive multicomponent behavioral interventions, or to offer these patients interventions.

Several days later, the FDA approved Belviq (lorcaserin hydrochloride; Eisai Pharmaceuticals) as an addition to a reduced-calorie diet and exercise for chronic weight management. Belviq was the first anti-obesity drug to be approved in the past 13 years,

The Future of Gastroenterology Practices: Is Bigger Better?

and marked a significant shift in FDA policy. For the past decade, the agency has been reluctant to approve new diet drugs, largely because of a history of product withdrawals and serious side effects.

Weeks after endorsing Belviq, the FDA also approved Qsymia (Vivus Pharmaceuticals), which combines the anti-seizure/migraine drug topiramate and the appetite-suppressant phentermine. “Obesity threatens the overall well-being of patients and is a major public health concern,� said Janet Woodcock, MD, director of the FDA’s see Obesity, page 18

I N S I D E EXPERTS’ PICKS Best of Digestive Disease Week (DDW): Part 3

I am very impressed that you all have considered patient safety, limiting surgical intervention with endoscopic procedures, specifically the endoscopic temporary ballooning, along with behavioral intervention, and new medications. I am a statistic in the obesity crisis. Medical issues have exacerbated weight and restricted surgical options for me. This is very exciting news. Count me in as [patient] number one when clinical trials start. Thank you all. This is news that I have been impatiently but diligently waiting for.

Lynn Jackson Web Via Web site on Sept. 13, 2012

Experts share their favorite abstracts from the 2012 DDW meeting....................page 8

BY MONICA J. SMITH

KNOXVILLE, TENN.—A common refrain at the 2012 GI Roundtable, a meeting that explored strategies to help medical practices remain successful in a rapidly changing health care environment, was “bigger is better.� But more than half of gastroenterology practices today are small, with no more than five physicians and most with less than 10.

Staying small and independent may take some innovative thinking as demand grows for lower-cost, high-quality health care services, said experts who spoke at the meeting.

Frank G. Gress, MD

Edward Loftus Jr., MD

see Gastro Practice, page 20

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Patient Preferences continued from page 1

feel that their desires and preferences are included as part of decision making are more likely to be compliant patients,” he said, adding that the “appropriate and continuing shift toward patient-centered care” is integral to the success of screening programs.

Some Favor CTC A recent survey indicates that some patients prefer CTC. The first large multicenter effort to assess patient satisfaction with CTC screening across diverse clinical settings was published this year (Pooler BD et al. AJR Am J Roentgenol 2012;198:1361-1366). Investigators queried 1,417 individuals using a 12-question survey that measured patient pretest preference, experience and satisfaction with CTC screening in three different settings: university academic center, military medical center and community practice. The cohort was composed of people voluntarily participating in clinical CTC screening programs.

Respondents reported a very high level of satisfaction with CTC, and those who had undergone both CTC and optical

colonoscopy (OC) indicated a preference for CTC over OC. Patients’ top reasons for preferring CTC for screening included “noninvasiveness” (68%), “avoidance of sedation/anesthesia” (63.1%), “ability to drive after the test” (49.2%), “avoidance of optical colonoscopy risks” (46.9%) and “identifying abnormalities outside the colon” (43.3%). Pain or moderate discomfort was reported by 9.7% of participants.

Of 441 patients who also had undergone OC at an earlier time point, 77.1% preferred CTC, whereas 13.8% preferred OC. More than 90% labeled their CTC experience at least “good” and said they would choose CTC for their next screening. Notably, 29.6% indicated that they would not have been screened were CTC not available—a point driven home by co-investigator Mark Baumel, MD, MS, of Colon Health Centers of America, Mendenhall, Penn., who cited this as the most impressive finding.

“We acknowledge that this was a population of convenience, which lends bias, but we found that 30% of the population would otherwise refuse screening. We are getting these people off the screening

sidelines, and that fact is undeniable,” Dr. Baumel said.

He also noted that the ability to obtain extracolonic information during CTC was a draw to many patients; abdominal aortic aneurysms and early renal, liver and pancreatic cancers have been found with CTC. “The opponents of CTC talk about these incidental findings as a disadvantage, and occasionally you do find yourself working up what turns out to be benign lesions. But if you are the patient with a serendipitous finding that turns out to be a curable cancer, you don’t care about unnecessary workups.”

A recent meta-analysis further demonstrated patient preference for CTC, citing 23 studies involving 5,616 subjects (Lin OS et al. J Gen Intern Medd 2012 Jun 15 [Epub ahead of print]). In 16 studies, CTC was the preferred approach; OC was the preferred method in three studies. However, the authors noted that, based on a stratified analysis, studies published in radiology journals seemed more likely than studies in gastroenterology or general medicine journals to report a preference for CTC (P<0.001).

Sometimes It’s a Draw A 2012 study from the United Kingdom took a different approach and reached a different conclusion (Ghanouni A et al. Patient Educ Couns 2012 Jun 15 [Epub ahead of print]). Investigators conducted six discussion groups with 30 screening-aged adults in each group, using a topic guide to provide information about the tests. They found that 46% preferred OC, whereas 42% preferred CTC. Those choosing OC cited the test’s sensitivity, avoidance of false-positives and capacity to remove polyps immediately as important advantages. Those who chose CTC cited its lack of invasiveness, ability for extracolonic evaluation and reduced interference with daily life as attractive features.

“With comprehensive information, colonoscopy and CTC were seen as having different advantages and disadvantages, yielding no clear preferences between the two,” the authors wrote.

“Health care professionals working in the screening context should be sensitive to the range of characteristics that can determine preferences for CRC screening tests.”

Preference for OC Surprises Investigators On the contrary, Canadian investigators observed a clear preference for OC among patients they surveyed in a study reported at the 2012 Digestive Disease Week (DDW) meeting (abstract 445).

Unlike the patients in the Pooler et al cohort who were already participating in a CTC screening program, the Canadian cohort underwent both CTC and OC on the same day.

“We were surprised by our findings,” said Greg Rosenfeld, MD, of the University of British Columbia in Vancouver, at a DDW press briefing. “Previous findings have shown that CTC is preferred by patients; however, our study showed a clear preference toward [optical] colonoscopy.”

The study compared same-day CTC (without sedation/analgesia) and OC among 90 average-risk adults. Within 2 hours of CTC completion, subjects underwent OC with conscious sedation.

Patients completed an 11-question survey immediately after undergoing CTC, and a similar questionnaire after OC. Overall, patients judged OC to be more satisfactory. Patients felt less anxious than with CTC (36% vs. 7%; P P=0.006) and reported that, although their pain was adequately controlled in both procedures, the pain was less during OC (69% vs. 4%; P<0.0001). see Patient Preferences, page 8

8

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Patient Preferences continued from page 7

Among patients who stated a preference, OC was considered more satisfactory than CTC by 30%, whereas 4% held the opposite opinion (P<0.0001).

For repeat screening, 77% preferred OC; the 23% who preferred CTC based their preference on the shorter procedural and recovery times with CTC. “We think the use of sedation was largely responsible for the difference,” Dr. Rosenfeld said. “The majority of patients reported some discomfort associated with CTC, mainly because of distension.”

David Lieberman, MD, professor of medicine and chief of gastroenterology at Oregon Health & Sciences University in Portland, said he was not surprised at the findings.

“That’s been the experience of others as well. When we do colonoscopy we sedate the patients, and they like that.”

“The things that patients are going to describe as preferences may vary substantially by when you ask the question and whether they know the outcome of the procedure when the question was asked,” he said. “If I say your colonoscopy was completely normal, you may tend to remember the discomfort because your brain is not cluttered with what is ultimately more important. On the other hand, if the exam was uncomfortable but the outcome was colon cancer, the chance that you will focus on the exam itself is relatively small.”

‘If this pans out and we move toward a laxativefree CTC, we will have to change the way we look at this modality.’

Question of Timing According to Dr. Weinberg, although the meta-analysis by Lin et al showed a general preference for CTC over OC in a “global” sense, a closer look at the findings reveals nuances—such as the tendency for CTC to be preferred in studies published in radiology journals or authored by radiologists, and for OC to be preferred in studies published in gastroenterology journals. Also, although patients generally preferred CTC as a screening approach, they did not prefer it for diagnostic indications.

Dr. Weinberg also pointed out, “To conduct studies comparing these preferences is hard.” At what time point is a question likely to elicit the most accurate response? Is it possible that the outcome of the exam confounds the experience?

Would the same individual give the same answers at different time points?

prediction, as long as there is no meaningful reduction in the clinical utility of CTC with a less-intensive bowel prep.

He also pointed out that the costeffectiveness of CTC needs to be proven before patients can fully embrace it, regardless of what the surveys show.

“In the screening world, it’s pretty clear that CTC is almost as good as OC, but the problem today is the cost of the exam remains too high as a screening test to compare favorably with some of the other screening options,” he said. “This is a ‘preference question’

—David Lieberman, MD

The Tipping Point Dr. Lieberman predicted that should bowel preparation become unnecessary for CTC, patient preference for this modality could grow. A recent study showed a laxative-free bowel preparation for CTC—which identifies and subtracts labeled feces—to be essentially as accurate as OC for detecting adenomas 10 mm or larger and to provide a better patient experience (Zalis ME et al. Ann Intern Medd 2012;156:692-702).

“If this pans out and we move toward a laxative-free CTC, we will have to change the way we look at this modality,” he suggested.

Dr. Weinberg agreed with this

because patients may have higher outof-pocket expenses with CTC, which is not accounted for in studies that assume there is no additional cost. If we could offer a test that would substantially increase the uptake of CRC screening and that was cost-effective and efficacious, then that would represent a useful addition to the screening armamentarium.”

Options Are Important Few specialists disagree that having a number of effective screening modalities increases screening acceptance rates.

“Options are important,” emphasized Dr. Weinberg, who cited a recent

randomized study from the University of Washington (Inadomi JM et al.

Arch Intern Medd 2012;172:575-582). In a sample of 997 patients, those whose providers recommended colonoscopy completed screening at a significantly lower rate (38%) than those who were instructed to undergo fecal occult blood testing (FOBT; 67%) or those given a choice between colonoscopy and FOBT (69%; P<0.001). Non-white patients adhered more often to FOBT, whereas white participants more often preferred colonoscopy. The authors concluded that “the common practice of universally recommending colonoscopy may reduce adherence to CRC screening. … Patient preferences should be considered when making CRC screening recommendations.”

Dr. Baumel added, “The main question should not be which test most patients prefer.” Rather, the issue should be what array of tests should be offered to maximize screening rates, he said.

“OC is not, by itself, getting the job done because 40% to 50% of eligible people are being left unscreened. The availability of CTC has the potential to increase screening rates, as it can impact on the sizeable group of patients not willing to, or unsure about, being screened.

The only option is to offer both tests and have them work symbiotically and in concert, the ultimate goal being to get as close to 100% compliance as possible,” he said.

■ Drs. Rosenfeld, Weinberg and Lieberman reported no conflicts of interest. Dr. Baumel has an equity state in Colon Health Centers of America, which provides virtual colonoscopy-related services to gastroenterology physician groups.

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DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Experts’ Picks:

The Best of Digestive Disease Week 20122: Inflammatory Bowel Disease C Compiled and written by D David Wild W

Gastroenterology and Endoscopy News asked inflammatory bowel disease (IBD) expert and Gastroenterology & Endoscopy Newss medical advisory board member, Ellen J. Scherl, MD D, to highlight the most noteworthy abstracts focusing on the biologic treatment of IBD presented at thee 2012 Digestive Disease Week (DDW) meeting. Following is a summary of her selections.

Ellen J. Scherl, MD Director, Jill Roberts Center for Inflammatory Bowel Disease NewYork-Presbyterian Hospital/ Weill Cornell Medical Center Director of Research, Jill Roberts Center for Inflammatory Bowel Disease Jill Roberts Associate Professor for Inflammatory Bowel Disease Associate Professor of Medicine Division of Gastroenterology and Hepatology Weill Cornell Medical College Adjunct Associate Professor of Medicine Columbia University College of Physicians and Surgeons New York, New York

Dr. Scherl: In my opinion, the overarching theme for the 2012 DDW meeting was how we can optimize therapeutic response to anti-tumor necrosis factor (TNF) therapies for IBD. There is more evidence pointing to the utility of monitoring immunologic response and using biomarkers of mucosal healing as indicators of treatment efficacy. These parameters can assist us in appropriately dosing treatments, addressing the problem of attenuated response to anti-TNF agents, and identifying patients most likely to maintain remission following discontinuation of anti-TNF agents.

I. Personalizing and optimizing biologic therapies: Patient selection is critical and biologics are not for everyone.

307.

Inflammatory Bowel Disease Patients on Immunosuppressive Therapy in Endoscopic Remission Have a High Rate of Post Inflammatory Bowel Disease-Irritable Bowel Syndrome Which Is Associated With a Diminished Quality of Life (Stein DJ et al) This retrospective chart review set out to document the incidence and impact of irritable bowel syndrome (IBS) among IBD patients in endoscopic remission. Analysis included 156 IBD patients receiving immunosuppressive

therapy who had at least two normal C-reactive protein (CRP) tests as well as colonoscopy showing normal mucosa or only mild inflammation. Pattients were classified according to the Rome III criteriaa for IBS. Analyses showed that 41.7% of patients met ROME III criteria, including 45.1% of patients with Crohn’s disease (CD) and 28.1% of patients witth ulcerative colitis (UC; P P=0.08). Women were more liikely than men to experience post-IBD IBS (58.3% with post-IBD IBS vs.

41.6% without post-IBD IBS; P P=0.0088).

Patients with post-IBD IBS scored significantly lower than those without IBS on the Shortt IBD Questionnaire, and higher on the Harvey-Brad dshaw Index and the Ulcerative Colitis Disease Activity Index (UCDAI).

There were no significant differences in medication use, number of colonoscopies, hospitalizations and surgeries, age, race, disease duration, smoking history, CD phenotype and UC extent between the IBS and non-IBS groups.

Differential diagnosis is critical in defining whether or not the patient has active inflammation and ensuring they are not unnecessarily and over-treated with an anti-TNF. In addition to possible IBS, lactose or fructose intolerance, bacterial overgrowth, g tropip cal sprue, Helicobacter pylori, pancreatic insufficiency, steatorrhea, bile salt diarrhea, chronic cholecystitis, overlapping celiac disease, depression or malnutrition should be considered. It is equally important to insure that patients are not taking nonsteroidal anti-inflammatory drugs (NSAIDs) and do not have an intercurrent Dr. Scherl: As this abstract demonstrates, persistent infection. abdominal symptoms may be accounted for by nonHowever, even when you identify patients with active inflammatory conditions, such as IBS. Jean-Frédéric disease and have ruled out pseudo-refractory, moderColombel, MD, and his ate to severe IBD, and even after team first underscored the selecting patients with active IBD importance of confirming refractory to conventional therapy, that symptoms are due to one-third of patients will be primary ‘As this abstract an inflammatory response nonresponders, as pivotal anti-TNF demonstrates, persistent prior to initiating immunoinduction trials have demonstrated. abdominal symptoms modulator treatment in their The reasons for primary nonresponse in this population include controlled trial comparing may be accounted for by azathioprine (AZA), inflixunderdosing, a surgical lesion, such noninflammatory conditions, imab (IFX) or combination as a tight fibrotic obstructing strictreatment (AZA-IFX; N ture or internal fistula or abscess, such as IBS.’ Engl J Medd 2010;362:1383and phlegmon. Inflammation also —Ellen J. Scherl, MD 1395). In the three arms can be mediated through a nonwhere CRP was less than TNF inflammatory pathway, such 0.8 mg/dL, week 26 steroidas interleukin (IL)-12/23 or JAK/ free remission rates were 35% for AZA alone, 40% for STAT. If patients have subtherapeutic levels of antiIFX alone and 51% for the AZA-IFX group. However, TNF agents and inflammation is mediated by a nonpatients with elevated CRP levels—and especially those TNF mechanistic pathway, increasing the dose will not with elevated CRP endoscopic ulcers—had a dramatic yield a response. response to both IFX monotherapy and combination therapy compared with weight-based dosing of AZA II. Preventing attenuation of response: (2.5 mg/kg). Specifically, week 26 steroid-free remis- secondary loss of response sion rates for those with baseline CRP levels greater than 0.8 mg/dL were 27.6% for those who received Dr. Scherl: In patients who do respond to anti-TNF AZA alone, 47.5% for IFX alone and 63.5% for AZA- induction therapy, a growing problem is secondary loss IFX treatment. of response. Controlled trials have shown that among

DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

the two-thirds of patients who are primary responders to anti-TNF therapy, up to 50% relapse within one year, so that at the end of one year, only one-third of patients maintain response. The question is: How do we optimize our therapies to ensure continued response?

Research continues to show that combining antiTNF therapy with immunosuppressant therapy decreases the likelihood of immunogenicity. There also is emerging data that a combination approach can improve the efficacy of some biologics, independent of immunogenic effects. Of course, choosing combination treatment has to be weighed against the increased risk for lymphoma associated with long-standing AZA treatment.

Key to reducing the likelihood of secondary loss of response, as the studies below demonstrate, is ensuring that treatment is associated with mucosal healing and not only clinical response. Two useful biomarkers of disease activity are fecal calprotectin and fecal lactoferrin, as reported by two recent studies.

11

to show a median level above the cut-off for active, endo- concentrations were measured at the same time points scopically and histologically proven active UC. However, as Mayo Scores were assessed. because the differences in levels between patients with Overall, median IFX concentrations were 33.0, 2.4 and without mucosal healing did not reach statistical and 3.6 mcg/mL at weeks 8, 30 and 54, respectively. significance, further investigation Median IFX concentrations of this potentially useful biomarker for patients achieving cliniis needed. cal response, clinical remission ‘Key to reducing the Earlier this year, De Vos et al preand mucosal healing at weeks 8, sented data at the European Crohn’s 30 and 54 were higher than in likelihood of secondary and Colitis Organization (ECCO) those not meeting criteria for loss of response is 2012 Congress (abstract OP07) these outcomes. showing that fecal calprotectin The clinical utility of IFX ensuring that treatment is also correlated with mucosal healconcentrations needs to be associated with mucosal ing in UC patients. That analysis prospectively validated in a healing and not only included 113 patients with UC in randomized controlled clinical deep remission treated with IFX 5 trial assessing the risk–benclinical response.’ mg/kg every eight weeks; fecal calefit associated with adjusting —Ellen J. Scherl, MD protectin was measured monthly for dose-to-target specific serum one year. Deep remission (defined concentrations compared with endoscopically and histologically, dose adjustment based purely not simply clinically) occurred in 26.5% of patients and on clinical parameters, the researchers qualified.

Lactoferrin was correlated with fecal calprotectin levels less than 50 Level Is an mg/kg at all time points. In contrast, the median fecal Dr. Scherl: This study highlights the importance calprotectin level among patients who experienced a of achieving adequate concentrations of serum IFX, Indicator flare was 477 mg/kg, with fecal calprotectin increases demonstrating that higher levels are associated with a of Mucosal Healing in Patients With Ulcerative Colitis: a Prospective 12-Month Monitoring Study occurring up to three months prior to flare. Two con- greater likelihood for clinical response, remission and secutive measurements of fecal calprotectin greater than mucosal healing. As a strategy to achieve therapeutic (Langhorst J et al) 300 mg/kg was predictive of relapse. serum IFX concentrations, dose intensification is known Langhorst et al studied 85 patients with UC in remisThe importance of mucosal healing as a predictor of to be effective in patients with CD; however, data on sion over a one-year period, documenting CRP levels sustained clinical response was highlighted in another patients with UC are lacking. The study below addressed (cut-off, 0.5 mg/dL), white blood cell count (WBC; cut- study presented at the ECCO Congress earlier this year this issue and found the need for IFX dose intensificaoff, 8.5/nL), and stool and serum fecal lactoferrin levels (abstract P278). David Laharie, MD, and colleagues tion is higher in patients with UC compared with CD (cut-off, 7.25 mcg/g). They set out to determine the cor- in five French centers recorded clinical, histologic and patients, and is done earlier. Further study on the effirelation between these laboratory data from 63 patients with cacy of intensification is required. markers and the extent refractory UC receiving maintenance of mucosal healing, IFX therapy. Among the 30 patients Need for comparing measures of who demonstrated mucosal healing Infliximab ‘Two useful biomarkers of these parameters with after a median 27 months of followDose disease activity are fecal sigmoidoscopy findup, colectomy-free survival rate was Intensification in Patients With Crohn’s Disease ings.

Sigmoidoscopy 96% at years 2 and 3. In contrast, the and Ulcerative Colitis (Taxonera C et al) calprotectin and fecal with histologic analysis colectomy-free survival rate was 65% lactoferrin, as reported by two was performed at baseat years 2 and 3 among patients who This was a single-center study of 61 patients with CD recent studies.’ line, at the time of an did not experience mucosal healing. and 41 patients with UC receiving treatment with IFX. acute flare (defined as Multivariate analyses confirmed that Researchers compared the number of patients and time —Ellen J. Scherl, MD UCDAI score >4) or at the sole prognostic factor associated on IFX prior to dose intensification. Intensification was the end of the one-year with colectomy-free survival was achieved by increasing the doses from 5 to 10 mg/kg, or study period. Mucosal mucosal healing (odds ratio, 18.01; by shortening the dosing interval. Most patients with healing was considered to have occurred in the absence 95% confidence interval, 1.58–204.92).

CD and UC had been receiving an immunomodulator at the time of IFX initiation. of acute immune cell infiltration, crypt abscess, mucin depletion and breaches in the surface epithelium.

The researchers found that 26% of CD patients and Infliximab Concentration and Among the 36 patients who experienced disease 39% of UC patients required dose escalation (P=0.02) P Clinical Outcome in Patients relapse, median fecal lactoferrin levels were 40 mcg/g after a median of 10.5 months (interquartile range With Ulcerative Colitis compared with a median 5 mcg/g among those who (Reinisch W et al) [IQR], 8.7-15.2 months) and 6.2 months (IQR, 3.5-8.3 maintained remission (P<0.0001). Median CRP levels months), respectively, following IFX induction (P=0.16).

P among patients who relapsed and or experienced remis- This post-hoc analysis of data from ACT (Active sion were 0.6 and 0.1 mg/dL, respectively (P P <0.001). Ulcerative Colitis Trial) 1 and 2 included patients III. Anti-TNF withdrawal in patients in clinical Median WBC levels were 7.6 and 6.0/nL, respectively with UC being treated with IFX. Mayo Scores were remission: How do we predict sustained (P P =0.01). assessed at weeks 8 and 30 in both trials, and at remission? Endoscopic and histologic mucosal Median fecal lactoferrin levels at 12 months among week 54 in ACT 1. Clinical response was defined as healing are important. those with mucosal inflammation and those with muco- a decrease in Mayo Scores from baseline of 30% or sal healing were 37 and 5 mcg/g, respectively (P=0.09); P greater and a total Mayo score of 3 or lower, with median CRP was 0.2 and 0.1 mg/dL, respectively, either a 1-point or greater decrease from baseline Dr. Scherl: Once initial response with IFX is (P=0.882).

P Median WBC was 5.9 and 6.0/nL among in the rectal bleeding subscore or a rectal bleeding achieved and then maintained, there is the question those with and without mucosal healing, respectively score of 0 or 1. Clinical remission was defined as a of predicting which patients can discontinue IFX and (P=0.787).

P Mayo score of 2 or lower, with no individual subscore maintain remission. Again, endoscopic and histologic greater than 1 and accompanying mucosal healing, mucosal healing as well as the utilization of surrogate Dr. Scherl: Fecal lactoferrin was the only biomarker indicated by an endoscopic subscore of 0 or 1. IFX see Best of DDW IBD, page 12

Mo1667.

Sa1888.

566.

12

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Best of DDW IBD continued from page 11

markers or biomarkers of mucosal healing, such as fecal lactoferrin or calprotectin, play an important role in identifying these patients.

Mucosal healing—and, therefore, clinical response—with IFX is much more likely to be achieved when the drug is administered in combination with AZA, as the combination more than doubles IFX serum levels in CD patients (Colombel JF et al. N Engl J Medd 2010;362:1383-1395). Median serum IFX concentrations after 30 weeks of treatment were 3.5 mcg/mL in patients who received combination AZA-IFX therapy compared with 1.6 mcg/mL in those receiving IFX with placebo. Remembering the Reinisch et al study, serum IFX concentrations are correlated with mucosal healing as well as clinical response and remission.

levels, adding an immunomodulator—or adjusting the dose if one is already in place—may be considered.

In ATI-negative patients with IFX levels greater than 3 mcg/mL but no response, differential diagnoses, such as those noted above, should be considered.

Again, this scenario may happen in a patient whose inflammation is driven by a pathway other than a TNF-mediated one. Once other diagnoses are ruled out,

the dose could be increased, or if dose intensification fails, the patient may be switched to another class of drug.

Finally, in ATI-positive patients with adequate IFX levels who are experiencing clinical and endoscopic remission, it is recommended to continue monitoring and either add or change the immunomodulator if relapse occurs, given that combination therapy may increase the efficacy of the anti-TNF.

1124.

Long Term Prognosis After Discontinuation of Infliximab in Patients With Inflammatory Bowel Disease in Clinical Remission (Steenholdt C et al) This observational study was designed to identify variables associated with relapse following discontinuation of IFX and response to retreatment with IFX.

Inadequate Bowel Preps: A Problem With Potentially Serious Consequences

‘Endoscopic and histologic mucosal healing as well as the utilization of surrogate markers or biomarkers of mucosal healing, such as fecal lactoferrin or calprotectin, play an important role in identifying which patients can discontinue infliximab and maintain remission.’

Colonoscopic view of cecum in patient using a split-dose bowel prep1

—Ellen J. Scherl, MD

Similarly, a study by Drastich et al presented at the 2001 DDW meeting (abstract Sa1371) found that IFX serum trough levels greater than 3 mcg/mL were reached in 59% of patients with CD and 55% of those with UC and correlated with deep remission in both groups.

In correlating serum drug levels with mucosal healing, it is necessary to consider the presence of antibodies-to-infliximab (ATI). In ATI-negative patients with subtherapeutic concentrations of IFX (<3 mcg/mL), it is recommended to increase the dose of IFX. However, in ATI-positive individuals with low IFX levels and no response, one should consider switching to another anti-TNF agent within the same class (i.e., certolizumab or adalimumab). For patients with ATIs who are experiencing clinical response but have inadequate serum IFX

Colonoscopic view of cecum in patient using a single-dose bowel prep1

In Bowel Cleansing, Location Matters Inadequate bowel cleansing can compromise detection of lesions in the right colon,2 where cancer often develops3

DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

It included data from 53 patients with CD and 28 patients with UC in IFXinduced steroid-free clinical remission who stopped therapy.

According to the findings, 61% of CD patients and 75% of UC patients maintained remission at the end of one year, with remission rates falling to 50% after a median of 680 and 1,334 days after IFX discontinuation, respectively (P=0.057).

P At the last follow-up, after 10 and 4.5 years in

the CD and UC groups, respectively, rates of sustained remission were 12% and 40% for CD and UC patients, respectively.

Univariate analysis showed that longer disease duration was predictive of relapse among CD patients.

The researchers also reported that of the 25 CD patients and seven UC patients retreated with IFX following relapse, 24 and five experienced renewed remission, respectively.

Dr. Scherl: Although the majority of patients with IBD who discontinue IFX while in remission do experience relapse over time, the response to retreatment after relapse in the subpopulation studied here was good, with higher sustained remission rates than expected from clinical trials. Louis E et al presented similar findings at the 2009 DDW meeting (abstract 961). They reported that approximately 50% of

How Common Are Inadequate Bowel Preps?

• In a review of over 236,000 outpatient colonoscopies, bowel preparation was inadequate in almost 24% of procedures4 • In another review of over 93,000 colonoscopies, bowel preparation was inadequate in 23% of procedures5

The Impact of Inadequate Bowel Preps on Colonoscopy: • Liquid residues remaining in the colon4 • Incomplete cleaning of right side of colon2 • Longer mean cecal intubation time6 • Higher rate of difficult colonoscopies6 • Greater likelihood of aborted examination6 Figure 1. Association of bowel cleansing quality with difficulty of colonoscopy (% of patients)6 Colonoscopy Quality

50

Low*

49.1

Intermediate*

% of Patients

40 30 20

High*

34.2

33.1

20.0 15.4

10 0

Easy†

12.4

Difficult† Difficulty of Colonoscopy

13

patients with CD in clinical, steroid-free remission following at least one year of combination IFX–immunosuppressant therapy maintained remission for up to one year following discontinuation of IFX. Patients with endoscopically and histologically active disease at the time of discontinuation were more likely to experience relapse, but also were successfully retreated with IFX. It should be non-negotiable that patients stay on IFX for at least one year.

After one year of treatment, the shortterm prognosis, if the drug is discontinued, seems favorable.

Again, these findings emphasize that defining remission in endoscopic and histologic terms, rather than simply clinical terms, is critical.

■ Dr. Scherl has served as a consultant or advisory board member for Abbott Laboratories, AstraZeneca, Axcan Pharma, Berlex, Centocor, Cerimon Pharmaceuticals, Cerium, Crohn’s & Colitis Foundation of America (CCFA), PDL BioPharma, Procter & Gamble, Prometheus Laboratories, Questcor, Salix Pharmaceuticals, Shire, Sigma Tau, Solvay Pharmaceuticals, TAP Pharmaceuticals and UCB. She has received grants or research support from Abbott Laboratories, Centocor, Cerimon Pharmaceuticals, Elan, Millennium, Osiris Therapeutics, Prometheus Laboratories, Salix Pharmaceuticals and UCB. She has received honoraria from Abbott Laboratories, AstraZeneca, Axcan Pharma, Centocor, Cerimon Pharmaceuticals, PDL BioPharma, Procter & Gamble, Prometheus Laboratories, Salix Pharmaceuticals, Shire, Sigma Tau, Solvay Pharmaceuticals, TAP Pharmaceuticals and UCB. She has received other financial or material support from Abbott Laboratories, CCFA, Centocor, PDL BioPharma, Prometheus Laboratories, Salix Pharmaceuticals and UCB.

* Cleansing quality was determined by endoscopist grading using a 5-point scale. High = completely clean (score 5) or clear liquid present (score 4); Intermediate = liquid plus solid stool present that can be aspirated (score 3); Low = liquid and solid stool present that cannot be totally aspirated (score 2) or solid stool preventing visualization (score 1). † Degree of difficulty of procedure was determined by endoscopist grading with a 6-point scale: extremely easy, easy, fairly easy, fairly difficult, difficult, extremely difficult.

The Impact of Inadequate Bowel Preps on Diagnosis: • In a survey of patients with poor/fair bowel preps (N=3047), 42% of adenomas found in a follow-up colonoscopy had not been detected in the first colonoscopy7 • 27% of advanced adenomas, which have a greater premalignant potential, were missed in the first colonoscopy7 • Smaller adenomas (<10 mm) were missed nearly twice as often as adenomas ≥10 mm when the prep was poor7 References: 1. Data on file. Braintree Laboratories, Inc., Braintree, MA. 2. Baxter N, Rabeneck L. ICES report: new findings about the risks and limitations of colonoscopy used in the early detection of colorectal cancer. Healthcare Quarterly. 2009;12:24-25. 3. Cappell MS. The pathophysiology, clinical presentation, and diagnosis of colon cancer and adenomatous polyps. Med Clin N Am. 2005;89:1-42. 4. Crispin A, Birkner B, Munte A, Nusko G, Mansmann U. Process quality and incidence of acute complications in a series of more than 230 000 outpatient colonoscopies. Endoscopy. 2009;41:1018-1025. 5. Harewood GC, Sharma VK, de Garmo P. Impact of colonoscopy preparation quality on detection of suspected colonic neoplasia. Gastrointest Endosc. 2003;58:76-79. 6. Froehlich F, Wietlisbach V, Gonvers J-J, Burnand B, Vader J-P. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study. Gastrointest Endosc. 2005;61:378-384. 7. Lebwohl B, Kasinos F, Glick M, Rosenbaum AJ, Wang T, Neugut AI. The impact of suboptimal bowel preparation on adenoma miss rates and the factors associated with early repeat colonoscopy. Gastrointest Endosc. 2011;73:1207-1214. ©2012 Braintree Laboratories, Inc.

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March, 2012

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14

EXPERT REVIEW

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Complications of Biologic Therapy for IBD At the Crohn’s & Colitis Foundation of America’s Advances in Inflammatory Bowel Diseases meeting, held last December, several experts in inflammatory bowel disease (IBD) discussed the latest data examining the risks and complications associated with anti-tumor necrosis factor (TNF) therapy for IBD. Following is a summary of their presentations.

Infusion Reactions Paul Rutgeerts, MD, PhD Professor of Medicine University of Leuven Leuven, Belgium

According to Dr. Rutgeerts, acute infusion reactions are frequent, but rarely serious, and often can be managed or prevented from recurring.

“Most infusion reactions do not require treatment discontinuation,” Dr. Rutgeerts said.

Immunoglobulin E–mediated reactions such—as pruritus, urticaria and bronchospasm—are uncommon, with anaphylaxis being an “extremely rare” infusion reaction. More common are reactions due to the presence of drugspecific antibodies, he said.

An analysis of data from a cohort of 651 Danish patients treated with infliximab between 1999 and 2005 documented a 4.4% rate of infusion reactions out of 3,351 infliximab infusions (Caspersen S et al. Clin Gastroenterol Hepatol 2008;6:1212-1217). Results from a retrospective chart review of 3,161 patients who received 20,976 infliximab infusions found a similar rate of reactions, although only 0.1% of all of these infusions led to a severe reaction, including

anaphylaxis, he noted (Ducharme J et al.

Can J Gastroenterol 2010;24:307-311).

Administering concomitant immunosuppression can prevent more than half of all infusion reactions, said Dr. Rutgeerts. He pointed to data from a 2009 study of 734 patients who were administered infliximab (Fidder H et al. Gut 2009;58:501-508). Data showed that 22% of patients who received infliximab alone experienced infusion reactions, whereas only 12% of individuals administered concomitant azathioprine had a reaction (P<0.001). Results from SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease) confirmed these insights, showing that 16.6% of patients receiving infliximab alone experienced an infusion reaction compared with 5% of patients receiving concomitant azathioprine (Colombel JF et al. N Engl J Med 2010;362:1383-1395). A subanalysis of data from SONIC suggests the protective effect conferred by co-administration of azathioprine with infliximab lies in its ability to prevent the formation of infliximab-specific antibodies, Dr. Rutgeerts explained. Specifically, 14% of patients receiving infliximab alone developed antibodies to the drug compared with 1% who received concomitant azathioprine.

The risk for infusion reactions also can be minimized by following a scheduled maintenance regimen, Dr. Rutgeerts said, pointing to the aforementioned 2009 study (Fidder H et al. Gut 2009;58:501508). In this study, 21% of patients who were treated sporadically developed reactions, whereas 13% of patients receiving

Development of a psoriasiform lesion following anti-TNF therapy Exclude infection

Up to 25% can have superinfection

Dermatology referral for evaluation and biopsy Severe psoriasis; intolerable lesions; patient prefers anti-TNF discontinuation STOP anti-TNF: Discuss alternative medical and surgical interventions

Treat psoriasis

IBD requiring anti-TNF; tolerable, <5% BSA Treat psoriasis: • Topical steroids • Topical keratolytic • Topical vitamin D analogs Recurrent psoriasis: Consider anti-TNF switch or discontinuation

Tolerable, >5% BSA or palmoplantar psoriasis

Consider alternative anti-TNF

Treat psoriasis (palm and sole occlusion): • PUVA therapy • Methotrexate • Acitretin • Cyclosporine

Figure. Algorithm for management of infusion reactions.

BSA, body surface area; TNF, tumor necrosis factor; PUVA, psoralen and ultraviolet light A Source: Paul Rutgeerts, MD, PhD. Adapted from Collamer AN et al. Arthritis Rheum 2008;59:996-1001; Conklin LS et al. Nat Rev Gastroenterol Hepatol 2010;7:174-177.

regular maintenance treatment experienced infusion reactions (P=0.03).

P Adherence to a regular maintenance schedule also was associated with a lower risk for rare, delayed-type hypersensitivity reactions, such as myalgia, arthralgia, fever and rash, which can occur up to two weeks after infliximab administration, he said.

Infusion reactions do not preclude continued treatment with infliximab, Dr. Rutgeerts noted, and prophylactic administration of antihistamines and corticosteroids can prevent reactions from recurring (Figure).

Nevertheless, the potential for firsttime and recurrent reactions should not

be taken lightly, Dr. Rutgeerts cautioned.

Infliximab should always be administered in a setting equipped for emergency treatment, and all patients should be monitored closely for changes in pulse and blood pressure.

Patients who do experience acute infusion reactions can most often be managed at the point of care by slowing the infusion rate and, if necessary, by administering intramuscular antihistamines, either alone or along with IV hydrocortisone.

Delayed infusion reactions also can be treated with antihistamines, mild analgesics and nonsteroidal anti-inflammatory drugs, Dr. Rutgeerts said.

■

Skin Complications Jean-Frédéric Colombel, MD Professor of Hepatogastroenterology University Hospital in Lille Lille, France

According to Dr. Colombel, the most common skinrelated complications of anti-TNF treatment are psoriasis and non-melanomatous skin cancers (NMSC).

Early referral to a dermatologist is imperative, given the possibility of severe, albeit rare, side effects, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. These complications typically appear following the

first or second administration of a biologic and can be mistaken for minor allergic reactions, since they initially manifest as erythematous rashes, he said.

“As the use of anti-TNF agents continues to increase, the diagnosis and management of cutaneous side effects will become an increasingly significant challenge,” Dr. Colombel said. “Counsel your patients about the signs and symptoms of cutaneous reactions and refer high-risk patients to a dermatologist.”

The FDA now includes a black box warning cautioning that psoriasis is a potential adverse event related to all biologics, he said. However, the rate of true antiTNF–related psoriasis is difficult to confirm, given the increased baseline incidence of this skin disorder in patients with IBD, Dr. Colombel explained.

Clinicians should weigh the extent and severity of psoriasis against the benefits of anti-TNF treatment, he said. Patients who develop psoriasis but are

benefiting from anti-TNF therapy should be tried on a course of topical treatment before discontinuing treatment. In a review of 150 patients with IBD who developed anti-TNF–related psoriasis, 41% responded to topical therapy, whereas approximately 43% required treatment discontinuation (Cullen G et al. Aliment Pharmacol Ther 2011;34:1318-1327). Half of the 27 patients who switched to an alternative biologic agent experienced recurrent or persistent psoriasis, Dr. Colombel noted.

As with the baseline incidence of psoriasis in IBD patients, IBD is also associated with a heightened risk for NMSC, Dr. Colombel noted, making it similarly difficult to evaluate the true incidence of treatmentassociated NMSC. Cumulative data from four large, published studies showed the incidence of NMSC may be up to 2.2 times higher in patients with IBD compared with the general population, and that males with

EXPERT REVIEW

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Treatment-Related Infections Edward Loftus Jr., MD Professor of Medicine Chair, Inflammatory Bowel Disease Interest Group Division of Gastroenterology & Hepatology Mayo Clinic Rochester, Minnesota

Although the FDA includes a black box warning that treatment with an anti-TNF can increase the risk for serious infection, according to Dr. Loftus, there are conflicting data on the incidence of such infections. Like Dr. Colombel, Dr. Loftus said a heightened baseline incidence of infections in patients with IBD makes it difficult to determine whether infections are in fact treatment-related. “ “Although there is a direct causal relationship between treatment with biologics and related infections, this relationship can be confounded by underlying disease and the use of other drugs,” Dr. Loftus said.

The risk for infection with the use of anti-TNF agents appears similar to that associated with other immunosuppressant medications, he said.

Specifically, results from SONIC, which compared combination infliximab–azathioprine treatment with the use of either drug alone, did not find a significant difference in rates of infections between the three groups (Colombel JF et al. N Engl J Med 2010;362:1383-1395).

Data from 15,000 IBD patient– years included in the TREAT (Crohn’s Therapy Resource, Evaluation and Assessment Tool) registry also showed similar infection risk among patients receiving infliximab,

thiopurines or methotrexate, Dr. Loftus noted (Lichtenstein GR et al. Gastroenterology 2006;130[suppl 4]:A-71; Lichtenstein GR et al. Clin Gastroenterol Hepatol 2006;4:621630). However, corticosteroids were associated with a significantly higher risk for infections than any of these drugs, he noted. Consistent with those findings, a meta-analysis of 21 placebo-controlled trials of infliximab, including 5,356 patients, found no

‘This relationship can be confounded by underlying disease and the use of other drugs.’

—Edward Loftus Jr., MD significant difference in the rates of serious infections among infliximab and placebo recipients (Peyrin-Biroulet L et al. Clin Gastroenterol Hepatol 2008;6:644-653).

However, there are conflicting data, Dr. Loftus said. Specifically, results from a 22-week randomized controlled trial comparing high- and low-dose infliximab induction with placebo in 1,084 patients with rheumatoid arthritis revealed that individuals who received a high-dose regimen of the drug (10 mg/kg)

were three times more likely than those who received a low-dose regimen (3-mg/kg induction, followed by 1.5-mg/kg dose escalations, as needed) or placebo to experience a serious infection, (P=0.013; P Westhovens R et al. Arthritis Rheum 2006;54:1075-1086).

Furthermore, a case–control study of 100 patients receiving various treatments showed that those administered infliximab were 4.4 times more likely than patients treated with a 5-aminosalicylate to develop opportunistic infections (Toruner M et al. Gastroenterologyy 2008;134:929936). However, opportunistic infection rates with anti-TNF agents were similar to the rates of such infections in patients taking corticosteroids, thiopurines and methotrexate, Dr. Loftus said.

Despite the lack of clarity regarding the risk for treatment-related infections, Dr. Loftus believes clinicians need to remain vigilant, particularly in higher-risk, older patients.

He pointed to data from a cohort study comparing 89 patients (aged ≥60 years) to 178 younger patients with IBD, all of whom received a biologic (Bhushan et al. Gastroenterology 2010;138[suppl 1]:S62). The findings showed that 22% of older patients developed a serious infection compared with 8% of younger patients. A separate case–control study of 100 patients confirmed the elevated risk for infection in older adults, showing that individuals older than age 50 years were three times more likely than younger patients to develop opportunistic infections (Toruner M et al. Gastroenterology 2008;134:929-936); however, that study did not parse the data according to treatment type.

■

Crohn’s disease have the highest risk for this cancer with an anti-TNF agent were 1.79 times more likely (Long MD et al. Inflamm Bowel Dis 2011;17:1423- to develop melanomas, corroborating data in the IBD 1427). Analyses examining population is lacking, Dr. the risk for NMSC associated Colombel said. specifically with anti-TNF ‘Counsel your patients about the Although it is unclear use are limited to studies of whether biologics are associpatients with arthritis or pso- signs and symptoms of cutaneous ated with an increased risk riasis, Dr. Colombel said. He reactions and refer high-risk for NMSC, thiopurine use is cited a systematic review and a significant NMSC risk facmeta-analysis of four prospec- patients to a dermatologist.’ tor, he added. An analysis of —Jean-Frédéric Colombel, MD prospective data from a crosstive, observational studies in arthritic or psoriatic patients sectional, nationwide French treated with an anti-TNF cohort of nearly 20,000 IBD agent (Mariette X et al. Ann Rheum Dis 2011;70:1895- patients showed the incidence of NMSC in those with 1904). The review showed that anti-TNF use was asso- ongoing or past thiopurine exposure was nearly six ciated with a 1.45-fold increase in the risk for NMSC and four times higher, respectively, than in the general compared with patients not treated with an anti-TNF. population (Peyrin-Biroulet L et al. Gastroenterology Although the review also showed that patients treated 2011;141:1621-1628).

■

15

Immunomodulators and Cancer Corey A. Siegel, MD, MS Assistant Professor of Medicine Dartmouth Institute for Health Policy and Clinical Practice Dartmouth Medical School Director, Dartmouth-Hitchcock IBD Center Lebanon, New Hampshire

Data on the risk for non-skin cancers with anti-TNF treatment are inconclusive, according to Dr. Siegel.

“More data are emerging, but right now there’s not enough information to know whether anti-TNF monotherapy is associated with an increased risk of cancer,” said Dr. Siegel.

‘More data are emerging, but right now there’s not enough information to know whether anti-TNF monotherapy is associated with an increased risk for cancer.’

—Corey A. Siegel, MD, MS Findings from a study comparing 221 Crohn’s disease (CD) patients treated with infliximab to 221 matched controls with CD suggested the overall risk for any type of cancer was similar among the two groups (Biancone L et al. Inflamm Bowel Diss 2011;17:758-766). Approximately 4% in either group were diagnosed with cancer within a median of six years of follow-up, the study showed.

However, a meta-analysis conducted by Dr. Siegel and colleagues that examined information from 8,905 patients with CD treated with combination anti-TNF/ immunosuppressant therapy showed an elevated incidence of non-Hodgkin lymphoma in this group (Siegel CA et al. Clin Gastroenterol Hepatoll 2009;7:874-881).

His team found 13 cases of this type of cancer—an incidence of 6.1 per 10,000 patient-years—compared with an incidence of 3.6 among patients treated with an immunosuppressant alone (P<0.05) and 1.9 per 10,000 patient-years in the general population, he said (P<0.05).

Data from patients with rheumatoid arthritis have yielded different results compared with patients with CD, Dr. Siegel said. Among nearly 20,000 patients enrolled in the National Data Bank for Rheumatic Diseases between 1998 and 2005, there was a similar rate of lymphomas among those who received an anti-TNF agent and those who did not, as well as between those who received combination anti-TNF–methotrexate therapy and those who received methotrexate alone (Wolfe F, Michaud K. Arthritis Rheum 2007;56:1433-1439).

Several cases of hepatosplenic T-cell lymphoma (HSTCL), reported in 2006 in patients with CD treated with a combination of infliximab and azathioprine or 6-mercaptopurine (6-MP), precipitated fear of an “epidemic” of these cancers, as the use of anti-TNF agents was poised to increase, Dr. Siegel said. However, the number of such cancers has remained low and consistent, with three to four treatment-related cases reported each year since 2006. see Biologics for IBD, page 17

16

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

More Data Needed on Efficacy of Herb in IBD Treatment

By David Wild More research is needed to determine the efficacy of curcumin in the treatment of inflammatory bowel disease (IBD), according to a systematic review of the literature. Investigators found mixed results in the few high-quality trials published that examined the supplement’s effects.

Despite the scant body of data, curcumin may still prove to be an effective

W LE O N LAB I A AV

adjunct to conventional medical treatments for IBD, said Richard Fedorak, MD, professor in the Department of Gastroenterology and associate vice president of research at the University of Alberta Faculty of Medicine and Dentistry, in Edmonton, Canada, who was not involved in the study.

“Existing studies have yielded promising results and shown that oral curcumin, when added to standard therapies, can

improve patient symptoms,” said Dr. Fedorak. “We look forward to additional appropriately populated and controlled clinical trials to confirm these exciting preliminary findings.”

Curcumin, the main phenol in the Indian spice turmeric, prevents activation of nuclear factor kappa B (or NF-κB), a pro-inflammatory transcription factor involved in the pathogenesis of IBD. Trials in animal models of IBD have

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confirmed the compound’s anti-inflammatory properties, and some trials in human subjects have also suggested curcumin may be effective against symptoms of both Crohn’s disease (CD) and ulcerative colitis (UC).

Lead researcher Sushil Kumar, MD, an intern in the Department of Gastroenterology at the All India Institute of Medical Sciences, in New Delhi, said the herb is being used more and more by IBD patients. Dr. Kumar and colleagues performed a systematic review of clinical trials examining curcumin’s efficacy in IBD patients that were included in PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane IBD Specialized Trial Register and abstracts presented at conferences.

They presented their findings at the Crohn’s & Colitis Foundation of America’s Advances in Inflammatory Bowel Diseases conference, held last December.

The investigators found two highquality randomized controlled trials and one open-label study. In the first randomized, controlled trial, Japanese investigators at several institutions randomized 43 patients with UC in remission to receive curcumin 2 g daily for six months and 39 similar subjects to receive a placebo (Hanai H et al. Clin Gastroenterol Hepatol 2006;4:1502-1506). Both groups were also treated with 5-aminosalicylic acid. Results showed that 4.65% of curcumin recipients relapsed during the six-month treatment period compared with 20.5% of placebo patients (relative risk, 0.24; P=0.04).

In the second randomized, controlled trial, eight steroid-dependent UC patients and five steroid-dependent Crohn’s disease patients in clinical remission were randomized to receive curcumin 660 mg twice daily for 16 weeks (Gut 2003;52[suppl 1]:abstract 230). An additional eight patients with UC and six patients with CD received placebo. The investigators found no significant differences in relapse rates between the two groups.

The open-label study included five UC and five CD patients who received curcumin daily for two months (Holt PR et al. Dig Dis Sci 2005;50:2191-2193). In that trial, all UC patients experienced a clinical response and 80% of CD patients had a reduction in Crohn’s Disease Activity Index scores of more than 70 points.

Overall, curcumin was well tolerated in all three studies, with no serious adverse events.

“The available evidence is not sufficient to recommend the routine use of curcumin in the management of patients with IBD,” the researchers concluded. “A

17

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

large-scale, methodologically rigorous randomized controlled trial is needed to test the efficacy of this intervention.”

“These studies involved small numbers of patients, with inconsistent measures of response or remission, and were not powered to detect small differences between curcumin or placebo,” added Alan Moss, MD, assistant professor of medicine at Harvard Medical School and

‘These studies involved small numbers of patients, with inconsistent measures of response or remission, and were not powered to detect small differences between curcumin

in the Division of Gastroenterology at Beth Israel Deaconess Medical Center, both in Boston, and senior investigator on the first trial. Dr. Moss also noted that his group could not conduct a pooled meta-analysis because the studies included different types of patients.

or placebo.’

■

—Alan Moss, MD The researchers reported no relevant conflicts of interest.

Biologics for IBD continued from page 15

“It’s not about the absolute number of cases, it’s how often they occur relative to the number of patients treated,” Dr. Siegel noted. “When you put the numerator over the denominator, the rate is indeed very low.”

“Furthermore,” he noted, “since only two cases of HSTCL have occurred with less than two years of treatment, both with combination anti-TNF–6-MP, one treatment strategy would be to treat with combination therapy for one year and then withdraw 6-MP while continuing the anti-TNF agent.”

The incidence of treatment-related leukemia also is unclear, Dr. Siegel said.

Although 147 postmarketing reports of the cancer following treatment with an anti-TNF agent led the FDA to identify a “possible association” between treatment with this class of drugs and the development of leukemia, these data are confounded by the fact that 61% of these patients also had been receiving concomitant immunosuppressive agents at the time of diagnosis, Dr. Siegel said.

■ Dr. Rutgeerts reported relationships with the following companies: Abbott Laboratories, Bristol-Myers Squibb, Centocor, Falk Pharma, Genentech/Hoffmann La Roche, Merck & Co., Merck/Serono, Millenium/ Takeda, Neovacs, Pfizer, Robarts Research Institute, Tillotts Pharma and UCB. Dr. Colombel has been a speaker or advisor, or has received research funding from Abbott Laboratories, Centocor and Merck Sharp & Dohme Corporation. Dr. Loftus has received research support from Abbott Laboratories, Amgen, Braintree Laboratories, Bristol-Myers Squibb, Genentech, Janssen Biotech, Millenium-Takeda, Pfizer, Shire Pharmaceuticals and UCB; he has served as consultant for Abbott Laboratories, BristolMyers Squibb, Pfizer and UCB. Dr. Siegel has been or is a consultant or advisory board member for Abbott Laboratories, Elan Pharmaceuticals, Janssen and UCB; he also is a speaker for CME activities for Abbott Laboratories, Axcan, Elan Pharmaceuticals, Janssen and UCB.

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18

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Pros and Cons of Combination Therapy for IBD combination treatment can most often be allayed. He pointed to one-year data from SONIC that showed similar rates of adverse events among patients receiving Should patients with inflammatory bowel disease (IBD) The Case for Monotherapy combination treatment and infliximab monotherapy. receive combination therapy or monotherapy to treat Jean-Frédéric Colombel, MD, professor of hepa- He argued that patients and clinicians need to weigh their disease? Two experts debated both sides of this togastroenterology at the University Hospital in Lille, the burden of illness and the risk for potential comcontroversial issue at the Crohn’s & Colitis Foundation’s France, presented the other side of the issue, stating that plications that accompany disease relapse against any Advances in Inflammatory Bowel Diseases meeting, held certain patients are more likely to maintain remission drug-related safety concerns. last December. with monotherapy, and therefore can be considered can“Patients need to know that the risks of switching “The pendulum has swung back and forth over the didates for a switch. to monotherapy include flare-ups and disability,” he years as to whether the risk–bentold attendees. “The efit analysis favors combination pragmatic approach ‘Discontinuing either infliximab or ‘The pragmatic approach to [treatment] or monotherapy,” said to treatment of most azathioprine may be considered for safety treatment of most patients is a one expert, Stephen Hanauer, patients is a combinareasons in certain groups of patients, MD, professor of medicine and tion approach, which combination approach, which clinical pharmacology, and chief involves the lowest particularly those in deep, steroid-free involves the lowest chances of of the Section of Gastroenterology chances of relapse and remission with halted disease progression relapse and adverse events.’ and Nutrition at the University of adverse events.” after a long period of combination Chicago Medical Center. “We still While acknowledg—Stephen Hanauer, MD haven’t settled on one position.” ing the short-term risk treatment.’ of combination treat—Jean-Frédéric The Case for ment, Dr. Colombel Combination Therapy Colombel, MD argued the implications Dr. Hanauer emphasized that of long-term combinathe bulk of evidence points to tion treatment are not the superiority of combining an yet clear. immunomodulator with an anti“It took us 30 years tumor necrosis factor (TNF) in to confirm the risk for inducing remission in patients cancer with azathiowith Crohn’s disease (CD) comprine use, but we still pared with an anti-TNF alone. don’t know the extent Dr. Hanauer said findings from of this risk and whether ‘Patients need to SONIC (Study of Biologic and there is a compounded know the risks of Immunomodulator Naive Patients risk that goes along ‘It took us 30 years to confirm the risk switching to monotherapy in Crohn’s Disease) provide the with combination thermost compelling data in favor apy,” Dr. Colombel said. for cancer with azathioprine use, but we include flare-ups and disability.’ of combination induction treat“This will only become —Stephen Hanauer, MD still don’t know the extent of this risk and ment. Results from that randomclear as time goes on.” whether there is a compounded risk that ized, double-blind, controlled He pointed to a study showed that remission rates meta-analysis of nine goes along with combination therapy.’ among patients with CD were randomized controlled —Jean-Frédéric Colombel, MD significantly higher at 50 weeks trials, three cohort in subjects who received combistudies and 14 case nation induction and maintenance treatment with infDr. Colombel pointed to a recent analysis from a pro- series that found an incidence of 0.61 cases of nonliximab than in those who received either drug alone spective study of 115 CD patients who achieved ini- Hodgkin’s lymphoma for every 100 patient–years of (Colombel JF et al. N Engl J Med 2010;362:1383-1395). tial steroid-free remission with combination induction combination treatment compared with 0.36 cases for But not all data support combination treatment over treatment and subsequently discontinued infliximab every 100 patient–years of immunosuppressant monomonotherapy for maintenance of remission, Dr. Hanauer (Louis E et al. Gastroenterology 2012;142:63-70). In that therapy (P=not P significant; Siegel CA et al. Clin Gastronoted. A 2007 study found no significant differences in study, 52 subjects experienced a relapse within a median enterol Hepatol 2009;7:874-881). relapse rates between CD patients who continued with of 28 months of infliximab discontinuation. Significant A literature review also indicated that immunosupcombination treatment and those who discontinued predictors of relapse included male gender, no history pressant monotherapy and combination treatment may concomitant immunosuppressants, including azathio- of previous resection, hemoglobin level less than 14.5 increase the risk for developing hepatosplenic T-cell prine and methotrexate (Van Assche G et al. Gastro- g/dL, fecal calprotectin greater than 300 mcg/g, leuko- lymphomas, Dr. Colombel noted (Kotlyar DS et al. enterologyy 2008;134:1861-1868). Approximately half of cyte count greater than 6 × 109/L and high-sensitivity Clin Gastroenterol Hepatol 2011;9:36-41). Those results all patients experienced flares of their disease within six C-reactive protein level equal to or greater than 5 mg/L. showed 36 reported cases of cancer in IBD patients months of initial infliximab treatment.

Data also showed that nearly 90% of the patients who receiving either thiopurine monotherapy or combinaIn a separate study, researchers found CD patients in relapsed were able to achieve remission after retreatment tion treatment with an anti-TNF agent, but no cases in remission after combination induction treatment had a with infliximab, which should be comforting for those patients receiving an anti-TNF alone.

59% chance of relapsing within 24 months of discontin- choosing to switch to monotherapy, Dr. Colombel said.

“Discontinuing combination therapy should be uing azathioprine (Oussalah A et al. Am J Gastroenterol “Discontinuing either infliximab or azathioprine may considered on a case-by-case basis,” Dr. Colombel 2010;105:1142-1149). Those investigators concluded be considered for safety reasons in certain groups of concluded. “Reliable data have identified specific risk that “azathioprine withdrawal is associated with a high patients, particularly those in deep, steroid-free remis- factors that can be used in making this decision.”

■ risk for relapse in patients with a duration of combina- sion with halted disease progression after a long period tion therapy of less than 27 months and/or the presence of combination treatment,” Dr. Colombel said.

Dr. Hanauer has served as a consultant for Janssen Pharof biological inflammation.” maceuticals, Inc. Dr. Colombel has received research support Dr. Hanauer noted that “immunomodulators seem Safety Concerns or served as a consultant for Abbott Pharmaceuticals, to reduce the risk for immunogenicity and antibody According to Dr. Hanauer safety concerns regarding Merck Sharp & Dohme Corporation and Janssen Biotech.

By David Wild

development, both of which lower serum drug levels and ultimately hamper the efficacy of drug treatment.”

19

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

From the Literature

New Investigational Oral Agent Effective for Moderate to Severe Ulcerative Colitis Positive Results for Phase II Dose-Finding Trial of Oral Janus Kinase Inhibitor, Tofacitinib

By David Wild In a Phase II, multicenter trial of the selective oral Janus kinase inhibitor, tofacitinib, 48% of patients with active moderate to severe ulcerative colitis (UC) who were administered the drug twice daily for eight weeks achieved clinical remission, significantly more than the 10% of placebo recipients who experienced remission (Sandborn WJ et al. N Engl J Med d 2012;367:616-624).

According to Alan Moss, MD, assistant professor of medicine at Harvard Medical School and a member of the staff in the Division of Gastroenterology at Beth Israel Deaconess Medical Center, both in Boston, “This agent has the advantage of being orally administered, making it easier to administer than injectable biologics [that are] approved, or in development, for moderate to severe UC. It

also has a completely different mechanism of action from other drugs approved for UC.” Targeting Janus kinase 1 and 3, as tofacitinib does, attenuates signaling by pro-inflammatory cytokines, such as interleukin-6 and interferon-γ, both of which play a role in the pathogenesis of UC. “It also appears to act rapidly, with a clear decrease in disease activity scores within two weeks of therapy initiation,” added Dr. Moss, who was not involved in the study. “Of particular interest, the data suggest efficacy in patients who have already failed infliximab.”

The dose-finding trial was led by William Sandborn, MD, chief of the Division of Gastroenterology and director of the University of California, San Diego Inflammatory Bowel Disease Center at the University of California, San Diego Health System. Dr. Sandborn and colleagues

randomized 195 patients with moderate to severe UC to receive 0.5 (n=31), 3 (n=33), 10 (n=33) or 15 mg (n=49) of the agent, twice daily for eight weeks, in a double-blind fashion. Additionally, 48 patients received a placebo twice daily. Aminosalicylates and glucocorticoids were used by 67.5% and 43.8% of study subjects, respectively, but all other UC drugs were discontinued prior to treatment.

At eight weeks, 78% of patients receiving 15 mg of the drug met established criteria for clinical response compared with 48% of placebo recipients (P ( <0.0001). Rates of response with the three lower doses were not significantly higher than placebo. Clinical remission at eight weeks occurred in 48% and 41% of those receiving 10 and 15 mg of tofacitinib, respectively, both significantly higher than the 10% experiencing clinical remission with placebo ((P≤0.01 for both).

As previously shown in studies of

the drug in patients with rheumatoid arthritis, higher doses of tofacitinib were associated with increases in low- and high-density lipoprotein cholesterol levels.

Dr. Moss cautioned that “altered lipid profiles are something we have not seen before in patients with IBD [inflammatory bowel disease] and the long-term consequences of this, if this agent were to be used for maintenance, are unknown.”

Safety data also showed that three patients in the 10- and 15-mg tofacitinib groups experienced absolute neutrophil counts below 1,500 cells/ cu mm, but higher than 1,000 cells/ cu mm.

Results from Phase III trials of the drug in patients with UC are expected in 2015.

■ Dr. Moss has attended medical advisory board meetings for Abbott Laboratories and Janssen Pharmaceuticals in the past 12 months.

Dr. Sandborn is a consultant for Pfizer.

Multidisciplinary Care, Counseling Improves Nutrition, Remission In Pediatric Patients With IBD

By David Wild Structured multidisciplinary care for patients with pediatric inflammatory bowel disease (IBD) is associated with improved nutritional status and a higher rate of remission. Results from a single-center study revealed remission rates rose by 22% after the clinic switched to a team-based care approach involving physicians, nurse practitioners, nurses and dietitians.

“Our analysis and experience suggest that standardizing documentation and coordinating a comprehensive model of care leads to increased nutritional status and remission rates over time,” said lead researcher Shari Huffman, MS, ARNP, a nurse in the Division of Pediatric Gastroenterology at Nemours Children’s Clinic in Jacksonville, Fla. Ms. Huffman and colleagues moved to a multidisciplinary care approach in 2010 as part of a quality improvement initiative. Similar programs have reported notable increases in remission rates (see www.ImproveCareNow.org). Ms. Huffman said her clinic was already ahead of the curve with its use of standardized electronic medical charts, which were shared among staff prior to the shift to team-based care. The goal of the comprehensive clinic, Ms. Huffman said, was to further enhance the coordination of care and ensure all patients received nutritional counseling with a nurse, nurse practitioner or dietitian. The team did this by improving documentation and by using clinical decision support tools to help health care providers comply with published recommendations.

In the study, which was presented at last year’s Crohn’s & Colitis Foundation of America’s Advances

in Inflammatory Bowel Diseases meeting (abstract P-271), researchers retrospectively analyzed data from 92 pediatric patients with Crohn’s disease, ulcerative colitis or indeterminate IBD who had been treated at the clinic both before and after the switch to a comprehensive model.

The team documented cases of nutritional failure, defined as a body mass index below the third percentile, and remission rates, as rated by physician global assessments (PGAs). The patients, who were an average of 14 years of age at the outset of the threeyear study, had been to the clinic an average of 10 times during the study period, for a total of 510 visits in the 18 months before the switch to the comprehensive format and 416 visits in the 18 months after the switch.

The investigators found that the number of patients in nutritional failure 18 months after the multidisciplinary model was implemented fell significantly, by nearly 50%, from 6.1% to 3.4% (P=0.029).

P Overall remission rates rose by nearly 22% after the multidisciplinary model was implemented, from 46.5% to 56.6% (P=0.03).

P Ms. Huffman noted two reasons these improvements may have occurred: the staff was more likely to 1) include key clinical data, such as PGAs, in their charts after implementing the new model, and 2) indicate whether patients had received nutritional counseling.

‘Our analysis and experience suggest that standardizing documentation and coordinating a comprehensive model of care leads to increased nutritional status and remission rates over time.’

—Shari Huffman, MS, ARN

She estimated that between 75% and 80% of patients now see a nutritionist at least once a year.

“This is a big improvement over our preintervention rates,” she said.

Maureen Kelly, RN, MS, CNP, clinical assistant professor at the University of North Carolina at Chapel Hill’s School of Nursing and a nurse practitioner in pediatric gastroenterology at the university’s Department of Pediatrics, said more research needs to be conducted to tease out which elements of the comprehensive approach led to the improvement in patient outcomes.

“Was it the multidisciplinary clinic, improvement in documentation in physician’s global assessment or see Multidisciplinary Care, page 23

NOW AVAILABLE! A NEW BOWEL PREP OPTION

Indication and Important Safety Information Prepopikâ&#x201E;¢ for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. r 1SFQPQJL JT DPOUSBJOEJDBUFE JO UIF GPMMPXJOH DPOEJUJPOT QBUJFOUT XJUI TFWFSFMZ SFEVDFE SFOBM GVODUJPO HBTUSPJOUFTUJOBM PCTUSVDUJPO PS JMFVT CPXFM perforation, toxic colitis or toxic megacolon, gastric retention, or in patients with a known allergy to any of the ingredients in Prepopik. Patients should CF BEWJTFE PO UIF JNQPSUBODF PG BEFRVBUF IZESBUJPO BOE QPTU DPMPOPTDPQZ MBC UFTUT TIPVME CF DPOTJEFSFE JG B QBUJFOU EFWFMPQT TJHOJGJDBOU WPNJUJOH or signs of dehydration after taking Prepopik r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r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r 1SFQPQJL TIPVME OPU CF VTFE JG HBTUSPJOUFTUJOBM PCTUSVDUJPO PS QFSGPSBUJPO JT TVTQFDUFE 1SFQPQJL JT OPU GPS EJSFDU JOHFTUJPO &BDI QBDLFU NVTU CF EJTTPMWFE JO PVODFT PG DPME XBUFS BOE BENJOJTUFSFE BU TFQBSBUF UJNFT JO BEEJUJPO UP BEEJUJPOBM DMFBS GMVJET BDDPSEJOH UP UIF EPTJOH SFHJNFO *O SBOEPNJ[FE NVMUJDFOUFS DPOUSPMMFE DMJOJDBM USJBMT OBVTFB IFBEBDIF BOE WPNJUJOH XFSF UIF NPTU DPNNPO USFBUNFOU FNFSHFOU BEWFSTF SFBDUJPOT (>1%) following Prepopik administration 1MFBTF TFF CSJFG TVNNBSZ PG 1SFTDSJCJOH *OGPSNBUJPO GPMMPXJOH UIJT BEWFSUJTFNFOU

New Prepopik helps patients arrive ready with: t Lowest volume of active prep solution and a flexible hydration schedule1 t Demonstrated non-inferiority, with both split-dose and day-before regimen1 t S uperior cleansing efficacy with ACG-recommended split-dose vs day-before regimen comparator*1 - 84% vs 74%, respectively, achieving “excellent or good” visualization, validated per the Aronchick scale* t A dual mechanism that stimulates peristalsis and produces osmotic water retention1 * Evaluated in a randomized trial. The comparator was 2L PEG with electrolytes (PEG+E) plus 2x 5 mg bisacodyl tablets, dosed as labeled. The primary efficacy endpoint was the proportion of patients with successful colon cleansing defined as bowel preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists.1

To learn more, scan this code with your smartphone, or go to www.prepopik.com.

Reference: 1. Prepopik™ Prescribing Information, July 2012.

Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.

© 2012 Ferring B.V. PREPOPIKTM is a trademark of Ferring B.V. PREP_LJAD_001_0912

22

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ OCTOBER 2012

Small Trial Evaluates New Disease Paradigm, Treatment for Ulcerative Colitis

By David Wild Researchers say they have developed a new treatment that effectively targets the underlying cause of ulcerative colitis (UC), based on a case series of 33 patients with mild to moderate UC. Investigators treated the patients with their novel

regimen, and nearly all experienced rapid and sustained clinical, endoscopic and histologic remission.

Senior investigator Jay Pravda, MD, clinical immunologist in West Palm Beach, Fla., came up with the new treatment by challenging the prevailing disease paradigm of UC. â&#x20AC;&#x153;There is no evidence for any

Aspiration 3DWLHQWV ZLWK LPSDLUHG JDJ UHĂ&#x20AC;H[ DQG SDWLHQWV SURQH WR UHJXUJLWDWLRQ RU DVSLUDWLRQ VKRXOG EH REVHUYHG GXULQJ WKH DGPLQLVWUDWLRQ RI PREPOPIK. Use with caution in these patients.

Not for Direct Ingestion (DFK SDFNHW PXVW EH GLVVROYHG LQ RXQFHV RI FROG ZDWHU DQG administered at separate times according to the dosing regimen.

The following is a brief summary only; see full Prescribing Ingestion of additional water is important to patient tolerance. Direct Information for complete product information.

LQJHVWLRQ RI WKH XQGLVVROYHG SRZGHU PD\ LQFUHDVH WKH ULVN RI QDXVHD YRPLWLQJ GHK\GUDWLRQ DQG HOHFWURO\WH GLVWXUEDQFHV INDICATIONS AND USAGE PREPOPIKâ&#x201E;˘ (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults.

Clinical Trials Experience %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV CONTRAINDICATIONS DGYHUVH UHDFWLRQ UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW PREPOPIK is contraindicated in the following conditions: EH GLUHFWO\ FRPSDUHG WR UDWHV LQ FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ Â&#x2021; 3DWLHQWV ZLWK VHYHUHO\ UHGXFHG UHQDO IXQFWLRQ FUHDWLQLQH FOHDUDQFH QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG LQ SUDFWLFH less than 30 mL/minute) which may result in accumulation of In randomized, multicenter, controlled clinical trials, nausea, headache, magnesium DQG YRPLWLQJ ZHUH WKH PRVW FRPPRQ DGYHUVH UHDFWLRQV !

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Serious Fluid and Serum Chemistry Abnormalities RU VKRZHG FOLQLFDOO\ VLJQLÂżFDQW ZRUVHQLQJ GXULQJ WKH VWXG\ WKDW ZDV $GYLVH SDWLHQWV WR K\GUDWH DGHTXDWHO\ EHIRUH GXULQJ DQG DIWHUU WKH QRW LQ WKH IUDPH RI WKH XVXDO FOLQLFDO FRXUVH DV GHWHUPLQHG E\ WKH XVH RI 35(323,. 8VH FDXWLRQ LQ SDWLHQWV ZLWK FRQJHVWLYH KHDUW LQYHVWLJDWRU IDLOXUH ZKHQ UHSODFLQJ Ă&#x20AC;XLGV ,I D SDWLHQW GHYHORSV VLJQLÂżFDQW YRPLWLQJ 35(323,. ZDV FRPSDUHG IRU FRORQ FOHDQVLQJ HIIHFWLYHQHVV ZLWK or signs of dehydration including signs of orthostatic hypotension D SUHSDUDWLRQ FRQWDLQLQJ WZR OLWHUV / RI SRO\HWK\OHQH JO\FRO SOXV after taking PREPOPIK, consider performing post-colonoscopy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compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were GRFXPHQWHG RXW WR VHYHQ GD\V SRVW FRORQRVFRS\ Table 1: Treatment-Emergent Adverse Reactions observed in at )OXLG DQG HOHFWURO\WH GLVWXUEDQFHV FDQ OHDG WR VHULRXV DGYHUVH HYHQWV Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** DQG HOHFWURO\WH DEQRUPDOLWLHV VKRXOG EH FRUUHFWHG EHIRUH WUHDWPHQW ZLWK 35(323,. ,Q DGGLWLRQ XVH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen IRU SDWLHQWV ZKR KDYH FRQGLWLRQV RU ZKR DUH XVLQJ PHGLFDWLRQV WKDW Reaction LQFUHDVH WKH ULVN IRU Ă&#x20AC;XLG DQG HOHFWURO\WH GLVWXUEDQFHV RU WKDW PD\ PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* LQFUHDVH WKH ULVN RI DGYHUVH HYHQWV RI VHL]XUH DUUK\WKPLD DQG UHQDO (N=305) with 2 x 5-mg (N=296) with 2 x impairment. n (% = n/N) bisacodyl n (% = n/N) 5-mg Seizures 7KHUH KDYH EHHQ UHSRUWV RI JHQHUDOL]HG WRQLF FORQLF VHL]XUHV ZLWK WKH XVH RI ERZHO SUHSDUDWLRQ SURGXFWV LQ SDWLHQWV ZLWK QR SULRU KLVWRU\ RI VHL]XUHV 7KH VHL]XUH FDVHV ZHUH DVVRFLDWHG ZLWK HOHFWURO\WH DEQRUPDOLWLHV H J K\SRQDWUHPLD K\SRNDOHPLD K\SRFDOFHPLD DQG K\SRPDJQHVHPLD DQG ORZ VHUXP RVPRODOLW\ 7KH QHXURORJLF DEQRUPDOLWLHV UHVROYHG ZLWK FRUUHFWLRQ RI Ă&#x20AC;XLG DQG HOHFWURO\WH DEQRUPDOLWLHV 8VH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. IRU SDWLHQWV ZLWK D history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or EHQ]RGLD]HSLQHV SDWLHQWV ZLWK NQRZQ RU VXVSHFWHG K\SRQDWUHPLD Use in Patients with Renal Impairment $V LQ RWKHU PDJQHVLXP FRQWDLQLQJ ERZHO SUHSDUDWLRQV XVH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. IRU SDWLHQWV ZLWK LPSDLUHG UHQDO IXQFWLRQ or patients taking concomitant medications that may affect renal IXQFWLRQ VXFK DV GLXUHWLFV DQJLRWHQVLQ FRQYHUWLQJ HQ]\PH LQKLELWRUV DQJLRWHQVLQ UHFHSWRU EORFNHUV RU QRQ VWHURLGDO DQWL LQĂ&#x20AC;DPPDWRU\ GUXJV 7KHVH SDWLHQWV PD\ EH DW LQFUHDVHG ULVN IRU UHQDO LQMXU\ $GYLVH WKHVH SDWLHQWV RI WKH LPSRUWDQFH RI DGHTXDWH K\GUDWLRQ EHIRUH GXULQJ DQG DIWHU WKH XVH RI 35(323,. &RQVLGHU SHUIRUPLQJ EDVHOLQH DQG SRVW FRORQRVFRS\ ODERUDWRU\ WHVWV HOHFWURO\WHV FUHDWLQLQH DQG %81

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tablets (N=298) n (% = n/N)

bisacodyl tablets (N=302) n (% = n/N) 1DXVHD 8 (2.6) 11 (3.7) 9 (3.0) 13 (4.3) Headache 5 (1.6) 5 (1.7) 8 (2.7) 5 (1.7) Vomiting 3 (1.0) 10 (3.4) 4 (1.4) 6 (2.0) / 3(* ( WZR OLWHUV SRO\HWK\OHQH JO\FRO SOXV HOHFWURO\WHV VROXWLRQ DEGRPLQDO EORDWLQJ GLVWHQVLRQ SDLQ FUDPSLQJ DQG ZDWHU\ GLDUUKHD QRW UHTXLULQJ DQ LQWHUYHQWLRQ ZHUH QRW FROOHFWHG

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antecedent immune abnormality in individuals with UC,â&#x20AC;? he said. â&#x20AC;&#x153;We have a hypothesis that UC is a metabolic disease that results from an inability to neutralize excess intracellular hydrogen peroxide.

When you treat the underlying cause of the disease by eradicating the hydrogen peroxide, which is what weâ&#x20AC;&#x2122;ve been doing with our treatment, you get remission.â&#x20AC;?

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Dr. Pravda first proposed the theory that UC was a disorder rooted in excessive intracellular hydrogen peroxide in 2005 (World J Gastroenterol 2005;11:23712384). He subsequently developed a therapeutic regimen consisting of an enema with mesalamine, budesonide, cromolyn sodium and sodium butyrate, and a concurrent, orally-administered Îą-lipoic acidâ&#x20AC;&#x201D;an antioxidant that reduces levels of hydrogen peroxide and oxygen radicals. In fact, two independent laboratories have confirmed that high levels of colonic intracellular hydrogen peroxide are present in patients with UC, as well as in mice with induced UC (Santhanam S et al. Gut 2007;56:1543-1549; Shi XZ et al. Am J Physiol Gastrointest Liver Physiol 2011;300:G41-G51).

Dr. Pravda and his collaborator, Lawrence Wruble, MD, clinical professor of medicine in the Department of Gastroenterology at the University of Tennessee School of Medicine, in Memphis, presented their latest finding at the 2011 Crohnâ&#x20AC;&#x2122;s & Colitis Foundation of Americaâ&#x20AC;&#x2122;s Advances in Inflammatory Bowel Diseases meeting (abstract P-121). They treated 33 patients with the experimental regimen over the past four years: 23 patients received the antioxidant-based treatment in addition to other UC therapies, and 10 patients discontinued all other treatments for UC prior to initiating the novel therapy. In the former group, 81% of patients were taking oral or rectal 5-acetylsalicylic acid (ASA) when they initiated the new treatment, 38% were taking corticosteroids, 13% were taking an immunosuppressant and 13% were taking an anti-tumor necrosis factor (TNF) agent. Those receiving combination therapy had Mayo scores ranging from 3 to 12. In the group of 10 patients receiving the new treatment alone, disease was limited to the distal 50 cm of the colon, with Mayo scores ranging from 5 to 9; seven of these patients had failed previous 5-ASA treatments.

The researchers conducted endoscopic examinations and biopsies in all subjects prior to and three and six weeks following treatment initiation.

23

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

‘We have a hypothesis that UC is a metabolic disease that results from an inability to neutralize excess intracellular hydrogen peroxide. When you treat the underlying cause of the disease by eradicating the hydrogen peroxide, which is what we’ve been doing with our treatment, you get remission.’

—Jay Pravda, MD Dr. Pravda reported that 95% of patients receiving concomitant treatment and all of those administered the novel treatment alone achieved clinical remission within six weeks of treatment. Average Mayo scores in the former group fell from 8.64 at baseline to 0.35 at six weeks, and corresponding scores in the latter group dropped from 7.6 to 0.1. Histologic features similarly improved after six weeks of treatment.

Dr. Pravda reported the novel treatment was generally safe and well tolerated. One patient contracted Clostridium difficile–related infectious colitis and required hospitalization and treatment with vancomycin. Two patients with

documented 5-ASA sensitivities developed rashes that resolved after the novel treatment was discontinued.

According to Alan Buchman, MD, MSPH, professor of medicine and surgery at the Feinberg School of Medicine at Northwestern University, in Chicago, the results are “remarkable and strongly suggest the need for an appropriately powered, placebo-controlled trial.

“My concern with the data is that mesalamine is also a hydrogen peroxide scavenger and since only two of the patients not receiving concomitant treatments

had received mesalamine enemas prior to study entry, it is possible patients in this group were responding to the mesalamine component of the treatment,” said Dr. Buchman, who was not involved in the study. “Therefore, although the researchers’ proposed pathophysiologic mechanism may be valid, the treatment may not be unique. Furthermore, sodium butyrate [another component of the new therapy] is well described in the treatment of UC and likely works primarily via a different mechanism, but the data on its efficacy are not fully convincing.”

Stephen Hanauer, MD, who also was not involved in the study, is waiting for the results of better-designed research before commenting on the efficacy of Dr. Pravda’s treatment.

“It is hard to comment on an openlabel, single-observer trial,” said Dr. Hanauer, professor of medicine and clinical pharmacology, and chief of the Section of Gastroenterology, Hepatology and Nutrition, at the University of Chicago Medical Center. “Those with enthusiasm have no controls, while those with controls have no enthusiasm.”

■

The Sand dhill Difference.

It’s our technical support people...likke Bill and John, who have always been there for you.

It’s our clin ed people...like Sandy, who hass trained thousands of nurses and doctors around the wo orld.

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It’s our software support people…like e Vince, who somehow always knows the right answer.

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Multidisciplinary Care continued from page 19

shared documentation?” asked Ms. Kelly, who was not involved in the study. “I suspect it was a combination of all three of these interventions but future studies need to determine that.”

Most of the physicians at the Nemours clinic warmly received the new multidisciplinary model, Ms. Huffman said.

However, she and her staff limited the number of patients seen daily to an average of six in response to physician concerns that involving more caregivers at each visit would affect the efficiency of clinic flow and quality of care.

She noted other centers wishing to implement similar programs or expand their services to include other disciplines may face reimbursement challenges.

“In an academic center where there are already a variety of specialists it might be easier to do, but a private practice might need to seek grants or outside funding to bring in a dietitian or other providers to get around the barrier that insurance companies may not reimburse visits to multiple specialists for the same problem on the same day.”

■ Ms. Huffman and Ms. Kelly reported no conflicts of interest.

Thank you for supporting us for the last 30 years...and here’s to 30 more!

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24

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Physicians Doing ‘Poor Job’ of Warning Patients With IBD About Risks of Medications, Studies Suggest

By David Wild Many gastroenterologists are failing to warn patients with inflammatory bowel disease (IBD) of the possible risks associated with live vaccinations and the effects of IBD medications on male fertility. Clinicians also are not consistently screening patients with IBD for hepatitis, tuberculosis (TB) and other opportunistic infections.

“Despite evidence to support the importance of vaccinations and prevention of infections in patients with IBD, especially in immunocompromised patients, physicians have done a poor job in this area,” said Miguel Regueiro, MD, professor in the Division of Gastroenterology, Hepatology and Nutrition and co-director of the Inflammatory Bowel Disease Center at The University of Pittsburgh’s Department of Medicine.

“In the era of outcomes and reimbursement measured by quality indices rather than quantity metrics, preventative strategies for IBD patients are of paramount importance,” said Dr. Regueiro, who was not involved in the research.

Medication-Related Fertility Issues Marie Borum, MD, EdD, MPH, professor of medicine and director of the Division of Gastroenterology and Liver Diseases at George Washington University in Washington, D.C., and colleagues conducted a series of medical record analyses, examining the rates of compliance with various IBD-related clinical guidelines. They presented their results at last year’s Crohn’s & Colitis Foundation of America’s Advances in Inflammatory Bowel Diseases meeting. In one analysis, they set out to determine whether male patients with IBD beginning immunosuppressive treatment received the same information as their female counterparts regarding the potential effect of medications on fertility. Female IBD patients routinely are counseled that some medications may affect conception, pregnancy and teratogenicity. Although sulfasalazine, methotrexate, thiopurines and anti-tumor necrosis factor (TNF) drugs all have known or suspected effects on male fertility, Dr. Borum’s team believed this group of patients may not be fully informed of these effects prior to initiating treatment.

To document their suspicions, the investigators analyzed medical records from 63 male patients with ulcerative colitis and 76 male patients with Crohn’s

disease treated at their institution between June 2010 and June 2011. Eight patients had received sulfasalazine, three were treated with methotrexate, 36 were administered a thiopurine and 33 had been treated with an anti-TNF agent, all for at least one year.

The findings confirmed the researchers’ concerns, showing only one patient receiving sulfasalazine and one patient treated with a thiopurine had a documented discussion with their gastroenterologists about drug-related fertility issues. There were no documented discussions on the topic among those receiving methotrexate or anti-TNF agents.

Dr. Borum said that although some of these discussions may have taken place, they were not documented and the findings, “strongly suggest a need for improved counseling with male patients.”

“Although there is limited and potentially conflicting data available regarding medication impact on spermatogenesis and pregnancy outcome, it is important that available information be provided to all patients,” Dr. Borum said.

‘Despite evidence to support the importance of vaccinations and prevention of infections in patients with IBD … physicians have done a poor job in this area.’

—Miguel Regueiro, MD

‘It is imperative that patients receiving immunosuppressants be specifically counseled against receiving live vaccinations because these may be administered by a non-gastroenterology specialist who may not be aware of the risks.’

—Marie Borum, MD, EdD, MPH

Risks Associated With Live Vaccines In a separate analysis, Dr. Borum’s team found many patients with IBD are not made aware of the risks associated with receiving live vaccines during immunosuppressant treatment.

“Commonly administered live vaccines are given during childhood and often prior to IBD onset, but live vaccines, such as annual influenza and yellow fever for international travel, can be administered in adults,” Dr. Borum noted. “These vaccinations are essential in IBD patients, a group at high-risk of infections, but should be administered in their inactivated form.”

Dr. Borum and her team analyzed medical records from 141 IBD patients receiving immunosuppressant drugs and found no documented discussions with patients advising them to avoid live vaccinations. Furthermore, only 15% of these immunosuppressed patients received inactivated influenza vaccinations, as per published guidelines, and most were vaccinated only “on occasion,” rather than annually (Moscandrew M et al. Inflamm Bowel Diss 2009;15:1399-1409).

“Appropriate vaccination is necessary to reduce the incidence of preventable disease and reduce mortality in the IBD population,” Dr. Borum emphasized.

“However, it is imperative that patients receiving immunosuppressants be specifically counseled against receiving live

vaccinations because these may be administered by a non-gastroenterology specialist who may not be aware of the risks.”

Risks for Opportunistic Infections The gravity of latent TB emerging with anti-TNF treatment also needs to be taken more seriously, Dr. Borum’s findings suggested. Of 44 patients treated with an anti-TNF agent between June 2010 and June 2011, only 66% had undergone appropriate TB screening, including the TB skin test (also known as PPD testing) with subsequent chest x-rays and QuantiFeron Gold testing if PPD tests proved positive.

“Although this study is limited by its small sample size, retrospective design and potential undocumented tuberculosis screening, the findings suggest the need for increased awareness among physicians to universally screen for tuberculosis in all IBD patients prior to and during antiTNF treatment,” Dr. Borum said.

In the same cohort of 44 patients, only 60% and 57% were screened for hepatitis B and C infection, respectively, prior to

initiating immunosuppressive treatment, despite recommendations that all patients should be screened for chronic hepatitis prior to immunosuppression. Many infected patients may be asymptomatic, and immunosuppression increases the risk for viral replication and disease progression (Moscandrew M et al. Inflamm Bowel Diss 2009;15:1399-1409).

Although there were no differences in the frequency of screening by age, gender or IBD disease type, patients taking adalimumab were significantly less likely to be screened for hepatitis infection than those taking infliximab, Dr. Borum said.

Dr. Regueiro noted that although the studies were retrospective, small and had a number of methodologic flaws, “they all demonstrated the need for physicians to do a better job screening IBD patients for opportunistic infections, vaccinating patients against preventable illnesses and counseling male patients on fertility.” ■ Drs. Borum and Regueiro reported no conflicts of interest.

© COOK 2012

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26

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Chemotherapy Safe Before Liver Resection For Colorectal Liver Metastases

By John Schieszer and Victoria Stern San Diego—Preoperative chemotherapy may be administered safely without increasing postoperative complications in patients with colorectal cancer (CRC) and multifocal metastatic disease in the liver, according to a study presented at the 2012 Digestive Disease Week meeting.

“I believe that preoperative chemotherapy prior to liver resection should become a standard in the patients with negative prognostic factors,” said study author Ilia Gur, MD, hepatobiliary fellow and clinical instructor in the Division of Surgical Oncology at Oregon Health & Science University (OHSU), Portland.

Dr. Gur added, “There has been concern that the use of chemotherapy before liver resection may decrease the liver’s ability to recover and lead to postoperative complications, but our study [eases those concerns]. We didn’t see increased rates of liver cancer–related complications in the patients who had chemotherapy.”

In the only prospective randomized trial to date that compares preoperative chemotherapy with no chemotherapy, investigators found disease-free survival (DFS) improved modestly in the preoperative chemotherapy group; however, overall survival (OS) did not differ significantly between the two groups (Nordlinger B et al.

Metformin continued from page 1

nationwide study from Taiwan showed HCC incidence plummeted in patients with diabetes who were taking metformin compared with diabetic patients who were not receiving the therapy.

The reports, presented at the 2012 Digestive Disease Week (DDW) meeting, represent a major step in prevention of liver cancer.

“The results are astonishing. If you put it together, these two papers, we have potentially a breakthrough in the prevention of liver cancer,” said Jacques Devière, MD, PhD, professor of medicine at Erasme University Hospital in Brussels, Belgium, after hearing the studies presented.

Previous epidemiologic studies have suggested that metformin may be protective against many cancers, and a recent study published in Cancer Prevention Research showed that metformin slowed tumor activity in mice given chemically-induced liver tumors (Bhalla K et al. 2012;5:544–552). But the two studies presented at the DDW meeting mark an important step in understanding the relationship between metformin and HCC. The studies are unique in size and scope, and the results leave little doubt that metformin has a statistically significant and clinically significant protective effect.

The Taiwanese study was conducted in two parts: a population-based study that

Lancet 2008;371:1007-1016). t Dr. Gur and colleagues performed a retrospective review of all patients who had liver resections for metastatic CRC between 2003 and 2011 at OHSU to help clarify the usefulness of preoperative chemotherapy. The investigators analyzed data from 157 patients who had a total of 168 liver resections. Median length of followup from a first liver resection was 22.3 months. The data showed 114 patients (72%) underwent chemotherapy before liver resection, most frequently with FOLFOX (oxaliplatin, 5-fluorouracil [5-FU], leucovorin; 68%) or FOLFIRI (folinic acid, 5-FU, irinotecan; 12%) protocols.

The mean size of lesions in the preoperative chemotherapy group was 3 cm compared with 4 cm in the no–preoperative chemotherapy group.

After undergoing a liver resection, patients’ OS was 89% at one year, 57% at three years and 27% at five years, and DFS was 61% at one year, 30% at three years and 23% at five years. There was no significant difference in overall complications, nor in liver-related complications, between patients who received preoperative chemotherapy and those who did not. After a multivariate analysis, Dr. Gur’s team found that the presence of three or more lesions as well as age older than 70 years were significant predictors of poor survival. Additionally, the presence of several variables—such as older age and multiplicity and synchronicity

started with almost all of the country’s 23 million people and an in vitro study that looked at metformin’s effects in humans and mice (abstract 596). In the first part, investigators used the Taiwanese national health insurance database to identify patients diagnosed with HCC. Between 1997 and 2008, investigators recruited all newly diagnosed HCC cases, totaling nearly 97,430 patients, and compared them with nearly 200,000 age-, gender- and first-visit-to-physician–matched controls.

As expected, people diagnosed with diabetes had a much higher risk for developing HCC—an increase of nearly 2.5-fold (odds ratio [OR], 2.29) compared with people without diabetes, a rate similar to that in previous large epidemiologic studies.

But for the first time, the study showed that in patients with diabetes taking metformin, HCC occurred significantly less often compared with other individuals with diabetes. HCC occurred most often in patients with diabetes who were not using metformin (OR, 1.95; 95% confidence interval [CI], 1.88-2.03), followed by patients with diabetes who rarely used metformin (OR, 1.74; 95% CI, 1.67-1.82) and, least often in patients with diabetes who regularly used metformin (OR, 1.56; 95% CI, 1.49-1.64). Moreover, metformin’s effect was shown to be dose dependent: For every year of metformin use, patients with diabetes had a 7% decrease in HCC risk, after controlling for other factors.

of liver lesions—pointed to a subset of patients with a particularly high risk for recurrence. The presence of these variables “justified the deecision to recommend use of chemotherapy [in these patients],” Dr. Gur said.

Dr. Gur’s team concluded that even with chemotherapy and aggressive resections, only a subset of patients remains free of disease after five years and that preoperative chemotherapy should be considered strongly in patients with risk factors.

“Although there was no disease-free or overall survival advantage in the preoperative chemotherapy group, [this may be explained by] the fact that the chemotherapy group had more risk factors and that the study was not powered enough nor were the groups randomized to detect a difference,” Dr. Gur added.

P. Marco Fisichella, MD, assistant professor of surgery at Loyola University Medical Center, Maywood, Ill., noted that this is an important study with significant clinical ramifications.

“This [study] is clinically relevant and has the potential to change the way we do things,” Dr. Fisichella said.

“This study offers evidence to support chemotherapy before resection.”

■

The investigators then performed cell line studies to look at the in vitro effects of metformin on cell proliferation and cell cycle. Studies of HepG2 and Hep3B hepatoma cell lines showed that metformin inhibited hepatocyte proliferation and induced cell cycle arrest at G0/G1 in two ways: by upregulating p21/Cip1 and p27/ Kip1 and by downregulating cyclin D1 in a dose-dependent manner. The effect was independent of p53, a protein strongly associated with tumor suppression.

“I think this is an exceptional piece of information because it shows that the decrease in HCC may not only be due to prevention but also by a therapeutic action of some sort,” said Mario Chojkier, MD, professor of medicine at the University of California, San Diego, in summarizing the paper during a “Best of DDW” session at the DDW meeting.

Dr. Chojkier said the findings have significant clinical implications. Although no experts called for patients to receive metformin prophylactically, investigators said more studies might lead to different prescribing patterns. Dr. Chojkier said that for now, physicians should “be stringent” in assessing insulin resistance according to the guidelines from the American Diabetes Association.

The second study on metformin compared 612 patients with histologically proven intrahepatic carcinoma who were seen at Mayo Clinic with 594 patients without a history of cancer matched for age, gender, ethnicity and residential

area (abstract 597). Sensitivity analysis showed that metformin use was associated with a 60% reduced risk for intrahepatic carcinoma in diabetics compared with diabetic patients who did not take metformin.

The finding is novel but will require further investigation and validation in another cohort, said lead author Roongruedee Chaiteerakij, MD, of Mayo Clinic, Rochester, Minn.

Experts say more work on this subject is needed. Hashem B. El-Serag, MD, MPH, chief of gastroenterology and hepatology, Baylor College of Medicine, Houston, said the Mayo study involved too few patients to be conclusive, and the findings may reflect a bias on the part of treating physicians.

“Physicians don’t like to give statin or metformin to people with cirrhosis, so it looks like those who develop cancer are using them less, not because of a biological phenomenon but because of an avoidance phenomenon,” said Dr. El-Serag.

But Chun-Ying Wu, MD, PhD, MPH, of the faculty of medicine at National Yang-Ming University in Taipei, Taiwan, and lead author of the Taiwanese study, believes that metformin should be recommended in patients with diabetes.

“We can say metformin is actually chemopreventive for HCC development.” ■ Drs. Chaiteerakij, Chojkier, Devière, El-Serag and Wu reported no relevant financial conflicts of interest.

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Telaprevir may be less effective in patients taking these agents concomitantly.

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See table under Drug Interactionss for co-administration of sildenafil and tadalafil when dosed for erectile dysfunction. b See table under Drug Interactionss for parenterally administered midazolam.

WARNINGS AND PRECAUTIONS Pregnancy: Use with Ribavirin and Peginterferon Alfa. 3JCBWJSJO NBZ DBVTF CJSUI EFGFDUT BOE PS EFBUI PG UIF FYQPTFE GFUVT &YUSFNF DBSF NVTU CF UBLFO UP BWPJE QSFHOBODZ JO GFNBMF QBUJFOUT BOE JO GFNBMF QBSUOFST PG NBMF QBUJFOUT 3JCBWJSJO UIFSBQZ TIPVME OPU CF TUBSUFE VOMFTT B SFQPSU PG B OFHBUJWF QSFHOBODZ UFTU IBT CFFO PCUBJOFE immediately prior to initiation of therapy.

Because INCIVEK must be used in combination with peginterferon alfa and ribavirin, the contraindications and warnings applicable to those drugs are applicable to combination therapy. Female patients of childbearing potential and their male partners as well as male patients and their female partners must use 2 effective contraceptive methods during treatment and for 6 months after all treatment has ended. Female patients should have monthly pregnancy tests during treatment and during the 6-month QFSJPE BGUFS TUPQQJOH USFBUNFOU &YUSFNF DBSF NVTU CF UBLFO UP BWPJE QSFHOBODZ JO GFNBMF QBUJFOUT BOE JO GFNBMF QBSUOFST PG NBMF QBUJFOUT BT TJHOJGJDBOU UFSBUPHFOJD BOE PS FNCSZPDJEBM FGGFDUT IBWF CFFO EFNPOTUSBUFE JO BMM BOJNBM TQFDJFT FYQPTFE UP SJCBWJSJO 3FGFS BMTP UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS SJCBWJSJO Female Patients-)PSNPOBM DPOUSBDFQUJWFT NBZ CF DPOUJOVFE CVU NBZ OPU CF SFMJBCMF EVSJOH */$*7&, EPTJOH BOE GPS VQ UP UXP XFFLT GPMMPXJOH DFTTBUJPO PG */$*7&, %VSJOH UIJT UJNF GFNBMF QBUJFOUT PG DIJMECFBSJOH QPUFOUJBM TIPVME VTF UXP FGGFDUJWF OPO IPSNPOBM NFUIPET PG DPOUSBDFQUJPO &YBNQMFT NBZ JODMVEF CBSSJFS NFUIPET PS intrauterine devices (IUDs). Two weeks after completion of INCIVEK treatment, hormonal contraceptives are again appropriate as one of the two required effective methods of birth control; however, specific prescribing information recommendations should be followed for the contraceptives.

Serious Skin Reactions. 4FSJPVT TLJO SFBDUJPOT JODMVEJOH %SVH 3BTI XJUI &PTJOPQIJMJB BOE 4ZTUFNJD 4ZNQUPNT %3&44 BOE 4UFWFOT +PIOTPO 4ZOESPNF 4+4 XFSF reported in less than 1% of subjects who received INCIVEK combination treatment compared to none who received peginterferon alfa and ribavirin alone. These serious TLJO SFBDUJPOT SFRVJSFE IPTQJUBMJ[BUJPO BOE BMM QBUJFOUT SFDPWFSFE 5IF QSFTFOUJOH TJHOT PG %3&44 NBZ JODMVEF SBTI GFWFS GBDJBM FEFNB BOE FWJEFODF PG JOUFSOBM PSHBO involvement (e.g., hepatitis, nephritis). Eosinophilia may or may not be present. The presenting signs of SJS may include fever,r target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips).

If a serious skin reaction occurs, all components of INCIVEK combination treatment must be discontinued immediately and the patient should be promptly referred for urgent medical care.

Rash. 3BTI EFWFMPQFE JO PG TVCKFDUT XIP SFDFJWFE */$*7&, DPNCJOBUJPO USFBUNFOU 4FWFSF SBTI F H B HFOFSBMJ[FE SBTI PS SBTI XJUI WFTJDMFT PS CVMMBF PS VMDFSBUJPOT PUIFS UIBO 4+4 XBT SFQPSUFE JO PG TVCKFDUT XIP SFDFJWFE */$*7&, DPNCJOBUJPO USFBUNFOU DPNQBSFE UP MFTT UIBO XIP SFDFJWFE QFHJOUFSGFSPO BMGB BOE SJCBWJSJO BMPOF The severe rash may have a prominent eczematous component.

Patients with mild to moderate rashes should be followed for progression of rash or development of systemic symptoms. If rash progresses and becomes severe or if systemic symptoms develop, INCIVEK should be discontinued. Peginterferon alfa and ribavirin may be continued. If improvement is not observed within 7 days of INCIVEK EJTDPOUJOVBUJPO TFRVFOUJBM PS TJNVMUBOFPVT JOUFSSVQUJPO PS EJTDPOUJOVBUJPO PG SJCBWJSJO BOE PS QFHJOUFSGFSPO BMGB TIPVME CF DPOTJEFSFE *G NFEJDBMMZ JOEJDBUFE FBSMJFS interruption or discontinuation of ribavirin and peginterferon alfa should be considered. Patients should be monitored until the rash has resolved. INCIVEK must not be SFEVDFE PS SFTUBSUFE JG EJTDPOUJOVFE EVF UP SBTI 5SFBUNFOU PG SBTI XJUI PSBM BOUJIJTUBNJOFT BOE PS UPQJDBM DPSUJDPTUFSPJET NBZ QSPWJEF TZNQUPNBUJD SFMJFG CVU FGGFDUJWFOFTT of these measures has not been established. Treatment of rash with systemic corticosteroids is not recommended.

Anemia. "OFNJB IBT CFFO SFQPSUFE XJUI QFHJOUFSGFSPO BMGB BOE SJCBWJSJO UIFSBQZ 5IF BEEJUJPO PG */$*7&, UP QFHJOUFSGFSPO BMGB BOE SJCBWJSJO JT BTTPDJBUFE XJUI BO BEEJUJPOBM EFDSFBTF JO IFNPHMPCJO DPODFOUSBUJPOT )FNPHMPCJO WBMVFT MFTT UIBO PS FRVBM UP H QFS E- XFSF PCTFSWFE JO PG TVCKFDUT XIP SFDFJWFE */$*7&, DPNCJOBUJPO USFBUNFOU DPNQBSFE UP PG TVCKFDUT XIP SFDFJWFE QFHJOUFSGFSPO BMGB BOE SJCBWJSJO )FNPHMPCJO WBMVFT MFTT UIBO H QFS E- XFSF PCTFSWFE JO PG TVCKFDUT XIP SFDFJWFE INCIVEK combination treatment compared to 5% of subjects receiving peginterferon alfa and ribavirin. *O TVCKFDUT SFDFJWJOH */$*7&, DPNCJOBUJPO USFBUNFOU EJTDPOUJOVFE */$*7&, EJTDPOUJOVFE */$*7&, DPNCJOBUJPO USFBUNFOU BOE VOEFSXFOU B SJCBWJSJO EPTF modification (reduction, interruption or discontinuation) due to anemia. In subjects treated with peginterferon alfa and ribavirin alone, there were two discontinuations and 12% underwent ribavirin dose modification due to anemia. )FNPHMPCJO TIPVME CF NPOJUPSFE QSJPS UP BOE BU MFBTU BU XFFLT BOE EVSJOH */$*7&, DPNCJOBUJPO USFBUNFOU BOE BT DMJOJDBMMZ BQQSPQSJBUF 'PS UIF NBOBHFNFOU PG anemia, ribavirin dose reductions should be used (refer to the prescribing information for ribavirin for its dose reduction guidelines). If ribavirin dose reductions are inadequate, discontinuation of INCIVEK should be considered. If ribavirin is permanently discontinued for the management of anemia, INCIVEK must also be permanently EJTDPOUJOVFE 3JCBWJSJO NBZ CF SFTUBSUFE QFS UIF EPTJOH NPEJGJDBUJPO HVJEFMJOFT GPS SJCBWJSJO 5IF EPTF PG */$*7&, NVTU OPU CF SFEVDFE BOE */$*7&, NVTU OPU CF SFTUBSUFE JG discontinued.

Drug Interactions. See the table above for a listing of drugs that are contraindicated for use with INCIVEK due to potentially life-threatening adverse events or potential loss PG UIFSBQFVUJD FGGFDU UP */$*7&, 3FGFS UP UIF UBCMF JODMVEFE VOEFS Drug Interactionss for established and other potentially significant drug-drug interactions.

Laboratory Tests. )$7 3/" MFWFMT TIPVME CF NPOJUPSFE BU XFFLT BOE BOE BT DMJOJDBMMZ JOEJDBUFE 6TF PG B TFOTJUJWF SFBM UJNF 35 1$3 BTTBZ GPS NPOJUPSJOH )$7 3/" MFWFMT EVSJOH USFBUNFOU JT SFDPNNFOEFE 5IF BTTBZ TIPVME IBWF BB MPXFS MJNJU PG )$7 3/" RVBOUJGJDBUJPO FRVBM UP PS MFTT UIBO *6 QFS N- BOE B MJNJU PG )$7 3/" EFUFDUJPO PG BQQSPYJNBUFMZ *6 QFS N- 'PS UIF QVSQPTF PG BTTFTTJOH SFTQPOTF HVJEFE UIFSBQZ FMJHJCJMJUZ BO iVOEFUFDUBCMFw )$7 3/" 5BSHFU /PU %FUFDUFE SFTVMU JT SFRVJSFE B DPOGJSNFE iEFUFDUBCMF CVU CFMPX MJNJU PGG RVBOUJGJDBUJPOw )$7 3/" SFTVMU TIPVME OPU CF DPOTJEFSFE FRVJWBMFOU UP BO iVOEFUFDUBCMFw )$7 3/" SFTVMU SFQPSUFE BT i5BSHFU /PU %FUFDUFEw PS i)$7 3/" /PU %FUFDUFEw

)FNBUPMPHZ FWBMVBUJPOT JODMVEJOH XIJUF DFMM EJGGFSFOUJBM DPVOU BSF SFDPNNFOEFE QSJPS UP BOE BU XFFLT BOE BOE BT D U MJOJDBMMZ BQQSPQSJBUF $IFNJTUSZ FWBMVBUJPOT FMFDUSPMZUFT TFSVN DSFBUJOJOF VSJD BDJE IFQBUJD FO[ZNFT CJMJSVCJO BOE 54) BSF SFDPNNFOEFE BT GSFRVFOUMZ BT UIF IFNBUPMPHZ FWBMVBUJPOT PS BT DMJOJDBMMZ JOEJDBUFE 3FGFS UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS QFHJOUFSGFSPO BMGB BOE SJCBWJSJO JODMVEJOH QSFHOBODZ UFTUJOH SFRVJSFNFOUT General. INCIVEK must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin. Therefore, the prescribing information for peginterferon alfa and ribavirin must be consulted before starting treatment with INCIVEK. 5IFSF BSF OP DMJOJDBM EBUB PO SF USFBUJOH QBUJFOUT XIP IBWF GBJMFE BO )$7 /4 " QSPUFBTF JOIJCJUPS CBTFE USFBUNFOU OPS BSF UIFSF EBUB PO SFQFBUFE DPVSTFT PG */$*7&, Hepatic Impairment. INCIVEK is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) or patients XJUI EFDPNQFOTBUFE MJWFS EJTFBTF 3FGFS UP QSFTDSJCJOH JOGPSNBUJPO GPS QFHJOUFSGFSPO BMGB BOE SJCBWJSJO XIJDI NVTU CF DP BENJOJTUFSFE XJUI */$*7&, ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: t 1SFHOBODZ 6TF XJUI 3JCBWJSJO BOE 1FHJOUFSGFSPO BMGB t 4FSJPVT 4LJO 3FBDUJPOT 3BTI t "OFNJB */$*7&, NVTU CF BENJOJTUFSFE XJUI QFHJOUFSGFSPO BMGB BOE SJCBWJSJO 3FGFS UP UIFJS SFTQFDUJWF QSFTDSJCJOH JOGPSNBUJPO GPS UIFJS BTTPDJBUFE BEWFSTF SFBDUJPOT 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 assessment is based on data from pooled adequate and well-controlled clinical trials including 1797 subjects who received INCIVEK combination treatment and XIP SFDFJWFE QFHJOUFSGFSPO BMGB BOE SJCBWJSJO 4FSJPVT BEWFSTF ESVH SFBDUJPOT PDDVSSFE JO PG TVCKFDUT XIP SFDFJWFE */$*7&, DPNCJOBUJPO USFBUNFOU DPNQBSFE UP OPOF PG UIF TVCKFDUT USFBUFE XJUI QFHJOUFSGFSPO BMGB BOE SJCBWJSJO 5IF NPTU GSFRVFOU TFSJPVT BEWFSTF FWFOUT JO TVCKFDUT USFBUFE XJUI */$*7&, DPNCJOBUJPO USFBUNFOU XFSF TLJO EJTPSEFST SBTI BOE PS QSVSJUVT BOE BOFNJB 'PVSUFFO QFSDFOU PG TVCKFDUT EJTDPOUJOVFE */$*7&, EVF UP BEWFSTF ESVH SFBDUJPOT 3BTI BOFNJB GBUJHVF QSVSJUVT OBVTFB BOE WPNJUJOH XFSF UIF NPTU GSFRVFOU BEWFSTF ESVH reactions leading to discontinuation of INCIVEK. INCIVEK was administered in combination with peginterferon alfa and ribavirin. The following table lists adverse drug reactionss that occurred in INCIVEK-treated subjects with an incidence at least 5% greater than in subjects receiving peginterferon alfa and ribavirin alone.

Clinical Adverse Drug Reactions Reported with at Least 5% Higher Frequency Among Subjects Receiving INCIVEK INCIVEK, peginterferon alfa, and ribavirin Peginterferon alfa and ribavirin Combination Treatment N=1797 N=493 3BTI 56%

Fatigue 56%

Pruritus

Nausea

"OFNJB

17% Diarrhea 26% 17% Vomiting

)FNPSSIPJET 12%

"OPSFDUBM EJTDPNGPSU 11%

Dysgeusia

"OBM QSVSJUVT 6% 1% a

ANTIARRHYTHMICS lidocaine (systemic), amiodarone, bepridil, flecainide, propafenone, quinidine

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Prolonged or increased sedation or respiratory depression

â&#x17E;&#x17E;

Orally administered midazolamb, triazolam

â&#x17E;&#x17E; â&#x17E;&#x17E;

4FEBUJWFT IZQOPUJDT

â&#x17E;&#x17E;

4JMEFOBGJM 3FWBUJPÂŽ PS UBEBMBGJM "EDJSDBÂŽ) [for treatment of pulmonary arterial hypertension]a

â&#x17E;&#x17E; â&#x17E;&#x17E; â&#x17E;&#x17E;

PDE5 inhibitor

Potential for myopathy including rhabdomyolysis 1PUFOUJBM GPS TFSJPVT BOE PS MJGF UISFBUFOJOH BEWFSTF SFBDUJPOT such as cardiac arrhythmias Potential for PDE5 inhibitor-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope

â&#x17E;&#x17E;

Lovastatin, simvastatin Pimozide

â&#x17E;&#x17E; â&#x17E;&#x17E;

).( $P" SFEVDUBTF JOIJCJUPST Neuroleptic

â&#x17E;&#x17E; â&#x17E;&#x17E; â&#x17E;&#x17E;

Dihydroergotamine, ergonovine, ergotamine, methylergonovine 1PUFOUJBM GPS BDVUF FSHPU UPYJDJUZ DIBSBDUFSJ[FE CZ QFSJQIFSBM vasospasm or ischemia Cisapride Potential for cardiac arrhythmias St. Johnâ&#x20AC;&#x2122;s wort Plasma concentrations of telaprevir can be reduced by (Hypericum perforatum) concomitant use of the herbal preparation St. Johnâ&#x20AC;&#x2122;s wort.

GI motility agent )FSCBM QSPEVDUT

â&#x17E;&#x17E;

Ergot derivatives

â&#x17E;&#x17E;

3JGBNQJO TJHOJGJDBOUMZ SFEVDFT UFMBQSFWJS QMBTNB DPODFOUSBUJPOT

â&#x17E;&#x17E;

Potential for hypotension or cardiac arrhythmia

3JGBNQJO

â&#x17E;&#x17E;

"MGV[PTJO

"OUJNZDPCBDUFSJBMT

zolpidem

&YQPTVSF UP [PMQJEFN XBT EFDSFBTFE XIFO DP BENJOJTUFSFE XJUI UFMBQSFWJS Clinical monitoring and dose titration of zolpidem is recommended to achieve the desired clinical response.

amlodipine

&YQPTVSF UP BNMPEJQJOF XBT JODSFBTFE XIFO DP BENJOJTUFSFE XJUI UFMBQSFWJS $BVUJPO should be used and dose reduction for amlodipine should be considered. Clinical monitoring is recommended.

Concentrations of other calcium channel blockers may be increased when telaprevir is co-administered.

Caution is warranted and clinical monitoring of patients is recommended.

â&#x17E;&#x17E;

"MQIB BESFOPSFDFQUPS BOUBHPOJTU

Anemia. In controlled clinical trials, the overall incidence and severity of anemia increased with INCIVEK combination treatment compared to peginterferon alfa and ribavirin BMPOF 5IF JODJEFODF PG BOFNJB BEWFSTF FWFOUT XBT XJUI */$*7&, DPNCJOBUJPO USFBUNFOU DPNQBSFE UP XJUI QFHJOUFSGFSPO BMGB BOE SJCBWJSJO BMPOF " EFDSFBTF JO IFNPHMPCJO MFWFMT PDDVSSFE EVSJOH UIF GJSTU XFFLT PG USFBUNFOU XJUI MPXFTU WBMVFT SFBDIFE BU UIF FOE PG */$*7&, EPTJOH )FNPHMPCJO WBMVFT HSBEVBMMZ SFUVSOFE UP MFWFMT observed with peginterferon alfa and ribavirin after INCIVEK dosing was completed.

Anorectal Signs and Symptoms. *O UIF DPOUSPMMFE DMJOJDBM USJBMT PG TVCKFDUT USFBUFE XJUI */$*7&, DPNCJOBUJPO USFBUNFOU FYQFSJFODFE BOPSFDUBM BEWFSTF FWFOUT compared to 7% of those treated with peginterferon alfa and ribavirin alone. The majority of these events (e.g., hemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate in severity; less than 1% led to treatment discontinuation and all resolved during or after completion of INCIVEK dosing.

Laboratory abnormalities White Blood Cells:: Treatment with peginterferon alfa is associated with decreases in mean values for total white blood cell, absolute neutrophil, and absolute lymphocyte DPVOU .PSF */$*7&, USFBUFE TVCKFDUT IBE EFDSFBTFT JO MZNQIPDZUF DPVOUT UP NN PS MFTT DPNQBSFE UP %FDSFBTFT JO UPUBM XIJUF DFMM DPVOUT UP NN PS MFTT XFSF DPNQBSBCMF DPNQBSFE UP 5IF JODJEFODF PG EFDSFBTFT JO BCTPMVUF OFVUSPQIJM DPVOUT UP NN or less was 15% in subjects treated with peginterferon alfa and ribavirin alone compared to 12% among those treated with INCIVEK combination treatment.

Platelets:: Treatment with peginterferon alfa is associated with decreases in mean platelet counts. More patients treated with INCIVEK combination treatment had EFDSFBTFT JO NFBO QMBUFMFU WBMVFT PG BMM HSBEFT DPNQBSFE UP USFBUFE XJUI QFHJOUFSGFSPO BMGB BOE SJCBWJSJO BMPOF 5ISFF QFSDFOU PG */$*7&, DPNCJOBUJPO USFBUNFOU TVCKFDUT IBE EFDSFBTFT UP NN or less compared to 1% of those treated with peginterferon alfa and ribavirin-treated alone.

Bilirubin: 'PSUZ POF QFSDFOU PG */$*7&, USFBUFE TVCKFDUT DPNQBSFE UP : PG QFHJOUFSGFSPO BMGB BOE SJCBWJSJO USFBUFE TVCKFDUT IBE BMM HSBEF FMFWBUJPOT JO CJMJSVCJO MFWFMT BOE PG TVCKFDUT SFTQFDUJWFMZ IBE HSFBUFS UIBO PS FRVBM UP Y 6-/ FMFWBUJPOT #JMJSVCJO MFWFMT JODSFBTFE NPTU TUFFQMZ EVSJOH UIF GJSTU UP XFFLT PG */$*7&, EPTJOH stabilized and between Weeks 12 and 16 were at baseline levels.

Uric Acid: %VSJOH UIF */$*7&, DPNCJOBUJPO USFBUNFOU QFSJPE PG TVCKFD : UT IBE FMFWBUFE VSJD BDJE MFWFMT DPNQBSFE UP GPS UIPTF USFBUFE XJUI QFHJOUFSGFSPO BMGB BOE ribavirin alone. Shifts to greater than or equal to 12.1 mg per dL from baseline in uric acid levels were also more frequent among subjects treated with INCIVEK (7%) DPNQBSFE UP QFHJOUFSGFSPO BMGB BOE SJCBWJSJO -FTT UIBO PG TVCKFDUT IBE DMJOJDBM FWFOUT PG HPVU HPVUZ BSUISJUJT OPOF XFSF TFSJPVT BOE OPOF SFTVMUFE JO USFBUNFOU discontinuation.

DRUG INTERACTIONS Potential for INCIVEK to Affect Other Drugs */$*7&, JT BO JOIJCJUPS PG $:1 " $P BENJOJTUSBUJPO PG */$*7&, XJUI ESVHT UIBU BSF QSJNBSJMZ NFUBCPMJ[FE CZ $:1 " NBZ SFTVMU JO JODSFBTFE QMBTNB DPODFOUSBUJPOT PG TVDI drugs, which could increase or prolong their therapeutic effect and adverse reactions. INCIVEK is also an inhibitor of P-gp. Co-administration of INCIVEK with drugs that are substrates for P-gp transport may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions. If dose adjustments of concomitant medications are made during INCIVEK treatment, they should be re-adjusted after administration of INCIVEK is completed.

Potential for Other Drugs to Affect INCIVEK */$*7&, JT B TVCTUSBUF PG $:1 " BOE 1 HQ UIFSFGPSF ESVHT UIBUU JOEVDF $:1 " BOE PS 1 HQ NBZ EFDSFBTF */$*7&, QMBTNB DPODFOUSBUJPOT BOE SFEVDF UIF UIFSBQFVUJD FGGFDU PG */$*7&, $P BENJOJTUSBUJPO PG */$*7&, XJUI ESVHT UIBU JOIJCJU $:1 " BOE PS 1 HQ NBZ JODSFBTF */$*7&, QMBTNB DPODFOUSBUJPOT Established and Other Potentially Significant Drug Interactions The table below provides effect of concentration of INCIVEK or concomitant drug with INCIVEK. These recommendations are based on either drug interaction trials (indicated XJUI PS QSFEJDUFE JOUFSBDUJPOT EVF UP UIF FYQFDUFE NBHOJUVEF PG JOUFSBDUJPO BOE QPUFOUJBM GPS TFSJPVT BEWFSTF FWFOUT PS MPTT PG FGGJDBDZ Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction Concomitant Drug Class: Effect on concentration Clinical Comment Drug Name of INCIVEK or Concomitant Drug

calcium channel blockers

â&#x17E;&#x17E;

INCIVEKKTM (telaprevir) Tablets Brief Summary of Prescribing Information. See package insert for full prescribing information.

INDICATIONS AND USAGE Chronic Hepatitis C INCIVEKKTM (telaprevir), in combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis, who are treatment-naĂŻve or who have previously been treated with interferon-based treatment, including prior null responders, partial responders, and relapsers.

The following points should be considered when initiating treatment with INCIVEK: t */$*7&, must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin. t " IJHI QSPQPSUJPO PG QSFWJPVT OVMM SFTQPOEFST QBSUJDVMBSMZ UIPTF XJUI DJSSIPTJT EJE OPU BDIJFWF B 4VTUBJOFE 7JSPMPHJD 3FTQPOTF 473 BOE IBE UFMBQSFWJS SFTJTUBODF associated substitutions emerge on treatment with INCIVEK combination treatment. t * /$*7&, FGGJDBDZ IBT OPU CFFO FTUBCMJTIFE GPS QBUJFOUT XIP IBWF QSFWJPVTMZ GBJMFE UIFSBQZ XJUI B USFBUNFOU SFHJNFO UIBU JODMVEFT */$*7&, PS PUIFS )$7 /4 " QSPUFBTF inhibitors.

CONTRAINDICATIONS Contraindications to peginterferon alfa and ribavirin also apply to INCIVEK combination treatment.

INCIVEK combination treatment is contraindicated in: t XPNFO XIP BSF PS NBZ CFDPNF QSFHOBOU 3JCBWJSJO NBZ DBVTF GFUBM IBSN XIFO BENJOJTUFSFE UP B QSFHOBOU XPNBO *G UIJT ESVH JT VTFE EVSJOH QSFHOBODZ PS JG UIF QBUJFOU becomes pregnant while taking this drug treatment, the patient should be apprised of the potential hazard to a fetus. t NFO XIPTF GFNBMF QBSUOFST BSF QSFHOBOU */$*7&, JT DPOUSBJOEJDBUFE XIFO DPNCJOFE XJUI ESVHT UIBU BSF IJHIMZ EFQFOEFOU PO $:1 " GPS DMFBSBODF BOE GPS XIJDI FMFWBUFE QMBTNB DPODFOUSBUJPOT BSF BTTPDJBUFE XJUI TFSJPVT BOE PS MJGF UISFBUFOJOH FWFOUT OBSSPX UIFSBQFVUJD JOEFY */$*7&, JT DPOUSBJOEJDBUFE XIFO DPNCJOFE XJUI ESVHT UIBU TUSPOHMZ JOEVDF $:1 " BOE UIVT NBZ MFBE UP MPXFS FYQPTVSF BOE MPTT PG FGGJDBDZ PG */$*7&, $POUSBJOEJDBUFE ESVHT BSF MJTUFE CFMPX Drug Class Drugs within Class that are Contraindicated with INCIVEK Clinical Comments

28

H E PAT O L O G Y I N F O C U S

NAFLD Guideline continued from page 1

practice guidelines for NAFLD. In the report, an expert panel representing the American Gastroenterological Association (AGA), the American Association for the Study of Liver Diseases (AASLD) and the American College of Gastroenterology (ACG) made 45 recommendations for clinicians who treat patients with this increasingly common disease.

The panel addressed many of the

Inhaled/Nasal fluticasone budesonide

4ZTUFNJD DPSUJDPTUFSPJET TVDI BT QSFEOJTPOF BOE NFUIZMQSFEOJTPMPOF BSF $:1 " TVCTUSBUFT 4JODF UFMBQSFWJS JT B QPUFOU $:1 " JOIJCJUPS QMBTNB DPODFOUSBUJPOT PG these corticosteroids can be increased significantly. Co-administration of systemic corticosteroids and telaprevir is not recommended.

4ZTUFNJD EFYBNFUIBTPOF JOEVDFT $:1 " BOE DBO UIFSFCZ EFDSFBTF UFMBQSFWJS QMBTNB concentrations. This may result in loss of therapeutic effect of telaprevir. Therefore this combination should be used with caution or alternatives should be considered.

prednisone methylprednisolone

â&#x17E;&#x17E;

Systemic EFYBNFUIBTPOF

Clinical Comment

â&#x17E;&#x17E; â&#x17E;&#x17E;

CORTICOSTEROIDS Systemic prednisone methylprednisolone

Effect on concentration of INCIVEK or Concomitant Drug

telaprevir

fluticasone budesonide

Concomitant use of inhaled fluticasone or budesonide and telaprevir may increase plasma concentrations of fluticasone or budesonide resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone or budesonide and telaprevir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

â&#x17E;&#x17E; â&#x17E;&#x17E;

Concomitant Drug Class: Drug Name

ENDOTHELIN RECEPTOR ANTAGONIST bosentan bosentan â&#x17E;&#x17E;

Concentrations of bosentan may be increased when co-administered with telaprevir.

Caution is warranted and clinical monitoring is recommended.

HIV-ANTIVIRAL AGENTS: HIV-PROTEASE INHIBITORS (PIs) BUB[BOBWJS SJUPOBWJS telaprevir atazanavir

$PODPNJUBOU BENJOJTUSBUJPO PG UFMBQSFWJS BOE BUB[BOBWJS SJUPOBWJS SFTVMUFE JO SFEVDFE TUFBEZ TUBUF UFMBQSFWJS FYQPTVSF XIJMF TUFBEZ TUBUF BUB[BOBWJS FYQPTVSF XBT JODSFBTFE S

â&#x17E;&#x17E;

â&#x17E;&#x17E;

$PODPNJUBOU BENJOJTUSBUJPO PG UFMBQSFWJS BOE EBSVOBWJS SJUPOBWJS SFTVMUFE JO SFEVDFE TUFBEZ TUBUF FYQPTVSFT UP UFMBQSFWJS BOE EBSVOBWJS *U JT OPU SFDPNNFOEFE UP DP BENJOJTUFS EBSVOBWJS SJUPOBWJS BOE UFMBQSFWJS

telaprevir fosamprenavir

$PODPNJUBOU BENJOJTUSBUJPO PG UFMBQSFWJS BOE GPTBNQSFOBWJS SJUPOBWJS SFTVMUFE JO SFEVDFE TUFBEZ TUBUF FYQPTVSFT UP UFMBQSFWJS BOE BNQSFOBWJS *U JT OPU SFDPNNFOEFE UP DP BENJOJTUFS GPTBNQSFOBWJS SJUPOBWJS BOE UFMBQSFWJS

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telaprevir darunavir

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telaprevir lopinavir

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HIV-ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS FGBWJSFO[ telaprevir efavirenz

Concomitant administration of telaprevir and efavirenz resulted in reduced steadyTUBUF FYQPTVSFT UP UFMBQSFWJS BOE FGBWJSFO[

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telaprevir tenofovir

$PODPNJUBOU BENJOJTUSBUJPO PG UFMBQSFWJS BOE UFOPGPWJS EJTPQSPYJM GVNBSBUF SFTVMUFE JO JODSFBTFE UFOPGPWJS FYQPTVSF *ODSFBTFE DMJOJDBM BOE MBCPSBUPSZZ NPOJUPSJOH BSF XBSSBOUFE 5FOPGPWJS EJTPQSPYJM GVNBSBUF TIPVME CF EJTDPOUJOVFE JO QBUJFOUT XIP EFWFMPQ UFOPGPWJS BTTPDJBUFE UPYJDJUJFT

atorvastatin

Plasma concentrations of atorvastatin are markedly increased when co-administered XJUI UFMBQSFWJS "WPJE DPODPNJUBOU BENJOJTUSBUJPO PG UFMBQSFWJSS BOE BUPSWBTUBUJO

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HMG-CoA REDUCTASE INHIBITORS atorvastatin

HORMONAL CONTRACEPTIVES/ESTROGEN FUIJOZM FTUSBEJPM ethinyl estradiol norethindrone norethindrone

&YQPTVSF UP FUIJOZM FTUSBEJPM XBT EFDSFBTFE XIFO DP BENJOJTUFSFE XJUI UFMBQSFWJS Two effective non-hormonal methods of contraception should be used during treatment with telaprevir.

Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency.

â&#x17E;&#x17E;

PDE5 INHIBITORS sildenafil tadalafil vardenafil

salmeterol

Concentrations of salmeterol may be increased when co-administered with telaprevir.

Concurrent administration of salmeterol and telaprevir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

3 NFUIBEPOF

Concentrations of methadone were reduced when co-administered with telaprevir. No adjustment of methadone dose is required when initiating co-administration of UFMBQSFWJS )PXFWFS DMJOJDBM NPOJUPSJOH JT SFDPNNFOEFE BT UIF EPTF PG NFUIBEPOF during maintenance therapy may need to be adjusted in some patients.

PDE5 inhibitors

Concentrations of PDE5 inhibitors may be increased when co-administered with telaprevir. For the treatment of erectile dysfunction, sildenafil at a single dose not FYDFFEJOH NH JO IPVST WBSEFOBGJM BU B TJOHMF EPTF OPU FYDFFEJOH NH EPTF JO IPVST PS UBEBMBGJM BU B TJOHMF EPTF OPU FYDFFEJOH NH EPTF JO IPVST DBO CF used with increased monitoring for PDE5 inhibitor-associated adverse events.

QT interval prolongation has been reported with vardenafil. Caution is warranted and clinical monitoring is recommended.

Co-administration of sildenafil or tadalafil and telaprevir in the treatment of pulmonary arterial hypertension is contraindicated.

â&#x17E;&#x17E; â&#x17E;&#x17E; â&#x17E;&#x17E; â&#x17E;&#x17E;

NARCOTIC ANALGESIC NFUIBEPOF

Plasma concentrations of cyclosporine and tacrolimus are markedly increased when co-administered with telaprevir. Plasma concentration of sirolimus may be increased when co-administered with telaprevir, though this has not been studied. Significant dose reductions and prolongation of the dosing interval of the immunosuppressant to achieve the desired blood levels should be anticipated. Close monitoring of the immunosuppressant blood levels, and frequent assessments of renal function and immunosuppressant-related side effects are recommended when co-administered with telaprevir. Tacrolimus may prolong the QT interval. The use of telaprevir in organ transplant patients has not been studied.

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INHALED BETA AGONIST salmeterol

cyclosporine sirolimus tacrolimus

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IMMUNOSUPPRESSANTS DZDMPTQPSJOF sirolimus UBDSPMJNVT

major questions in the field, including when patients should be screened and when they should undergo liver biopsy, and outlined the evidence supporting diagnostic techniques and interventions, as well as diagnosis and treatment of children with NAFLD. The guidelines were published simultaneously in the June issues of the journals Gastroenterology, Hepatologyy and the American Journal of Gastroenterology.

Senior author Naga Chalasani, MD, professor of medicine and director of the Division of Gastroenterology and

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= no change) indicates the direction of the change in PK.

In addition to the drugs included in the table above, the interaction between INCIVEK and the following drug was evaluated in clinical trials and no dose adjustment is needed for either drug: esomeprazole, raltegravir, or buprenorphine.

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ OCTOBER 2012

Hepatology at Indiana University, in Indianapolis, urged gastroenterologists and hepatologists to read the guideline and â&#x20AC;&#x153;apply it as they deem appropriate for their practice.â&#x20AC;?

Recommendations of the Report The panel opposed routine screening for NAFLD in adults, even those at diabetes or obesity clinics, because of uncertainties surrounding diagnostic tests and treatment options, and a lack of knowledge about long-term benefits and costeffectiveness. They also recommended

against routine screening of family members of patients with known NAFLD. The panel also stressed the importance of ruling out excessive daily alcohol consumption before making a NALFD diagnosis. However, they used a liberal definition of â&#x20AC;&#x153;significant alcohol consumptionâ&#x20AC;?â&#x20AC;&#x201D;at more than 21 drinks, on average, per week for men and more than 14 drinks per week for women.

This recommendation was made on a relatively low level of evidence (2C).

For patients with unsuspected hepatic steatosis detected on imaging, the panel

USE IN SPECIFIC POPULATIONS Pregnancy Because INCIVEK must be used in combination with ribavirin and peginterferon alfa, the contraindications and warnings applicable to those drugs are applicable to combination treatment. Extreme care must be taken to avoid pregnancy in female patients and in female partners off male patients.

INCIVEK/Peginterferon Alfa/Ribavirin Combination Treatment Pregnancy Category X: "OJNBM TUVEJFT IBWF TIPXO UIBU SJCBWJSJO DBVTFT CJSUI EFGFDUT BOE PS GFUBM EFBUIT XIJMF QFHJOUFSGFSPO BMGB JT BCPSUJGBDJFOU 4FF UIF QSFTDSJCJOH information for ribavirin.

4JHOJGJDBOU UFSBUPHFOJD BOE PS FNCSZPDJEBM FGGFDUT IBWF CFFO EFNPOTUSBUFE JO BMM BOJNBM TQFDJFT FYQPTFE UP SJCBWJSJO BOE UIFSFGPSF SJCBWJSJO JT DPOUSBJOEJDBUFE JO XPNFO who are pregnant and in the male partners of women who are pregnant. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans (see peginterferon alfa prescribing information). &YUSFNF DBVUJPO NVTU CF UBLFO UP BWPJE QSFHOBODZ JO GFNBMF QBUJFOUT BOE GFNBMF QBSUOFST PG NBMF QBUJFOUT XIJMF UBLJOH UIJT DPNCJOBUJPO 8PNFO PG DIJMECFBSJOH QPUFOUJBM and their male partners should not receive ribavirin unless they are using effective contraception (two reliable forms) during treatment with ribavirin and for 6 months after treatment. Systemic hormonal contraceptives may not be as effective in women while taking INCIVEK. Therefore, two alternative effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with INCIVEK and concomitant ribavirin.

A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Health care providers and patients are encouraged to report such cases by calling 1-800-593-2214.

INCIVEK (telaprevir) Tablets Pregnancy Category B: 5FMBQSFWJS USFBUNFOU BMPOF JO NJDF BOE SBUT EJE OPU SFTVMU JO IBSN UP UIF GFUVT 5IF IJHIFTU EPTFT UFTUFE QSPEVDFE FYQPTVSFT FRVBM UP BOE GPME UIF FYQPTVSFT JO IVNBOT BU UIF SFDPNNFOEFE DMJOJDBM EPTF SFTQFDUJWFMZ 5FMBQSFWJS USFBUNFOU BMPOF IBE FGGFDUT PO GFSUJMJUZ QBSBNFUFST JO SBUT 5IF OP PCTFSWFE BEWFSTF FGGFDU MFWFM /0"&- GPS UFTUJDVMBS UPYJDJUZ XBT FTUBCMJTIFE BU FYQPTVSFT GPME UIF IVNBO FYQPTVSFT BU UIF SFDPNNFOEFE DMJOJDBM EPTF 1PUFOUJBM FGGFDUT PO TQFSN F H EFDSFBTFE NPUJMF TQFSN BOE JODSFBTFE OPO NPUJMF TQFSN DPVOU XFSF PCTFSWFE JO B SBU GFSUJMJUZ TUVEZ BU FYQPTVSFT GPME UIF IVNBO FYQPTVSFT BU UIF SFDPNNFOEFE DMJOJDBM EPTF "EEJUJPOBM FGGFDUT PO GFSUJMJUZ JODMVEF NJOPS JODSFBTFT JO QFSDFOU QSFJNQMBOUBUJPO MPTT JO QFSDFOU PG EBNT XJUI OPOWJBCMF FNCSZPT BOE QFSDFOU U PG OPOWJBCMF DPODFQUVTFT QFS MJUUFS 5IFTF FGGFDUT BSF MJLFMZ BTTPDJBUFE XJUI UFTUJDVMBS UPYJDJUZ JO NBMF CVU DPOUSJCVUJPOT PGG UIF GFNBMF DBOOPU CF SVMFE PVU 5IFSF BSF IPXFWFS no adequate and well-controlled trials in pregnant women.

4JHOJGJDBOU UFSBUPHFOJD BOE PS FNCSZPDJEBM FGGFDUT IBWF CFFO EFNPOTUSBUFE JO BMM BOJNBM TQFDJFT FYQPTFE UP SJCBWJSJO &YUSFNF DBSF NVTU CF UBLFO UP BWPJE QSFHOBODZ JO female patients and in female partners of male patientsâ&#x20AC;&#x201D;both during treatment and for 6 months after the completion of all treatment. INCIVEK combination treatment should not be started unless a female patient has a negative pregnancy test immediately prior to initiation of treatment. Pregnancy testing should occur monthly during INCIVEK combination treatment and for 6 months after all treatment has ended. Pregnancy testing in non-pregnant female partners is recommended before INCIVEK combination therapy, every month during INCIVEK combination therapy, and for 6 months after ribavirin therapy has ended. )PSNPOBM DPOUSBDFQUJWFT NBZ CF DPOUJOVFE CVU NBZ OPU CF SFMJBCMF EVSJOH */$*7&, EPTJOH BOE GPS VQ UP UXP XFFLT GPMMPXJOH DFTTBUJPO PG */$*7&, %VSJOH UIJT UJNF GFNBMF QBUJFOUT PG DIJMECFBSJOH QPUFOUJBM TIPVME VTF FGGFDUJWF OPO IPSNPOBM NFUIPET PG DPOUSBDFQUJPO &YBNQMFT NBZ JODMVEF CBSSJFS NFUIPET PS *6%T 3FGFS BMTP UP UIF QSFTDSJCJOH information for ribavirin.

Two weeks after completion of INCIVEK treatment, hormonal contraceptives are again appropriate as one of the 2 required effective methods of birth control; however, TQFDJGJD QSFTDSJCJOH JOGPSNBUJPO SFDPNNFOEBUJPOT TIPVME CF GPMMPXFE GPS UIF DPOUSBDFQUJWFT 3FGFS BMTP UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS SJCBWJSJO Nursing Mothers *U JT OPU LOPXO XIFUIFS UFMBQSFWJS JT FYDSFUFE JO IVNBO CSFBTU NJML 8IFO BENJOJTUFSFE UP MBDUBUJOH SBUT MFWFMT PG UFMBQSFWJS XFSF IJHIFS JO NJML DPNQBSFE UP UIPTF PCTFSWFE S JO QMBTNB 3BU PGGTQSJOH FYQPTFE UP UFMBQSFWJS JO VUFSP TIPXFE OP FGGFDUT PO CPEZ XFJHIU BU CJSUI )PXFWFS XIFO GFE WJB NJML GSPN UFMBQSFWJS USFBUFE EBNT CPEZ XFJHIU HBJO PG QVQT XBT MPXFS UIBO QVQT GFE NJML GSPN DPOUSPM EBNT "GUFS XFBOJOH SBU QVQ CPEZ XFJHIU HBJO XBT TJNJMBS JO PGGTQSJOH GSPN UFMBQSFWJS USFBUFE BOE DPOUSPM EBNT #FDBVTF of the potential for adverse reactions in nursing infants, nursing must be discontinued prior to initiation of treatment. See also the prescribing information for ribavirin.

Pediatric Use The safety, efficacy and pharmacokinetic profile of INCIVEK in pediatric patients have not been established.

Geriatric Use Clinical trials of INCIVEK did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, DBVUJPO TIPVME CF FYFSDJTFE JO UIF BENJOJTUSBUJPO BOE NPOJUPSJOH PG */$*7&, JO HFSJBUSJD QBUJFOUT SFGMFDUJOH UIF HSFBUFS GSFRVFODZ PG EFDSFBTFE IFQBUJD GVODUJPO BOE PG concomitant disease or other drug therapy.

Hepatic Impairment INCIVEK is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) because no pharmacokinetic PS TBGFUZ EBUB BSF BWBJMBCMF SFHBSEJOH UIF VTF PG */$*7&, JO )$7 JOGFDUFE QBUJFOUT XJUI NPEFSBUF PS TFWFSF IFQBUJD JNQBJSNFOU BOE BQQSPQSJBUF EPTFT IBWF OPU CFFO FTUBCMJTIFE /P EPTF BEKVTUNFOU PG */$*7&, JT OFDFTTBSZ GPS QBUJFOUT XJUI NJME IFQBUJD JNQBJSNFOU $IJME 1VHI " TDPSF 3FGFS BMTP UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS peginterferon alfa and ribavirin which must be co-administered with INCIVEK. Renal Impairment /P EPTF BEKVTUNFOU JT OFDFTTBSZ GPS */$*7&, JO )$7 JOGFDUFE QBUJFOUT XJUI NJME NPEFSBUF PS TFWFSF SFOBM JNQBJSNFOU */$*7&, IBT OPU CFFO TUVEJFE JO )$7 JOGFDUFE QBUJFOUT XJUI $S$M MFTT UIBO PS FRVBM UP N- QFS NJO 5IF QIBSNBDPLJOFUJDT PG UFMBQSFWJS XFSF BTTFTTFE BGUFS BENJOJTUSBUJPO PG B TJOHMF EPTF PG NH UP )$7 OFHBUJWF TVCKFDUT XJUI TFWFSF SFOBM JNQBJSNFOU $S$M MFTT UIBO øN- QFS NJO */$*7&, IBT OPU CFFO TUVEJFE JO TVCKFDUT XJUI FOE TUBHF SFOBM EJTFBTF &43% PS PO IFNPEJBMZTJT 3FGFS BMTP UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS QFHJOUFSGFSPO alfa and ribavirin which must be co-administered with INCIVEK. Co-infection 5IF TBGFUZ BOE FGGJDBDZ PG */$*7&, IBWF OPU CFFO FTUBCMJTIFE JO QBUJFOUT DP JOGFDUFE XJUI )$7 )*7 PS )$7 )#7 Solid Organ Transplantation The safety and efficacy of INCIVEK have not been established in solid organ transplant patients.

OVERDOSAGE 5IF IJHIFTU EPDVNFOUFE EPTF BENJOJTUFSFE JT NH FWFSZ IPVST GPS EBZT JO IFBMUIZ TVCKFDUT XJUI */$*7&, BMPOF *O UIBU USJBM UIF GPMMPXJOH DPNNPO BEWFSTF FWFOUT XFSF SFQPSUFE NPSF GSFRVFOUMZ XJUI UIF NH R I SFHJNFO DPNQBSFE UP UIF NH R I SFHJNFO OBVTFB IFBEBDIF EJBSSIFB EFDSFBTFE BQQFUJUF EZTHFVTJB BOE vomiting. No specific antidote is available for overdose with INCIVEK. Treatment of overdose with INCIVEK consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. In the event of an overdose, it is reasonable to employ the standard supportive measures, such as, removing unabsorbed material from the gastrointestinal tract, employing clinical monitoring (including obtaining an electrocardiogram), and instituting supportive therapy if required.

It is not known whether telaprevir is dialyzable by peritoneal or hemodialysis.

Manufactured for 7FSUFY 1IBSNBDFVUJDBMT *ODPSQPSBUFE $BNCSJEHF ."

6 4 1BUFOU /P ÂŞ 7FSUFY 1IBSNBDFVUJDBMT *ODPSQPSBUFE "MM SJHIUT SFTFSWFE */$*7&, BOE UIF #MVF "SSPX MPHP BSF USBEFNBSLT PG 7FSUFY 1IBSNBDFVUJDBMT *ODPSQPSBUFE 7&35&9 BOE UIF 7&35&9 USJBOHMF MPHP BSF SFHJTUFSFE USBEFNBSLT PG 7FSUFY 1IBSNBDFVUJDBMT *ODPSQPSBUFE 5IF CSBOET MJTUFE BSF UIF SFHJTUFSFE USBEFNBSLT PG UIFJS SFTQFDUJWF PXOFST BOE BSF OPU USBEFNBSLT PG 7FSUFY 1IBSNBDFVUJDBMT *ODPSQPSBUFE L 79

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

suspected NAFLD, the guidelines recommend that clinicians exclude all competing etiologies for steatosis and coexisting chronic liver disease. A liver biopsy should be considered, when necessary, to rule out competing etiologies.

Additionally, persistently high serum ferritin and increased iron saturation, especially in the context of homozygote or heterozygote C282Y HFE E mutations, may warrant a liver biopsy.

It was premature to recommend serum/plasma CK18 as a biomarker for identifying steatohepatitis, the panel said

and noted that patients with high serum titers of autoantibodies, and other features suggesting autoimmune liver disease, should undergo a more complete workup for this.

Several recommendations for treatment were presented that stressed weight loss and lifestyle interventions as key to the management of steatosis. Treatments aimed at improving liver disease should be limited to patients with nonalcoholic steatohepatitis (NASH), as NAFLD patients without steatohepatitis have an “excellent prognosis from a liver

29

standpoint,” the panel said.

With regard to specific interventions, they found the following: • Weight loss generally reduces hepatic steatosis, and a weight loss of up to 10% may be needed to improve necroinflammation.

• Metformin has no significant effect on liver histology and is not recommended as a specific treatment for liver disease in patients with NASH. • Pioglitazone can be used to treat steatohepatitis in patients with see NAFLD Guideline, page 30

The panel opposed routine screening for NAFLD in adults, even those at diabetes or obesity clinics, because of uncertainties surrounding diagnostic tests and treatment options, and a lack of knowledge about long-term benefits and cost-effectiveness.

For overt HE* patients

OUT OF THE HOSPITAL DOESN’T MEAN OUT OF THE WOODS 75% of patients develop HE recurrences, even on lactulose.1 Protect your patients with Xifaxan 550 mg continuously from the moment they experience their first overt episode.

made several recommendations backed by the highest level of evidence (1A).

They called for patients with symptoms or signs of liver disease or abnormal liver biochemistries to be evaluated as though they have suspected NALFD. Patients with normal liver biochemistries and no symptoms should be assessed for metabolic risk factors and other causes for hepatic steatosis. The panel did not recommend liver biopsies for asymptomatic patients with normal liver biochemistries.

They confirmed liver biopsy as the gold standard for characterizing liver histology in patients with NAFLD. However, they said liver biopsy should be reserved for those who would benefit the most from the information gleaned by biopsy.

Patients with metabolic syndrome or those with suspected NAFLD who are at increased risk for steatohepatitis and advanced fibrosis may be good candidates for liver biopsy, according to the panel.

When evaluating a patient with

58% proven reduction in the risk of overt HE breakthrough2† 50% proven reduction in the risk of HE-related hospitalizations2‡§

Prescribe. Protect. Repeat.

Visit booth 731 at ACG to learn more about protecting your HE patients *HE=hepatic encephalopathy. † Over a 6-month period; P<0.0001 vs placebo.2 ‡ Over a 6-month period; P=0.0129 vs placebo.2 § HE-related hospitalization defined as hospitalization directly caused by HE or a hospitalization during which an HE event occurred.2

IMPORTANT SAFETY INFORMATION 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. XIFAXAN has not been studied in patients with MELD 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. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C).

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.

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.

The most common adverse reactions occurring in >8% of patients in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), ascites (11%), muscle spasms (9%), pruritus (9%), and abdominal pain (9%).

Xifaxan550 is not available for sale outside the U.S. Xifaxan550 is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc. Please see adjacent brief summary of Prescribing Information.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range

References: 1. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):10121017. 2. Xifaxan [prescribing information]. Morrisville, NC: Salix Pharmaceuticals, Inc; 2010.

Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIF 12/16-1

www.Xifaxan550.com

30

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

NAFLD Guideline continued from page 29

biopsy-proven NASH, but its longterm safety and efficacy in patients with NASH is not established.

• Vitamin E administered at a daily dose of 800 IU per day should be considered a first-line pharmacotherapy in nondiabetic adults with biopsyproven NASH; however, without more data supporting its effectiveness, vitamin E is not recommended to treat NASH in diabetic patients,

NAFLD without liver biopsy, NASH cirrhosis or cryptogenic cirrhosis.

• Ursodeoxycholic acid is not recommended for the treatment of NAFLD or NASH. Omega-3 fatty acids may be considered first-line therapy for hypertriglyceridemia in patients with NAFLD but it is premature to recommend Omega-3 for the specific treatment of NAFLD or NASH. • Statins can be used to treat

dyslipidemia in patients with NALFD and NASH but should not be used to treat NASH specifically until randomized controlled trials (RCTs) are conducted.

The panel briefly addressed bariatric surgery, saying most patients who undergo weight loss surgery have associated fatty liver disease. They noted that foregut bariatric surgery is not contraindicated in otherwise eligible obese individuals with

NALFD or NASH but without established cirrhosis. It is premature to consider foregut bariatric surgery as an established option to treat NASH, they said.

The small number of RCTs limits recommendations for treatment options in children, the panel noted. The treatment recommendations for children were similar to adults: Intensive lifestyle modification should be the first-line treatment, metformin offers no benefit and vitamin E offers histologic benefits but confirmatory studies are needed.

‘I think this guideline gives us The following is a brief summary only; see full Prescribing Information for complete product information.

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.

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 2.

(These include adverse events that may be attributable to the underlying disease).

Table 1: Adverse Reactions Occurring in ≥ 5% of Patients Receiving XIFAXAN and at a Higher Incidence Than Placebo

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 End-Stage 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 [[see Warnings and Precautions (5.4), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

CONTRAINDICATIONS 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 [see Adverse Reactions (6.2)].

WARNINGS AND PRECAUTIONS

Travelers’ Diarrhea Not Caused by Escherichia coli 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 difficile-Associated Diarrhea

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.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile 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 confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, 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 benefit 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) [see Use iin Specific Populations (8.7), Nonclinical Toxicology (13.2) and Clinical Studies (14.2)].

ADVERSE REACTIONS Clinical Studies 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.

Hepatic Encephalopathy

The data described below reflect 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

Number (%) of Patients

MedDRA Preferred Term

XIFAXAN Tablets 550 mg TWICE DAILY N = 140

Placebo N = 159

21 (15%) 20 (14%) 18 (13%) 17 (12%) 16 (11%) 13 (9%) 13 (9%) 12 (9%) 11 (8%) 11 (8%) 10 (7%) 10 (7%) 10 (7%) 10 (7%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 7 (5%)

13 (8%) 21 (13%) 13 (8%) 18 (11%) 15 (9%) 11 (7%) 10 (6%) 13 (8%) 12 (8%) 6 (4%) 11 (7%) 8 (5%) 11 (7%) 10 (6%) 8 (5%) 4 (3%) 10 (6%) 10 (6%) 7 (4%) 5 (3%) 6 (4%)

Edema peripheral Nausea Dizziness Fatigue Ascites Muscle spasms Pruritus Abdominal pain Abdominal distension Anemia Cough Depression Insomnia Nasopharyngitis Abdominal pain upper Arthralgia Back pain Constipation Dyspnea Pyrexia Rash

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, influenza 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 identified 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. difficile-associated colitis have been reported [see Warnings and Precautions (5.2)].

General Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration.

expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.

An in vitro study suggested that rifaximin is a substrate of P-glycoprotein. It is unknown whether concomitant drugs that inhibit P-glycoprotein can increase the systemic exposure of rifaximin [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy g y Category g yC

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 benefit justifies 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.

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, 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 sufficient 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 identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

what patients we should be aggressive in evaluating. Until now, there has been limited guidance on the necessity of procedures such as biopsy, given the high prevalence of NAFLD.’ —Eric Kallwitz, MD

The guidelines offer a good summary of the published evidence for NAFLD but, unfortunately, the evidence is limited, said Eric Kallwitz, MD, assistant professor of medicine at Loyola University Medical College, Maywood, Ill. “I think this guideline gives us clearer recommendations on what patients we should be aggressive in evaluating. Until now, there has been limited guidance on the necessity of procedures such as biopsy, given the high prevalence of NAFLD.” He added that he would like to see more information on screening patients’ dietary intake and evidence supporting specific prescription for dietary modifications and exercise requirements.

■

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., AUC␶) 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 [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3), Nonclinical Toxicology (13.2), and Clinical Studies (14.2)].

Manufactured for Salix Pharmaceuticals, Inc., Raleigh, NC 27615, under license from Alfa Wassermann S.p.A. XIFAXAN® is a trademark of Salix Pharmaceuticals, Inc., under license from Alfa Wassermann S.p.A. Copyright © Salix Pharmaceuticals, Inc.

DRUG INTERACTIONS

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 [see Clinical Pharmacology (12.3)]. Rifaximin is not expected to inhibit these enzymes in clinical use.

An in vitro study has suggested that rifaximin induces CYP3A4 [see Clinical Pharmacology (12.3)]. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not

clearer recommendations on

Web site: www.salix.com E-mail: customer.service@salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIF 12/16-1

Authors of the guidelines reported financial relationships involving Abbott Laboratories, Advanced Life Sciences, Amylin, Astellas Pharma, Biolex Therapeutics, Bristol-Myers Squibb, Celgene, Cumberland Pharmaceuticals, Daiichi Sankyo, Eli Lily, Genentech, Geneva Foundation, Gilead, GlaxoSmithKline, Ikaria, Immuron, Intercept, Johnson & Johnson, Karo Bio, Merck & Co., Mochida, Norgine, Pfizer, Quark Pharmaceuticals, Raptor Pharmaceuticals, Roche, Rottapharm, Salix Pharmaceuticals, Sanofi-Aventis, ScheringPlough, Synageva BioPharma, Takeda, Teva Pharmaceuticals, Tibotec and Vertex Pharmaceuticals.

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

31

Promising New Oral Therapy for HCV Enters Phase III Trial Up to 80% of HCV Genotype 1 Patients Achieved SVR; Better Tolerability Than Current Drugs

By Christina Frangou

The SVR rates are among the highest reported in patients for whom earlier treatments failed to eradicate the virus.

San Diego—An investigational oncedaily therapy for hepatitis C virus (HCV) infection, TMC435 (Simeprevir), significantly improved rates of sustained virologic response (SVR) in patients infected with HCV genotype 1 who had prior unsuccessful treatment with pegylated-interferon (Peg-IFN) and ribavirin, according to a Phase II study presented at the 2012 Digestive Disease Week (DDW) meeting (abstract 943f ).

In the trial, between 61% and 80% of patients infected with HCV genotype 1 who had previously failed treatment went on to achieve a SVR after a course of TMC435, given in conjunction with Peg-IFN and ribavirin. The SVR rates are among the highest reported in patients for whom earlier treatments have failed to eradicate the virus.

“Following treatment with TMC435 plus Peg-IFN/ribavirin, patients who failed previous treatment exhibited significantly higher SVR rates, including the difficult-to-treat prior responders with cirrhosis,” said senior investigator Fred Poordad, MD, chief medical officer of Texas Liver Institute/Alamo Medical Research and professor of medicine at the University of Texas, San Antonio, who presented the results of the double-blind, placebo-controlled, multicenter, multinational Phase IIb ASPIRE (A Study to Prevent Infection with a Ring for Extended Use) at the DDW meeting.

TMC435 is an investigational oral therapy that inhibits HCV NS3/4A protease and has been shown to have activity against all HCV genotypes, except genotype 3.

It’s delivered as a single pill that can be taken daily.

In the ASPIRE trial, investigators randomized 462 patients to one of seven treatment arms: TMC435 in 100-mg or 150-mg daily doses for 12, 24 or 48 weeks in combination with 48 weeks of Peg-IFN/ribavirin, or placebo with Peg-IFN/ribavirin for 48 weeks. All patients had chronic HCV genotype 1 infection and had documented evidence of a prior null response to therapy (<2 log10-reduction in HCV RNA by week 12 of treatment), partial response (≥2 log10-reduction in HCV RNA by week 12 of treatment but detectable viral load at the end of treatment) or relapse. One-fifth of patients had Metavir scores of F3 and 18% had scores of F4; 41% of patients had HCV genotype 1a and the remainder had genotype 1b. People co-infected with hepatitis B virus or HIV were excluded from the trial.

Patients who received TMC435 showed significantly higher rapid virologic response (RVR) and SVR rates than patients in the placebo group, with the greatest responses among patients who received the 150-mg dose daily. RVR occurred in 53% to 67% of patients receiving the 100-mg dose and in 62% to 68% of patients in the

TMC435-treated patients were headache, fatigue, influenza-like illness and pruritus.

Lab tests revealed that patients in the ‘I think TMC435 is going to be 100- and 150-mg TMC435 treatment groups had mild, transient asymptomatic a significant advance over bilirubin increases over time. However, the telaprevir and boceprevir, changes were not accompanied by other in part because of the changes in liver parameters. Hemoglobin and neutrophil counts were similar ease of administration.’ between the treatment and control groups.

—Donald M. Jensen, MD TMC435 has now moved into Phase III trials and final results from these trials are expected in January 2013. In these trials, patients are receiving the 150-mg dose with therapy administered for 12 weeks.

Donald M. Jensen, MD, professor of medicine and director of the Center for Liver Diseases at the University of Chicago, said the hepatitis C community has high expectations for TMC435, one of two new protease inhibitors now in Phase III trials.

“I think TMC435 is going to be a significant advance over telaprevir and boceprevir, in part because of the ease of administration. It seems to have fewer side effects and, since it’s a once-daily protease inhibitor, adherence should be better,” said Dr. Jensen.

The strong safety profile is what may set TMC435 apart from the already approved protease inhibitors, said Dr. Poordad.

“The distinguishing featuring is the safety and tolerability profile,” he said.

150-mg group. In comparison, only one patient in the “There is no anemia with this, whereas that appears to placebo group exhibited RVR (1 of 66); the patient had be the weakness with others. In addition, there is no previously responded to Peg-IFN/ribavirin and relapsed. rash, no anorectal symptoms.”

The SVR rates ranged from 61% for patients who Future trials should address whether TMC435 with received 100 mg for 48 weeks to 80% in patients who Peg-IFN/ribavirin is comparable or better than telaprereceived 150 mg for 48 weeks. In the control group, vir with Peg-IFN/ribavirin, Dr. Jensen suggested. They only 23% of patients managed to achieve SVR. Among also should give more information about AEs with the patients who received TMC435, prior relapsers had the new compound. strongest response (77% to 89%), followed by prior parTMC435 also is being tested in Phase II trials in tial responders (48% to 86%). combination with Bristol-Myer Squibb’s investigational Null responders were “perhaps the most difficult to compound daclatasvir (BMS-790052) and with Gilead treat population,” said Dr. Poordad. Between 38% and Sciences’ nucleotide analog GS-7977.

■ 59% of null responders in the treatment group achieved SVR compared with 19% of null responders in the plaDr. Poordad has served as a speaker or a member of a cebo group. speaker’s bureau for Genentech, Gilead Sciences, Merck & In the TMC435 treatment group, 9% to 17% of Co., Onyx Pharmaceuticals, Salix Pharmaceuticals and patients discontinued treatment due to viral breakVertex Pharmaceuticals. He has received research support through or lack of on-treatment response, which was from Abbott Laboratories, Achillion, Anadys Pharmamuch lower than the 53% discontinuation rate among ceuticals, Bristol-Myers Squibb, Boehringer Ingelheim, placebo patients. Additionally, relapses occurred less Genentech, Gilead, Idenix Pharmaceuticals, Janssen/Tioften in the TMC435 group, at 6% to 18% versus 44% botec, Merck & Co., Novartis, Pharmasset, Salix Pharmain the placebo group. ceuticals and Vertex Pharmaceuticals. Dr. Jensen has served The incidence of adverse events (AEs) leading to on advisory boards for Abbott Laboratories, Bristol-Myers treatment discontinuation and serious AEs was similar Squibb, Boehringer-Ingelheim, Genentech, Gilead, Jansen/ across all treatment groups, with little difference between Tibotec, Merck & Co., and Vertex Pharmaceuticals, and the TMC435 and control groups. Serious AEs affected has received research support from Abbott Laboratories, 6% to 10% of the treated patients and 6% of placebo Bristol-Myers Squibb, Boehringer-Ingelheim, Genentech, patients. The most frequently reported AEs among Gilead and Janssen/Tibotec.

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H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

CDC Updates Guidelines for HBV-Infected Health Care Providers

By Victoria Stern The Centers for Disease Control and Prevention (CDC) has issued revised guidelines for managing health care providers and medical students who are infected with hepatitis B virus (HBV).

“The primary goal of this report is to promote patient safety while providing risk management and practice guidance to HBV-infected health care providers and students, particularly those performing exposure-prone procedures such as certain types of surgery,” the CDC wrote in the report (MMWR Recomm Rep 2012;61:1-12).

The new guidelines echo the 1991 CDC recommendations (MMWR Recomm Rep 1991;40:1-9) that HBV infection should not disqualify infected individuals from practicing surgery, dentistry or medicine, while also updating the recommendations in several key ways. Most notably, the CDC no longer advocates that providers or students with HBV inform patients of

their HBV status, because disclosing this information “might actually be counterproductive to public health.”

“In general, I think these recommendations are a first step toward preventing discrimination against HBV-infected health care workers while still protecting patient safety,” said Robert S. Brown Jr., MD, MPH, Frank Cardile Professor of Medicine, chief, Center for Liver Disease and Transplantation, Columbia University College of Physicians and Surgeons, NewYork-Presbyterian Hospital/Columbia University Medical Center, in New York City. “It is clear that HBV-infected health care providers should not be restricted in their ability to practice medicine and surgery, and this is now clearly stated,” said Dr. Brown, who was not involved in creating the new guidelines.

The new guidelines discuss advances in the management of chronic HBV infection, notably that HBV DNA serum levels should be used to monitor infectivity instead of hepatitis B e-antigen status.

They also recommend a threshold serum HBV DNA value of less than 1,000 IU/ mL as safe for practice.

Three main situations in which health care providers would pose a risk to patients are addressed in the guidelines: • Providers with an infectious virus circulating in the bloodstream; • Providers with an injury (a puncture wound) or a condition that permits exposure to infectious fluids; and • Providers whose infectious fluid comes into direct contact with a patient’s wound or exposed tissue.

Most HBV-infected health care workers do not meet these criteria and pose no risk to patients, but those who might meet the criteria (notably providers performing exposure-prone procedures) should be monitored by an expert review panel, according to the report.

“The importance and efficacy of standard precautions and other measures are critical as highlighted in this piece; however, I am concerned that the creation of local expert panels may lead to variability

across facilities and ongoing discrimination in some institutions which is not based on data or clear risk to the patients,” Dr. Brown said.

Specifically, the new guidelines state that this expert panel would evaluate the provider’s HBV status, assess practices and adherence to recommended surgical and dental techniques, and would investigate providers for suspected and documented breaches resulting in patient exposure. The panel also would reinforce the practice of standard precautions, including double gloving, regular glove changes and avoiding the use of blunt surgical needles.

Based on these guidelines, the authors encourage institutions to develop their own policies for identifying and managing HBV-infected health care providers and students.

To view the recommendations, visit www.cdc.gov/mmwr/preview/mmwrhtml/ rr6103a1.htm.

■ Dr. Brown reported no relevant conflicts of interest.

From the Literature

Milk Thistle No Better Than Placebo for Treating Hepatitis C Infection

By Victoria Stern Even at very high doses, the herbal extract milk thistle (silymarin) does not improve disease status or relieve symptoms in patients with chronic hepatitis C virus (HCV) infection, according to a study published in the July 18 issue of the Journal of the American Medical Association (Fried MW et al. 2012;308:274-282).

“Silymarin did not provide greater benefit than placebo for patients with treatment-resistant chronic HCV infection,” wrote lead author Michael W. Fried, MD, professor of medicine and director of hepatology, University of North Carolina, Chapel Hill. Dr. Fried presented preliminary results of the study at The Liver Meeting 2011.

Although up to 33% of patients with chronic HCV infection and cirrhosis have taken silymarin to treat liver disease, previous clinical trials evaluating the drug’s efficacy have yielded conflicting results (Rambaldi A et al. Cochrane Database Syst Revv 2007:CD003620; Jacobs BP et al. Am J Med

2002;113:506-515). The current randomized, double-blind, placebo-controlled study was designed to settle the debate.

Study investigators randomly assigned 154 patients with chronic HCV infection who had failed previous interferon (IFN)-based therapy to receive an approved silymarin preparation (Legalon 140, Rottapharm Madaus) at higher-than-normal doses (420 mg three times daily or 700 mg five times daily) or a placebo capsule five times daily for 24 weeks. Standard doses of silymarin are between 230 and 600 mg per day.

The median age of study participants was 54 years, and most were men (71%). The primary outcome measure was serum alanine aminotransferase (ALT) level of 45 U/L or lower, or a 50% decline in serum ALT level to below 65 U/L after the 24-week treatment period.

The investigators found that overall, only six patients (two in each group) achieved the primary end point. A total of five patients had serum ALT levels less than 45 U/L: one in the placebo group (1.9%), two in the 420-mg silymarin group (4%)

‘Although [this study was] disappointing in its results, further research will help determine the utility of milk thistle in hepatitis C patients.’

—Alan Cutler, MD

and two in the 700-mg silymarin group (3.8%; P=0.80). Additionally, one participant treated with placebo had serum ALT levels reduced by 57% from baseline, achieving levels below 65 U/L. The researchers also found that HCV RNA serum levels remained unchanged during the study.

Adverse events (AEs) did not differ significantly among the treatment groups. The most frequently reported AEs were gastrointestinal symptoms in 12% and 5% of participants receiving silymarin and placebo, respectively. Twelve serious AEs were reported as well: one in the placebo group, six in the 420-mg silymarin group and five in the 700-mg silymarin group.

“The article by Fried et al is a well-designed, randomized, controlled study [in which] the study medication did not achieve significant improvement in biochemical markers of hepatitis C activity,” said Alan Cutler, MD, clinical associate professor of medicine at Wayne State University in Detroit, who was not involved in the study.

“Although [this study was] disappointing in its results, further research will help determine the utility of milk thistle in hepatitis C patients.”

Dr. Fried serves on advisory committees on review panels for GlaxoSmithKline; he serves as a consultant for Abbott Laboratories, Merck & Co., Pharmasset, Roche and Tibotec; he receives research support from, Abbott Laboratories, Anadys Pharmaceuticals, Bristol-Myers Squibb, Merck & Co., Roche, Tibotec and Vertex Pharmaceuticals; and he is a shareholder in Pharmasset. Dr. Cutler has a financial interest in Cass Labs, which markets and distributes EThistle, a combination of milk thistle and vitamin E to support liver wellness.

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34

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

OASIS, an Inner-City, Community-Based HCV Clinic in Oakland, Takes on Tough Cases Unique Program Tackles HCV in Drug Users

At noon every Tuesday, dozens of people pile into Oakland’s OASIS Clinic to sit in on the flagship program of one of the world’s most novel hepatitis C treatment centers.

They come for a weekly support group at OASIS (Organization To Achieve Solutions in Substance abuse), an innercity community-based clinic known for its work in treating hepatitis C virus (HCV) infection in drug users.

OASIS takes a unique approach to hepatitis C treatment. Set in Oakland’s rough Ghost Town neighborhood, the clinic provides free HCV education and treatment to people with substance abuse problems. The center’s treatment strategy revolves around a weekly support group led by former patients. It’s a model of education, testing and treatment that lowers the barrier to engagement in a population with the greatest need and the least access to care for HCV infection.

“When people find out they have HCV, they panic and will race to a place that deals with HCV even though they have far more pressing and lethal problems, like drug use,” said Diana Sylvestre, MD, founder and executive director of OASIS. “That gives us the opportunity to gain their trust, then guide them toward addressing these other more important issues that they had left untouched.”

‘When people find out they have HCV, they panic and will race to a place that deals with HCV even though they have far more pressing and lethal problems, like drug use.’

—Diana Sylvestre, MD Dr. Sylvestre opened the nonprofit clinic in 1998. She had just moved to California after finishing her internal medicine residency at Harvard University, in Boston. At the time, the medical community was beginning to realize that HCV infection was an epidemic among drug users. But few resources were available to help this population.

From the start, OASIS stood out. It was among the first clinics in the country to target medically marginalized, former or current drug and alcohol users, offering

them hepatitis C treatment, regardless of their current addictions.

“OASIS is the only clinic in the Bay Area that not only provides care and treatment services to low-income, uninsured people but actively organizes many of them to become involved in grassroots advocacy around issues that directly affect them,” said Ryan Clary, director of public policy at Project Inform, a San Franciscobased group that works in HIV and hepatitis C advocacy.

All photos: Bill Hackwell

By Christina Frangou

Peer-supported Care OASIS offers free testing and consultation with a physician, and lunch, as part of the weekly support meeting. Some weeks, 10 people come to the meeting. Other times, as many as 50 bodies fill the room.

“To walk into a room and see that many drug addicts focused on their health is almost shocking,” said Larry Galindo, one of the peer educators who leads the support group and the director of volunteers at the center. “It’s amazing to watch these people who were or are drug addicts, some have no high school education, and they sit there and discuss their health with doctors, almost as equals.”

Mr. Galindo has been, in chronological order, a Marine, a heroin addict, a guy who protected drug dealers, a gunshot victim (five times), a prison inmate (20 years) and, then, a hepatitis C patient. He met Dr. Sylvestre more than a decade ago when she tested him for HCV at a local drug treatment center. Soon after, Mr. Galindo started to volunteer at the clinic, sweeping the floors and quietly hanging around the edges of the room as the support group met.

“Eventually, it pulled me in and I was ready to talk,” he said.

Today, Mr. Galindo starts off the weekly support meetings by telling his story. Then, the meeting opens up to everyone. The group discusses everything relating to HCV: difficulties with adhering to hepatitis C treatments, lab reports, HCV genotypes, the effects of interferon (IFN) therapy, and their personal breakdowns and successes.

“It’s very nonjudgmental,” said Orlando Chavez, a 61-year-old former drug user who was diagnosed with hepatitis C in 1999 at a local methadone clinic. “The program is based on your ability to adhere to hepatitis treatment, not your abstinence or lack thereof.”

Mr. Chavez started treatment in 2004 at OASIS and turned his life around.

Diana Sylvestre, MD, founder and executive director of the OASIS Clinic in Oakland, Calif., gives a patient at the clinic some good news.

Patients and volunteers from the OASIS Clinic in Oakland, Calif., rally to educate the community about hepatitis C.

He cleared the infection in 2005 (he was infected with HCV genotype 1 and treated with pegylated-IFN) and now works with a number of hepatitis organizations in California. In 2011, he was recognized by the California Hepatitis Alliance for his service on behalf of those with and at risk for viral hepatitis.

The clinic’s peer-support model has been a key factor in its success.

“I was in a place where people were firm but fair, talked plainly about addiction and didn’t put addicts down. We already get enough of that, mostly from ourselves,” wrote Mr. Galindo in a 2007 article published in the International Journal of Drug Policyy (Galindo L et al.

18:411-416).

Some OASIS patients are struggling to quit using drugs when they show up for the support group, while others are

active users. More than 50% have substance abuse histories that date back more than 20 years.

“That we have a weekly meeting with food helps the most disorganized people to become engaged in the hepatitis C process because they don’t have to remember an appointment. All they have to do is remember Tuesday at noon,” said Dr. Sylvestre. “When they walk in the door, they see a lot of people [with whom] they can identify. They might not trust me, a doctor, so we have the program co-led by peer-educator types who have grown up in the system.”

Dr. Sylvestre said the meetings help her to monitor her patients in a way she could not during a regular one-on-one appointment.

“If you are watching people who are getting depressed or getting manic or

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Patients and volunteers from the OASIS Clinic spread awareness about hepatitis C on World Hepatitis Day.

Dr. Sylvestre discusses test results with a patient.

H E PAT O L O G Y I N F O C U S

visits, he or she was deemed ineligible for treatment.

Results showed that the majority of methadone-maintained drug users stuck with HCV treatment, even those with psychiatric illnesses and relatively limited pretreatment drug abstinence (Sylvestre DL, Clements BJ. Eur J Gastroenterol Hepatoll 2007;19:741-747). The researchers found that lack of pre-HCV treatment drug abstinence and regular drug use during HCV treatment may be “relative barriers to medication adherence” but these barriers often could be overcome.

They suggested that initiation of psychiatric medications during HCV treatment could be a useful intervention.

“It became clear that seeing how they can organize themselves around doing something once a week is a very good proxy for measuring adherence because the people who started on hepatitis C treatment within that project did extremely well,” said Dr. Sylvestre. “Are they ready for it? That’s the outcome that we need to focus on. When they’re using drugs, they can get through the treatment as well as you or I, for the most part, as long as they take their medicines.”

People sometimes need to address their hepatitis before they’re ready to deal with their drug addiction, Dr. Sylvestre said.

“They are still using but they keep showing up. Much to my surprise, people would get through treatment successfully and it would be the first thing that they ever did for themselves. That motivated them, even those with psychiatric illness and relatively limited pretreatment drug abstinence.”

Clinical Research Backs Up Approach something within a setting of a group, for some reason, these things are magnified,” she said. “Not only can I talk to them and get a sense of [the problem], but I can watch them interact with others in the group setting and get a good sense of how they are and how to try to stabilize whatever the problem is in a much more timely fashion than in a regular office visit.”

Adherence and Recovery Studies have shown that injection drug users rarely have access to health care, and often are denied hepatitis C treatment due to concerns about medication adherence (Mehta SH et al. J Community Health 2008;33:126-133).

But that reasoning is unjustified, said Dr. Sylvestre. When her patients elect to have treatment, they can do as well as any patient, and, often, even better because

they’re motivated to quit their addictions, as well as deal with their hepatitis.

“The measures of success are far beyond the measures of success that anyone of us would see with the patients we consider standard of care.”

Dr. Sylvestre said the key is that her patients must commit to adhering to treatment. Active drug users will benefit from HCV treatment as long as they stick to the treatment, her research has showed.

In the mid-2000s, Dr. Sylvestre and colleagues launched a prospective study of active, street-recruited heroin users with hepatitis C. Patients had to come in once a week for buprenorphine for three to six months. If they kept up with the weekly visits, they could then choose to undergo treatment for HCV infection.

But if a patient missed one-fourth of the

Staff at OASIS have led several important studies that address hepatitis C treatment in drug users. They studied 50 methadone-maintenance patients undergoing IFN–ribavirin combination therapy. Results showed that the patients exhibited a number of factors that make HCV treatment more difficult: older age, a higher prevalence of psychiatric illness and more advanced liver disease. However, their end-oftreatment response rate to the combination therapy was similar to that of patients without a history of IV drug use (Sylvestre DL. Drug Alcohol Depend 2002;67:117-123). The clinic staff have worked with the National Institutes on Drug Abuse to develop a model of care for treating people with HCV infection and active drug use and/or major depressive illness, of which the latter

35

two are typically considered contraindications to treatment for HCV infection (Sylvestre DL et al. J Urban Health 2004;81:719-734).

Today, the advent of direct-acting antivirals poses new challenges for the OASIS clinic. These new medications carry an increased risk for drug-resistance that could extend to an entire class of drugs.

‘OASIS is the only clinic in the Bay Area that not only provides care and treatment services to low-income, uninsured people but actively organizes many of them to become involved in grassroots advocacy around issues that directly affect them.’

—Ryan Clary

“We could blow it for the protease inhibitors for the foreseeable future.

Given the fragility of these patients and marginalization of these patients, whether they are going to be able to stick to it, my big concern is that we make sure absolutely that the patients do everything they can take those pills every eight hours,” Dr. Sylvestre said.

“We’ve just spent more time educating them about the importance of adherence, why they have to adhere,” she added.

Her patients practice taking pills every eight hours so they can get accustomed to pattern of adherence before they start treatment.

“So far, the results have been fabulous.

I think we’re doing okay and I think these guys are going to be just fine. But again these are untested waters, and the potential to do harm with not taking these medicines has just grown immensely now.

So we’re just much more careful.”

Dr. Sylvestre’s patients, whom she called the “face of the disease” in a 2011 editorial published in Nature, are not represented in large-scale treatment studies (2011;474:S11). In the article, she called on regulators, pharmaceutical companies and health care workers to include these patients in more clinic trials.

“These new therapies raise the possibility of eradicating hepatitis C,” she said. “But that won’t happen unless the key parties in this medical drama develop a more realistic approach to understanding and treating this disease.”

■

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H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

NASH Set To Surpass Hepatitis C as Primary Indication for Liver Transplantation

By Christina Frangou San Francisco—America’s stretched donor pool and limited resources for liver transplantation will come under further stress in the next decade as nonalcoholic steatohepatitis (NASH) supplants hepatitis C virus (HCV) infection as the primary indication for liver transplant, experts say.

According to a study presented at the 2012 annual meeting of the American Surgical Association, NASH is now the fastest growing indicator for liver transplantation at the University of California, Los Angeles (UCLA), which has one of the country’s largest transplant programs.

In 2002, NASH was the primary indication in about 3% of all liver transplants at UCLA. By 2011, it accounted for 19% of all liver transplants and was the second most common indication for liver transplant at the center, representing a fivefold increase over nine years.

“NASH will soon become the leading indication for liver transplantation in the United States,” said Vatche Agopian, MD, a transplant surgeon at the David Geffen School of Medicine at UCLA. The situation in Los Angeles is similar to that at transplant centers across the country, said John P. Roberts, MD, professor of surgery and chief of transplantation at the University of California, San Francisco.

NASH is rising dramatically in the United States, yet another consequence of the sky-high obesity rates. Populationbased studies suggest that about 12% of Americans may have fat and inflammation present in the liver. At the same time, the epidemic of hepatitis C, which currently accounts for about half of liver transplantations in the United States, appears to have peaked and the numbers are expected to slide downward.

Even at its highest point, hepatitis C affected about 1% of the U.S. population.

The growing prevalence of NASH suggests that a much larger proportion of the population could one day be candidates for liver transplantation, said Dr. Roberts.

“It’s changing very fast. My sense is that you are going to see a big switch in indication for liver transplant from hepatitis C to NASH within the next decades,” said Dr. Roberts. “This is where the future is going and it is has the potential to overwhelm the system. We’re already short of organs now.”

For example, a study presented at The Liver Meeting 2011 from researchers at the University of California, San

Francisco showed that NASH accounts for an increasing proportion of liver transplantations nationally (Brandman D et al. Abstract 12).

The UCLA Experience The UCLA study is the largest, single-institution experience of liver transplantation for NASH. Unlike previous

research, it demonstrates that NASH patients can have outcomes that are comparable to other patients undergoing liver transplantation. Even so, NASH patients place increased demand on hospital ‘NASH will soon become the resources, the study showed.

Between 1997 and 2011, 144 patients leading indication for liver underwent liver transplantation for transplantation in the United States.’

NASH, representing 12% of all liver

—Vatche Agopian, MD

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

‘This is where the future is going it and is has the potential to overwhelm the system. We’re already short of organs now.’

—John P. Roberts, MD

H E PAT O L O G Y I N F O C U S

transplants at UCLA during that time.

Before 2002, only eight patients in total underwent liver transplantation for NASH. Since then, the number has leapt upward annually.

Patients with NASH had more pretransplant comorbidities and higher pretransplant acuity than patients who underwent liver transplants for other causes. Two-thirds of NASH patients had a body mass index (BMI) of 30 kg/ m2 or greater and/or diabetes, 50% of patients had hypertension, and 30% had metabolic syndrome, all significantly

37

higher than in other transplant patients.

NASH patients had an average Model for End-Stage Liver Disease score of 33, 45% were on hemodialysis and 17% were receiving vasopressors.

Analysis showed that patients with NASH required more resources during their surgery and postoperatively. They had significantly longer operative times, reaching a median of 6.9 hours compared with 5.3 hours for other patients (P<0.001); they had greater operative blood loss (18 vs. 14 units of packed red blood cells, P P=0.004) and a longer total hospital length of stay (35 vs. 29 days; P P=0.046).

But long-term, survival of patients with NASH matched those of other transplant recipients. One- and threeyear graft survival reached 80% and 70%, respectively, and one- and threeyear patient survival was 84% and 75%, respectively. The survival rates were similar to those for all other patients undergoing liver transplantation, except for patients with hepatitis C: Patients with hepatitis C infection who received liver transplants had much poorer outcomes: a 62% survival rate and a 57% graft survival rate after three years.

Two factors appear to be important predictors of survival in patients with NASH: Namely, patients who had a BMI greater than 35 kg/m2 and patients requiring pretransplant hemodialysis had worse outcomes after transplantation.

The authors said these factors might help guide the selection of patients who may benefit most from liver transplant.

■

*Hepatic encephalopathy (HE) recurrence can come crashing in at any time—with catastrophic consequences HE recurrence is a constant, unpredictable threat for most patients. Yet, many go without maintenance therapy for their condition. Prescription claims data from 2011 reveal that 64% of outpatients are not taking any HE medication.1 Even for the minority who are on lactulose, 75% still develop recurrences of HE.2 With each recurrence threatening to leave them disoriented, confused, and less alert at any time, the damage can be devastating.

Visit booth 628 at ACG or HEsBack.com to learn more about the October 21st evening premiere of a film about HE from Academy Award–winning documentarian Cynthia Wade.

Questions, comments, suggestions?

Contact the Editor

Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIFHE 12/68-2

212.957.5300 x277 cgordon@mcmahonmed.com

References: 1. Data on file. Salix Pharmaceuticals, Inc, Raleigh, NC. 2. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):1012-1017.

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H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Bariatric Surgery Improves Candidacy for Transplantation In Morbidly Obese Patients With End-Stage Organ Failure

By Christina Frangou San Diego—Obese or overweight adults with end-stage organ failure can safely undergo laparoscopic sleeve gastrectomy, resulting in significant weight loss and improving their candidacy to receive organ transplantation, a new study shows.

Without weight loss, many of these patients would not be considered as candidates for transplantation at some transplant centers.

In a pilot study of 26 obese or overweight liver transplant candidates, all patients safely underwent laparoscopic sleeve gastrectomy. They experienced more nonfatal complications than the regular bariatric patient population, but no deaths within 30 days were reported.

Importantly, all patients lost enough weight to place them in the acceptable body mass index (BMI) threshold for solid organ transplantation.

“Bariatric surgery is technically feasible, even in patients with cirrhosis or portal hypertension,” said study author Matthew Yi-Chih Lin, MD, a fellow in minimally invasive surgery at the University of California, San Francisco (UCSF). “It provides excellent sustained weight loss and improves candidacy for liver transplantation,” added Dr. Lin, who presented the study at the 2012 annual meeting of the American Society for Metabolic and Bariatric Surgery.

At the time the study was reported, eight patients had undergone successful solid organ transplantation: Six patients underwent liver transplants, one patient had a combined liver and kidney transplant and one patient received a kidney transplant. Transplant patients had a mean BMI of 46 kg/m2 prior to bariatric surgery. By the time of transplantation, mean BMI had dropped to 31 kg/m2.

Transplant patients did not experience negative effects from having bariatric surgery. There were no cases of acute rejection, and no patients had difficulty maintaining immunosuppression. All patients maintained weight loss for at least six months after transplantation, despite being immunosuppressed.

When the study was reported, an additional 14 patients were on the transplant list and had lost enough weight to qualify for transplantation at UCSF. This study demonstrates that obese adults who need a transplant have “excellent” treatment options and should not be ruled out as candidates, said Jose Oberholzer, MD, C. & B. Frese and G. Moss

‘There is huge

Nationally, 15% to 20% of

discrimination toward

patients on the transplant

obese patients who are in need of transplantation

list are morbidly obese with a BMI greater than

and … we have to get

35 kg/m2. Many of these

away from this statistical

patients will be denied a

thinking where we refuse

transplant if they cannot

to do transplants on

lose weight.

patients who are obese because we don’t want to report poor outcomes.’

—Jose Oberholzer, MD

Professor of Transplant Surgery, Bioengineering and Endocrinology, and chief of transplantation at the University of Chicago.

“There is huge discrimination toward obese patients who are in need of transplantation and I really think that, as a physician, we have to get away from this statistical thinking where we refuse to do transplants on patients who are obese because we don’t want to report poor outcomes.”

Dr. Oberholzer regularly performs transplants on obese patients and has performed transplants on post-bariatric patients as well. He said adhesions can be problematic after bariatric surgery but this should not deter transplant surgeons from operating on these patients.

Nationally, 15% to 20% of patients on the transplant list are morbidly obese with a BMI greater than 35 kg/m2. Many of these patients will be denied a transplant if they cannot lose weight.

At UCSF, all patients who undergo liver transplantation must have a BMI less than 40 kg/m2; those who undergo kidney transplantation must have a BMI less than 38 kg/m2; and diabetic patients needing a kidney transplant must have a

BMI less than 34 kg/m2.

It is hoped that bariatric surgery will enable more obese or overweight patients to undergo transplantation, Dr. Lin said.

Pre-transplant bariatric surgery is a good option for patients who are languishing on the wait list and are likely to wait five to seven years for an organ, added Dr. Oberholzer.

But for many of those patients, bariatric surgery is not an option, particularly patients with kidney disease. They may be too sick to undergo bariatric surgery, or could die undergoing dialysis in the year or two after bariatric surgery while they are losing weight. Only 50% of dialysis patients are still alive three years after the start of therapy for end-stage renal disease, according to figures from the United States Renal Data System.

“If it takes, that means you are going to tell the patient that he has probably— depending on how you do the math and other risk factors—only a 60% to 70% chance to be alive when he has lost the weight, two years after bariatric surgery, but is still undergoing dialysis,” said Dr. Oberholzer.

An obese patient with renal disease would have better odds for survival if

he or she has a living donor transplant as soon as possible and has a minimally invasive transplant.

The UCSF Experience In this study, the investigators set out to test the hypothesis that laparoscopic sleeve gastrectomy can be safely performed in high-risk patients with liver or kidney failure. It is the first study to examine laparoscopic sleeve gastrectomy in a transplant population.

Investigators chose sleeve gastrectomy because they wanted to avoid the foreign-body implantation of a gastric band.

Unlike gastric bypass, the sleeve gastrectomy allows surgeons to maintain access to the biliary system and has reduced surgical complexity.

The study group consisted of six patients with end-stage kidney disease (including five patients requiring dialysis) and 20 patients with severely compromised liver function and a mean Model for End-Stage Liver Disease score of 11.

Patients had an average BMI of 48.3 kg/ m2 before bariatric surgery and needed a kidney or liver transplant or both. Mean age was 57 years.

Twenty-six percent of patients developed complications, a rate on the upper end of the range for complications. Previous studies reported complication rates ranging from 0 to 24%.

Six patients developed complications within 30 days of bariatric surgery. Two patients had superficial wound infections that required antibiotics and one patient developed transient encephalopathy, required admission to the ICU and eventually recovered. Another patient was admitted to the ICU as a precaution after a rise in creatinine levels. One patient developed postoperative bleeding and required blood transfusion, and another was diagnosed with a staple-line leak.

Two patients died while waiting for an organ and another patient died of progressive liver failure four years after bariatric surgery. All deaths occurred more than 30 days after surgery.

The study cohort lost weight at a rate similar to that reported for a standard bariatric procedure. After surgery, the patients lost 17% of excess weight by one month, 26% by three months, 50% at 12 months and 66% at 24 months.

“This study suggests sleeve gastrectomy may be performed safely in carefully selected morbidly obese patients with impending organ failure, and the significant weight loss they achieve may make them more suitable candidates for transplantation,” Dr. Lin concluded. ■

In combination with a proton pump inhibitor (PPI), for the treatment of adults with exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis or pancreatectomy When an uncoated pancreatic enzyme is your choice for your patients, VIOKACE™ is now available.

Uncover it Again.

For more information about VIOKACE, please visit www.VIOKACE.com

Important Safety Information t Fibrosing colonopathy is associated with high--dose use of pancreatic enzyme replacement. Exercise caution n when doses of VIOKACE exceed 2,500 lipase units/kg of bo ody weight per meal (or greater than 10 ody 10,000 000 lipase units/kg of b body weight per day) t To avoid irritation of oral mucosa, do not chew w VIOKACE or retain in the mouth t Exercise caution when prescribing VIOKACE to o patients with gout, renal impairment, or hyperuricemia t There is theoretical risk of viral transmission with all pancreatic enzyme products including VIOKACE t In rare cases, patients taking pancreatic enzym me products with different formulations of the same active ingredient (pancrelipase) have experienced severe allergic reactions including anaphylaxis, asthma, hives, and pruritus.

Exercise caution when administering pancrelipase pase to a patient with a known allergy to proteins of porcine o origin t VIOKACE tablets contain lactose monohydrate. Patients who have lactose intolerance may not be able to tolerate VIOKACE t Adverse reactions occurring in at least 2 chronic pancreatitis or pancreatectomy patients (greater than or equal to 7%) receiving VIOKACE are biliary tract stones and anal pruritus t The safety and effectiveness of VIOKACE in pediatric patients have not been established.

VIOKACE use in pediatric patients may result in suboptimal growth due to tablet degradation in the gastric environment. In general, delayed release (enteric-coated) capsules should be used for pediatric patients t VIOKACE is not interchangeable with any other pancrelipase product

VIOKACE on the following page.

© 2012 Aptalis Pharma US, Inc., Birmingham, AL. All rights reserved. Printed in USA. VI036-0512b

40

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

New Ablative Procedures Promising for Risky, Untreatable Tumors Two New Modalities Tested on Tumors of the Liver and Pancreas

By David Wild Chicago—Two emerging ablative technologies hold promise for treating tumors that are too risky to ablate with existing technologies, experts told attendees of the 2012 World Conference on Interventional Oncology (WCIO).

These new technologies—irreversible electroporation (IRE) and imageguided high-intensity focused ultrasound (HIFU)—were discussed as potential options for ablating tumors located in close proximity to critical structures and blood vessels, but experts noted that their exact place in the treatment armamentarium remains unknown because of a paucity of data.

VIOKACETM (pancrelipase) tablets, for oral use Brief Summary of Prescribing Information for VIOKACE (pancrelipase). See package insert for full prescribing information.

INDICATIONS AND USAGE VIOKACE (pancrelipase) is a combination of porcine-derived lipases, proteases, and amylases. VIOKACE, in combination with a proton pump inhibitor, is indicated in adults for the treatment of exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Fibrosing Colonopathy: Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products. Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in children less than 12 years of age. Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs. It is generally recommended, unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g fat ingested per day [see Dosage and Administration (2.2) in full prescribing information].]

Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.

Potential for Irritation to Oral Mucosa: Care should be taken to ensure that no drug is retained in the mouth to avoid irritation of oral mucosa, and/or loss of enzyme activity.

VIOKACE should not be crushed or chewed [see Dosage and Administration (2.1) and Patient Counseling Information (17.1) in full prescribing information].]

Potential for Risk of Hyperuricemia: Caution should be exercised when prescribing VIOKACE to patients with gout, renal impairment, or hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.

Potential for Viral Exposure from the Product Source: VIOKACE is sourced from pancreatic tissue from pigs used for food consumption. Although the risk that VIOKACE will transmit an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported.

Allergic Reactions: Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase). The risks and benefits of continued VIOKACE treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient.

Potential for Exacerbation of Symptoms of Lactose Intolerance: VIOKACE tablets contain lactose monohydrate. Patients who have lactose intolerance may not be able to tolerate VIOKACE. ADVERSE REACTIONS The most serious adverse reactions reported with different pancreatic enzyme products of the same active ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and allergic reactions [see Warnings and Precautions].]

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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The short-term safety of VIOKACE was assessed in a single, multicenter, randomized, parallel, placebo-controlled, double-blind study of 50 patients, ages 24-70 years, with exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis or pancreatectomy. VIOKACE Tablets (20,880 USP units of lipase per tablet) or placebo were administered as 22 tablets per day (6 tablets with 3 meals and 2 tablets with 2 of 3 snacks). Duration of exposure ranged from 6 to 7 days. The majority of the subjects were Caucasian (96%) and male (82%).

The most common adverse reactions (greater than or equal to 7%) were biliary tract stones and anal pruritus. Table 1 enumerates adverse reactions that occurred in at least 1 patient (greater than or equal to 3%) treated with VIOKACE at a higher rate than with placebo. Two adverse reactions reported in greater than one patient were biliary tract stones and anal pruritus.

TABLE 1 Adverse Reactions Occurring in at Least 1 Patient (greater than or equal to 3%) in Chronic Pancreatitis or Pancreatectomy MedDRA Primary System Organ Class/ Adverse Reactions Blood And Lymphatic System Disorders Anemia Gastrointestinal Disorders Anal pruritus Abdominal pain Ascites Flatulence

Treatment Group VIOKACE Placebo (N=30) (N=20) 1 ( 3%)

0

2 ( 7%) 1 ( 3%) 1 ( 3%) 1 ( 3%)

0 0 0 0

“These are very interesting technologies that may have applications in selected patients,” said Eileen O’Reilly, MD, associate member of the GI oncology medical service at Memorial Sloan-Kettering Cancer Center and associate professor of medicine at Weill Cornell Medical College, both in New York City.

Dr. O’Reilly said that IRE has been used at her institution to ablate tumors

TABLE 1 Adverse Reactions Occurring in at Least 1 Patient (greater than or equal to 3%) in Chronic Pancreatitis or Pancreatectomy (continued) General Disorders and Administration Site Conditions Edema peripheral 1 ( 3%) 0 Hepatobiliary Disorders Biliary tract stones 2 ( 7%) 0 Hydrocholecystis 1 ( 3%) 0 Infections and Infestations Viral infection 1 ( 3%) 0 Nervous System Disorders Headache 1 ( 3%) 0 Renal and Urinary Disorders Renal cyst 1 ( 3%) 0 Skin and Subcutaneous Tissue Disorders Rash 1 ( 3%) 0 Postmarketing Experience: Post-marketing data for VIOKACE have been available since 2003. The safety data are similar to that described below. 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.

Pancreatic enzyme products (delayed and immediate-release) with different formulations of the same active ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has been described in the medical literature. The most serious adverse events included fibrosing colonopathy, distal intestinal obstruction syndrome (DIOS), recurrence of pre-existing carcinoma, and severe allergic reactions including anaphylaxis, asthma, hives, and pruritus. The most commonly reported adverse events were gastrointestinal disorders, including abdominal pain, diarrhea, flatulence, constipation and nausea, and skin disorders including pruritus, urticaria and rash.

DRUG INTERACTIONS No drug interactions have been identified. No formal interaction studies have been conducted.

USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic g effects: Pregnancy Category C. Animal reproduction studies have not been conducted with pancrelipase. It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. VIOKACE should be given to a pregnant woman only if clearly needed. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes.

Nursing Mothers: It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when VIOKACE is administered to a nursing woman. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency.

Pediatric Use: The safety and effectiveness of VIOKACE in pediatric patients have not been established. In general, delayed-release (enteric-coated) capsules should be used for pediatric patients. Due to greater degradation in the gastric environment, VIOKACE, a non-enteric-coated, pancreatic enzyme replacement product, may have decreased bioavailability and therefore may be less efficacious than enteric-coated formulations. Thus, use of VIOKACE in pediatric patients may increase the risk of inadequate treatment of pancreatic insufficiency and result in suboptimal weight gain, malnutrition and/or need for larger doses of pancreatic enzyme replacement [See Warnings and Precautions]. ] The efficacy of VIOKACE was established in adult patients with concomitant proton pump inhibitor (PPI) therapy. The long-term safety of PPI use in pediatric patients has not been established.

Geriatric Use: Clinical studies of VIOKACE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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 concomitant disease or other drug therapy.

OVERDOSAGE There have been no reports of overdose in clinical trials or post-marketing surveillance with VIOKACE. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures [see Dosage and Administration (2) in full prescribing information and Warnings and Precautions].] High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment [see Warnings and Precautions].]

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase.

Marketed by: Aptalis Pharma US, Inc 22 Inverness Center Parkway Birmingham, AL 35242 USA Manufactured by: Confab Laboratories, Inc. St. Hubert, Canada VIOKACE and APTALIS are trademarks. © 2012 APTALIS PHARMA US, INC.

close to blood vessels and the biliary tract in selected patients and has proven safe. However, outcomes data for both IRE and HIFU, the latter of which has not received FDA approval for use, are lacking.

“Given that the field of ablative technologies is crowded and reported experience with these two technologies is relatively limited, further prospective study is needed to determine where they might fit,” she said.

IRE for Metastatic Liver Tumors According to Govindarajan Narayanan, MD, chief of vascular and interventional radiology at the University of Miami’s Miller School of Medicine, the strength of IRE is that, unlike radiofrequency ablation (RFA), microwave ablation (MWA) and cryoablation, it is a non-thermal technology. Instead, it uses high-level electrical pulses to damage cell membranes and induce apoptosis.

“Since it does not emit heat, IRE is safer than thermal ablation when used in close proximity to critical structures like bile ducts and blood vessels,” Dr. Narayanan said.

IRE treatment led to few bile duct complications, including a 5% incidence of mild biliary dilatation, but no instances of strictures, stenoses, leaks or fistulas, in a retrospective review of 76 patients with 114 primary and metastatic liver tumors (WCIO paper 35).

Similarly low rates of complications were reported by Riccardo Lencioni, MD, professor and director of diagnostic imaging and intervention at Pisa University School of Medicine, in Italy, and colleagues at several European centers.

In 26 patients with 29 early-stage, unresectable hepatocellular carcinomas, major complications with IRE included one punctured intercostal artery and one case of transient hepatic decompensation that resolved without treatment (WCIO paper 9). Complete response occurred in 77% of patients and 79% of tumors.

“IRE appears to be safe and effective and could potentially be a very promising new tool for image-guided ablation of solid tumors,” Dr. Lencioni said. “Of course, these early findings are just the first step, and research is ongoing.”

IRE for Pancreatic Cancer Perhaps most exciting is the potential for IRE to manage unresectable, locally advanced pancreatic cancer, Dr. Lencioni said.

“Thermal ablation has been out of the question for treating pancreatic cancer

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

because of the potential of damage to structures in the pancreatic area,” Dr. Lencioni said. “But our very early clinical experience suggests IRE can be conducted in these patients.”

Dr. Narayanan’s own unpublished anecdotal experience using IRE in 15 patients with pancreatic cancer, including seven tumors located in the pancreatic head, confirmed the safety of the technology when used near adjacent critical structures. Treatment was associated with minor complications, such as a hematoma, pneumothorax post-intubation and a single case of post-procedure pancreatitis.

Despite the enthusiasm surrounding IRE, “there are lots of challenges with the procedure,” Dr. Narayanan said.

The treatment involves placing multiple needles in parallel around the tumor in order to administer sufficient levels of electrical pulses, and its complexity translates into a steep learning curve. Moreover, the placement of multiple needles means tumor access is critical.

“In the pancreatic cancer population, we’ve aborted more IRE procedures than with other patient groups because patient characteristics or cancer stage changed between work-up and treatment to include multiple new areas of metastasis or because access to the lesion was considered to be unsafe,” Dr. Narayanan said.

“I don’t see IRE as a replacement for existing treatments, but rather as a potential treatment for previously untreatable tumors,” Dr. Lencioni remarked, noting the procedure is also more expensive than other ablative techniques.

“Image-guided thermal ablation has shown excellent results in a range of cancers, so IRE will likely be used only for those cancers where these approaches have proven less successful. However, if emerging study results suggest an added benefit with IRE, even in conventionally treatable tumors, it could begin to play an increasingly important role.”

HIFU for Pancreatic Cancer Another technology touted at the meeting for its ability to treat tumors deemed unablatable with conventional technology is HIFU. This modality uses highly focused, high-temperature ultrasonic waves to coagulate target tissue.

According to Franco Orsi, MD, director of the unit of interventional radiology at the European Institute of Oncology, in Milan, HIFU is more precise than RFA, MWA or cryoablation.

“The treatment zone with every other ablative modality is limited by the fixed location of the delivery instrument, whereas with HIFU, because it is so focused, you can shape your ablation

zone,” said Dr. Orsi, who reviewed existing data on HIFU at the WCIO. Cumulative data from nearly 200 HIFU-treated patients with pancreatic cancer showed HIFU significantly decreased pain, led to a partial tumor response in approximately 15% of patients and stopped tumor progression in 57% of patients, although none experienced complete response (Al-Bataineh O et al. Cancer Treat Rev 2012;38:346353). HIFU also has been tested in the

treatment of prostate, breast, uterine, liver, kidney, bone and brain tumors, Dr. Orsi said.

Dr. O’Reilly said outcomes data are needed to demonstrate whether the benefits of HIFU outweigh the risk for adverse events and to identify what incremental benefits HIFU may add over other conventional treatments.

“Moreover, I am concerned about complications of HIFU, given that skin burns and fistulae have been reported in

the limited literature that is available,” she said. “It is likely there is a learning curve with this technology, but that remains to be determined.”

For both new technologies, Dr. O’Reilly said, “Until randomized, controlled studies are conducted, it will remain unclear what their benefits truly are.”

■ Dr. Narayanan is a consultant for AngioDynamics. Drs. O’Reilly, Lencioni and Orsi reported no conflicts of interest.

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H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Combination of Interventional and Medical Therapies For Hepatic Tumors May Bolster Efficacy of Each Positive Data From Early Studies Warrant Further Research

By David Wild Chicago—The pairing of interventional treatments, like ablation and radioembolization, with medical treatments, such as liposomal doxorubicin or sorafenib, is being explored for the ability to lower post-ablation and post-transplant hepatocellular carcinoma (HCC) recurrence rates, and possibly improve the tumor downstaging potential of local ablation. This was a topic of discussion at the recent 2012 World Conference on Interventional Oncology (WCIO) and is the subject of several past and ongoing studies.

“Combination minimally invasive interventions and adjuvant chemotherapy will become the next cutting edge of interventional oncologic treatment,” said Nahum Goldberg, MD, professor and vice-chairman for research in the Department of Radiology at Hadassah Hebrew University Medical Center, in Jerusalem, in a presentation at the meeting.

“Interventional oncologists and medical oncologists will be working very closely in the future to optimize the therapeutic options for patients with focal liver, lung, renal and bone tumors.”

RFA Plus Liposomal Doxorubicin Dr. Goldberg’s confident prediction is based on results from a small but growing body of research, including his own, examining several interventional–medical therapeutic combinations. His group has focused efforts on studying the physiologic and clinical effects of liposomal doxorubicin administered in conjunction with radiofrequency ablation (RFA) for the treatment of HCC and other liver tumors measuring 3 to 8 cm.

A 2002 pilot study including 10 patients with 14 focal hepatic tumors, authored by Dr. Goldberg, showed that the use of the heat-sensitive drug prior to RFA significantly increased the volume of tumor destroyed compared with either RFA or liposomal doxorubicin alone (Goldberg SN et al. AJR Am J Roentgenol 2002;179:93-101).

“Normally, we see a zone of partially necrotic or inflamed tissue around the core ablation zone when using RFA alone,” Dr. Goldberg explained. “However, by adding certain adjuvant treatments, we can increase the necrotic zone by either amplifying RF-induced apoptosis or reducing heat shock protein production.”

The synergistic effect of RFA and liposomal nanodrugs runs both ways, Dr. Goldberg said.

“Ablation can more than triple intratumoral drug uptake by inducing leaky vessels at the periphery of the ablation zone, while liposomal doxorubicin can widen the coagulation zone,” he explained.

The addition of a second drug may confer even greater benefits, suggests research in rats implanted with mammary adenocarcinomas and treated with RFA, liposomal doxorubicin, liposomal paclitaxel or a combination of the three (Yang W et al. Radiology 2010;257:685696). Those results showed that animals administered triple therapy had higher volumes of coagulated tissue and longer survival than those given dual- or single-modality therapy. Clinical studies using this approach in humans are being planned, Dr. Goldberg said.

The combination approach is promising but much more investigation is required before it can be said to improve outcomes, Dr. Goldberg noted.

“The topic requires patient recruitment in large multicenter trials with a long-term follow-up,” he said.

Chemoembolization Plus Sorafenib Keith Stuart, MD, professor of medicine at Tufts University School of Medicine and chairman of the Department of Hematology and Oncology at the Lahey Clinic Medical Center, both in Burlington, Mass., agreed. In an interview with Gastroenterology & Endoscopy News, he commented that physiologic data demonstrating the additive effect of combination treatment is compelling, but the most clinically relevant questions still need to be addressed.

“This combined approach needs to be evaluated to see whether it affects overall recurrence and, most importantly, overall survival,” Dr. Stuart said. “If it proves to be as effective a treatment as chemoembolization or radioembolization for tumors larger than 5 cm, we may be able to use it as an alternative [therapy] and spare some of our patients the side effects associated with those treatments.”

Dr. Stuart’s involvement in a large, multicenter placebo-controlled trial sponsored by the National Cancer Institute, investigating a chemoembolization–drug combination for unresectable HCC without vascular invasion, reflects the growing interest in this combined approach. That study (CTSU E1208)

is examining chemoembolization using drug-eluting doxorubicin beads along with systemic sorafenib.

“Over the past few years, the emergence of sorafenib as a reasonably effective systemic therapy has renewed interest in finding a more effective combination of local and systemic therapies for HCC patients, and this has required ever closer collaboration between interventionalists and medical oncologists,” Dr. Stuart said.

‘Combination minimally invasive interventions and

Radioembolization Plus Sorafenib

adjuvant chemotherapy will

Sorafenib is also being studied for its potential to improve the tumor downstaging capacity of yttrium-90 (Y-90) radioembolization and to reduce posttransplant recurrence of HCC. Lead investigator Laura Kulik, MD, who also spoke at the WCIO, explained the reasoning behind combining the two treatments.

“The rationale for adding sorafenib to Y-90 is that while the latter can downstage patients to the point of transplant candidacy, it also upregulates expression of vascular endothelial growth factor and increases angiogenesis, potentially increasing the risk of post-transplant recurrence,” said Dr. Kulik, who is associate professor of gastroenterology and hepatology, and also of radiology and surgery–organ transplantation at Northwestern University’s Feinberg School of Medicine, in Chicago. “The addition of sorafenib, with its anti-angiogenic effects, may counteract this.”

A proof-of-concept study is in its early stages and 19 patients have been recruited to date. The study’s primary outcomes will focus on the effects of combination treatment on angiogenic tumor parameters instead of clinical outcomes.

Sorafenib-related adverse events have been a barrier to treatment completion in some patients, Dr. Kulik noted, with dermatologic events and fatigue leading to dose reductions in several patients, with some patients withdrawing from the study.

“If findings from this study are positive, further clinical research would be warranted,” Dr. Kulik said.

become the next cutting

TACE Plus Sorafenib Two trials examining the combination of transarterial chemoembolization (TACE) and sorafenib for intermediatestage HCC have “not shown a beneficial effect of combined treatment compared to sorafenib alone,” according to Richard Kim, MD, assistant professor of oncology

edge of interventional oncologic treatment.’

—Nahum Goldberg, MD at H. Lee Moffitt Cancer Center, in Tampa, Fla., who published an article in 2011 reviewing the data on combination interventional–chemotherapeutic approaches (Oncology [Williston Park] 2011;25:283-291, 295).

“The pre-clinical rationale for adding sorafenib to radioembolization or chemoembolization are strong but findings from two randomized studies have not demonstrated a significant clinical benefit,” Dr. Kim noted.

One Phase III trial presented at the 2010 American Society of Clinical Oncology (ASCO) annual meeting (abstract LBA128; Okita K et al) compared TACE with sorafenib or a placebo and did not meet its clinical end points.

Another study, the SPACE (Sorafenib or Placebo in Combination With Transarterial Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma) trial, presented at the 2012 ASCO annual meeting (abstract LBA154; Lencioni R et al) produced statistically significant but clinically negligible delays in radiologic tumor progression.

“The results of SPACE haven’t changed our practice patterns, and results from ongoing trials need to demonstrate a significant overall derived benefit before we can draw any firm conclusions about the efficacy of an ablation–medication combination either way,” he said.

■ Dr. Goldberg is a consultant for AngioDynamics on irreversible electroporation devices. Dr. Stuart reported no conflicts of interest. Dr. Kulik has been a speaker for Bayer/Onyx and Nordion. Dr. Kim has received an honorarium from Bayer Pharmaceuticals for an advisory board meeting.

1

WITH LOWER DOSE

EFFICACY YOU EXPECT1

HalfLytely and Bisacodyl Tablet Bowel Prep Kit is a combination of PEG-3350, an osmotic laxative and bisacodyl, a stimulant laxative, indicated for cleansing of the colon as a preparation for colonoscopy in adults.

Most common adverse reactions (>3%) are overall discomfort, abdominal fullness, abdominal cramping, nausea, and vomiting. There have been reports of ischemic colitis in patients with use of HalfLytely and 10 mg or 20 mg Bisacodyl Tablets Bowel Prep Kit. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus.

Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reďŹ&#x201A;ex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. 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.

Please see brief summary of Prescribing Information on adjacent page.

44

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Managing Patients on Blood Thinners Undergoing Endoscopy Is a Balancing Act for Physicians Endoscopists Must Weigh Risk for GI Bleeding, Risk for CV Event

By Monica J. Smith Despite the frequent use of blood thinners in the general population, most of the data regarding the management of these drugs in patients undergoing

endoscopy is based on expert opinion— determining the safest scenario requires patient individualization and excellent clinical judgment.

“The risk is gastrointestinal (GI) bleeding if you continue antiplatelet/ anticoagulant therapy through your

procedure versus the risk for a cardiovascular [CV] or cerebrovascular event if you stop the [drug],” said David Greenwald, MD, of Montefiore Medical Center, New York City, who spoke on the subject at last year’s New York Society for Gastrointestinal Endoscopy annual course.

EFFFICACY YOU EXPECT1

WITH WIT TH LO OWER R DOSE1

• LLowest volume phosphate-free lavage1,2 •N No oral sodium phosphate

Referennces: 1. HalfLytely® andd Bisacodyl Tablet Boweel Prep Kit [ppackage inseert]. Braintreee, MA: Brainntree Laboraatories, Inc; 2010. 2. See package inserts: GoLYTELYY®(PEG-3350 and Elecctrolytes forr Oral Solutioon), 2001; NuLYTELYY® (PEG-3350, Sodium Chlooride, Sodiuum Bicarbonate and Potaassium Chloride for Oral Solution), 2008. Braintree, MA: Braintree PEG-3350, 3350 Sodium Sulfate Sulfate, Sodium m Chloride, Chloride Potassium Chloride, Chloride Soodium Ascorrbate and Ascorbic Acid for Oral Solution), 2006; Morrisville, NC: Laborattories, ories Inc.; Inc ; MoviPrep® ( PEG Salix Phharmaceuticcals, Inc.

Brieff Summ mary: Before prescribing, please see fulll Prescribing Information and Medication Guide for HalfLytely HalfL Lytely aand nd Bisa Bisacodyl acodyl TTablet ablet Bowel Bowel Prep Prep Kit. Kitt INDIC INDICATIONS CATION NS AND USAGE: Combination of PEG-3350, an osmotic laxative and bisacodyl, a stimulant 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. WARNINGS AND PRECAUTIONS: HalfLytely and Bisacodyl Tablet Bowel Prep Kit is a combination of PEG-3350, an osmotic laxative and bisacodyl, a stimulant laxative, indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>3%) are overall discomfort, abdominal fullness, abdominal cramping, nausea, and vomiting. There have been reports of ischemic colitis in patients with use of HalfLytely and 10 mg or 20 mg Bisacodyl Tablets Bowel Prep Kit. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. 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. 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 148 patients who took HalfLytely and 5 mg Bisacodyl Tablet Bowel Prep Kit in clinical trials, 42 (28%) were 65 years of age or older, while 10 (7%) were 75 years of age or older. The rates of success appear to be lower in patients 65 years and older. DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of HalfLytely may not be absorbed completely. Do not take the bisacodyl delayed-release tablet within one hour of taking an antacid. ADVERSE REACTIONS: Most common adverse reactions (>3%) are overall discomfort, abdominal fullness, abdominal cramping, nausea, and vomiting. Oral Administration: Take one 5 mg bisacodyl tablet with water. Do NOT chew or crush. Dissolve the HalfLytely powder in 2 liters of water. Wait for a bowel movement (or maximum of 6 hours) then drink all the HalfLytely solution at a rate of 8 ounces every 10 minutes. Consume only clear liquids until the colonoscopy. STORAGE: Store at 20-25°C (68-77°F).

Excursions permitted between 15-30°C (59-86°F). The reconstituted solution, may be refrigerated, use within 48 hours. Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit us at www.halfl flytely.com ©2011 Braintree Laboratories, Inc.

HL-12437T

January, 2011

“The important point is that GI bleeding is something we can often see at the time of the endoscopy when we have that complication, and it’s usually readily treatable; CV events, including myocardial infarctions and strokes, are often devastating and can be fatal.”

The use of blood thinners is quite common; about 25% of the population uses aspirin or a nonsteroidal antiinflammatory drug (NSAID) regularly.

But the frequency of their use should not belie their potential risks. A recent report showed that blood thinners are one of the two drug categories that most commonly result in adverse events leading to emergency room visits and hospitalization in older adults; the other category is diabetes medications (Budnitz DS et al. N Engl J Medd 2011;365:2002-2012).

National organizations, including the American Society for Gastrointestinal Endoscopy (ASGE) and the American College of Gastroenterology (ACG), along with the American Heart Association (AHA) and the American College of Cardiology (ACC), have been working together in recent years to educate gastroenterologists on the risks associated with interrupting antiplatelet/anticoagulant therapy.

“As gastroenterologists, we have always seen our risk for GI bleeding, and cardiologists have always seen their risk for [complications] like stent thrombosis and stent occlusion,” said David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School, Norfolk. “GI bleeding is something we can typically control endoscopically, while stent occlusion and stent thrombosis are associated with a 50% myocardial infarction rate, and a 25% increased risk for death. So, [the cardiologists] win.

“The new understanding is to fully assess the risk profile for patients being evaluated for endoscopic procedures. That may mean postponing an endoscopy, especially if it’s

45

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

‘GI bleeding is something we can often see at the time of the endoscopy when we have that complication, and it’s usually readily treatable; cardiovascular

patients on antiplatelet therapy should discontinue those medications until hemostasis is achieved (ASGE Standards of Practice Committee et al. Gastrointest Endosc 2009;70:1060-1070).

“The cardiologists, on the other hand, said aspirin should be started as soon as possible once the risk for CV complication is thought to outweigh the risk for bleeding,” Dr. Greenwald said, citing an international consensus recommendation (Barkun AN et al. Ann Intern Med 2010;152:101-113).

Stent thrombosis in patients with

stents is always a concern, but the highest risk for thrombosis is in the time just after the stent is placed.

“You should be continuing the aspirin in all patients with stents. With a bare metal stent, you can consider stopping clopidogrel after 30 days; with a drug-eluting stent, [stopping] after six months or a year is generally reasonable in the short term.”

For elective GI procedures, the risk for post-procedural bleeding is about 1% to 3% for colonoscopy and polypectomy. Most of the information about aspirin and NSAID use at the time of

endoscopy comes from an 18-year-old study that suggests the risk for significant GI bleeding after biopsy and polypectomy is small—about 5%—with a small increase in self-limiting bleeding in patients taking aspirin and NSAIDs, but no difference in major bleeding between those taking the drugs and those who did not (Shiffman ML et al. Gastrointest Endosc 1994;40:458-462). Several subsequent studies had similar findings. “[We] come to the conclusion that endoscopic procedures can be performed see GI Bleeding, page 46

events, including myocardial infarctions and strokes, are often devastating and can be fatal.’

—David Greenwald, MD

being done electively,” Dr. Johnson continued. “This allows patients to continue antiplatelet therapy for an acute period of time if they have a new CV stent and therefore should not stop antiplatelet therapy, at least for minimum times as defined acceptable by the cardiologists.” Dr. Johnson pointed to several studies supporting this (Abraham NS et al. Am J Gastroenterol 2010;105:25332549; Becker RC et al. Am J Gastroenterol 2009;104:2903-2917).

“The risks in maintaining antiplatelet or anticoagulant agents while we’re doing endoscopy are an increased risk for bleeding, whether that’s because the patient is bleeding to start with or because we’re doing something like a biopsy and polypectomy that might induce bleeding,” Dr. Greenwald said. “But all that is balanced against a decision to reverse the anticoagulation or take away the antiplatelet agent, and risk the thromboembolic complications of doing that.”

As no two patients are the same, and no two clinical scenarios are the same, “it requires thoughtful consideration for every decision that’s made,” Dr. Greenwald said.

Aspirin and Antiplatelet Use Aspirin is often used for primary or secondary CV prophylaxis, and dual antiplatelet therapy is used for a variety of indications, such as unstable angina and unstable CV disease as well as after the placement of bare or drug-eluting metal stents.

When aspirin is used alone as a primary or secondary CV prophylaxis, the risk for an adverse CV event occurring after discontinuation of therapy is quite low, about 1% to 2%. When dual therapy—aspirin and an antiplatelet agent— used after stent placement or myocardial infarction is discontinued, the risk for a recurrent CV event can be as high as 30% in the first 30 days.

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GI Bleeding continued from page 45

in patients taking aspirin and NSAIDs in standard doses, which is stipulated in the guidelines established by ASGE in 2009,” Dr. Greenwald said.

In the setting of high-risk procedures, the guidelines suggest that the drugs may be discontinued five to seven days prior to the procedure.

Warfarin Although used far less commonly than aspirin and NSAIDs, warfarin is still used substantially; about 2 million people in the United States take the anticoagulant to prevent the formation of blood clots. The management of this drug during endoscopy also comes down to a high-risk/low-risk assessment of the likelihood that a patient might have a thromboembolic event if the anticoagulant were discontinued.

Data cards printed by ASGE have been in place for many years and clearly categorize procedures and patient conditions as either low-risk or high-risk. For low-risk procedures, such as endoscopy or colonoscopy with and without biopsy, ASGE guidelines recommend no change in anticoagulant or antiplatelet medication, with a choice to delay elective procedures if blood tests reveal that the international normalized ratio (INR) is supratherapeutic. For high-risk procedures, the guidelines recommend stratifying the patient’s risk for having a thromboembolic event and adjusting drug therapy accordingly.

If a patient needs to discontinue an anticoagulant, the question then becomes when to restart.

“Guidelines from the cardiology groups suggest the benefits of immediately instituting anticoagulation need to be weighed against the risk for hemorrhage—so again, a risk–benefit analysis,” Dr. Greenwald said. “But they specifically provide guidance for patients with valvular heart disease [who are] felt to have a low risk for thromboembolic disease and who should have their anticoagulation restarted within 24 hours. Patients felt to have a higher risk for thromboembolic disease should be started as quickly as possible on a short-acting anticoagulant.”

For patients with GI bleeding whose anticoagulant needs to be reversed, options include high-dose or low-dose vitamin K, as well as fresh frozen plasma (FFP). Dr. Greenwald advocates for low-dose vitamin K and FFP. “The bottom line here is that high-dose vitamin K seems to lead to a hypercoagulable state, and should probably be avoided in this situation,” he said.

Other Agents Thienopyridines (clopidogrel and ticlopidine) are often used in combination

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

with another antiplatelet agent, such as aspirin, and they require a similar highrisk/low-risk assessment around the time of endoscopy. Management of patients with cardiac stents, though, is particularly difficult.

In patients with bare metal stents, dual antiplatelet therapy—which may increase the risk for GI bleeding substantially—is recommended for at least one month, and often for 12 months or longer. The risk for stent thrombosis is higher in patients who have drug-eluting stents, and that risk is greatest when dual antiplatelet

‘You should be continuing the aspirin in all patients with stents.’

—David Greenwald, MD therapy is discontinued. The AHA recommends at least 12 months of dual antiplatelet therapy in these patients.

“So what do we do with patients who have stents placed, are on thienopyridines and are having endoscopy? High risk for stent thrombosis is a compelling

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reason for continuing these agents until it is absolutely necessary to stop them,” Dr. Greenwald said. “Recommendations include delaying or not going forward with elective or semi-elective procedures until the patient receives the minimum length of therapy recommended by the

47

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

ACC/AHA guidelines. The decisions on how to proceed should involve the patient and often other specialists.”

Dabigatran, an oral reversible direct thrombin inhibitor, is being used increasingly for the management of patients with uncomplicated atrial fibrillation; it is also approved for prophylaxis against the formation of deep vein thrombosis. Few data are available concerning its use in the peri-endoscopic period. What is known is that when dabigatran is discontinued, levels of the drug fall to 25% within 24 hours, and to 5% to 10% within 48 hours.

“The prescribing information tells you that patients at high risk for bleeding or who require complete hemostasis should discontinue the agent two to four days before surgery, and there is no specific information about endoscopy,” Dr. Greenwald said. “But plasma levels of dabigatran are very dependent on renal function; patients with diminished renal function need to stop the agent quite a bit sooner for blood levels to fall to zero.”

A relatively new drug, Ticagrelor, was approved by the FDA in 2011.

“It has a completely different

mechanism of action, and has been shown to decrease the rate of CV death, myocardial infarction or stroke compared with clopidogrel, so I think we may see its use more and more,” Dr. Greenwald said. “Again, it has been associated with significant, sometimes fatal bleeding.

Prescribing labeling recommends discontinuation of this product at least five days before surgery, and again there is no specific guidance about endoscopy.”

Although the decision to stop or continue aspirin, antiplatelet agents and anticoagulants hinges on a risk–benefit

analysis, “there is little data on this, so the recommendations come mostly from expert opinion,” Dr. Greenwald said. “The situation for each patient requires a practitioner’s knowledge and best judgment.”

He added, “In general, NSAIDs and aspirin should be continued in standard doses when performing endoscopic procedures, while decisions about anticoagulants and thienopyridine use should be guided by the previously mentioned highrisk/low-risk assessments, which allow for an individualized analysis of the risks and benefits as much as possible.”

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49

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Sedationless Colonoscopy Preferred For Some Patients, Experts Say

By Monica J. Smith Sedationless colonoscopy may be an appropriate option for the right patients, particularly as technological refinements and advancements are making sedationless procedures more comfortable.

“We know that to gain acceptance, sedationless colonoscopy requires minimal discomfort, with no pain as the goal,” said Douglass Howell, MD, director of the Pancreaticobiliary Center and the Advanced Interventional Endoscopy Fellowship at Maine Medical Center, in Portland. “Several articles now exist suggesting that variable-stiffness and pediatric colonoscopes may give a more comfortable examination,” he said.

More than a decade ago, Douglas Rex, MD, and colleagues found that a proportion of colonoscopy patients, specifically older men with no abdominal pain, could be offered the procedure without sedation by experienced endoscopists (Gastrointest Endoscc 1999;49:554-559).

“His feeling, though, was that about 10% of patients have a bad experience, and you don’t want to risk putting even a small fraction of patients through an uncomfortable examination,” Dr. Howell said. “But now, 12 years have passed; the technology has improved; and we have come to a point where we can offer sedationless endoscopy to selected patients,” said Dr. Howell, who spoke on the subject at last year’s New York Society for Gastrointestinal Endoscopy annual course.

In a series comparing various colonoscopes for patient comfort and examining the feasibility of performing colonoscopy without sedation, Dr. Howell and colleagues found that a substantial proportion of 600 patients studied had a satisfactory exam without sedation (Howell DA et al. Gastrointest Endoscc 2000;51:AB58).

“In the patients who were willing to begin their exam without medication, only about 10% of them asked for or required medications,” Dr. Howell said.

Following this experience, he and his team compiled an anesthesia/deep sedation worksheet that predicted fairly well which patients would do well with low or no sedation and which patients should not be offered that option.

“You would not want to offer sedationless colonoscopy to patients who had a previous bad experience. If their report documented they previously required a lot of medicine for their procedure, they should probably be put to sleep,” Dr. Howell said.

Other unsuitable candidates include patients with a body mass index less than 20 kg/m2, women with a history of pelvic surgery or endometriosis, patients with chronic pelvic pain and those who have undergone radiation. As Dr. Rex found, the best candidates for sedationless colonoscopy tended to be older men.

“Fit, middle-aged to older males don’t have a lot of these [confounding] problems, so the proportion of people who can undergo sedationless endoscopy is disproportionately weighted to that group,” Dr. Howell said. “I encourage them usually to start without medicine, and it’s successful in the majority of those patients.”

Currently, about 30% of women and 50% of men who undergo colonoscopy at Dr. Howell’s clinic receive a sedationless procedure.

“About 5% to 10% stand out on the questionnaire and receive propofol; the remaining patients receive conscious

sedation with [midazolam] and fentanyl,” Dr. Howell said. “We try to individualize so that patients receive the appropriate and most cost-effective care for their needs.”

Medication is always available for patients who begin an exam without sedation but who at some point find the exam to be uncomfortable.

‘About 5% to 10% stand out on the questionnaire and receive propofol; the remaining patients receive conscious sedation with [midazolam] and fentanyl.’

—Douglass Howell, MD

Pragmatic Approach When Dr. Howell first started pondering the question of sedationless colonoscopy, about a decade ago, his interest was driven partly by concern about the expense that sedation added to the procedure. “My thought was that we were at risk of being squeezed out of the best screening procedure,” he said.

At that time, computed tomographic colonography (CTC) seemed poised to compete with standard colonoscopy. “I felt we might compete poorly with technologies that might not be as invasive or expensive. That hasn’t happened yet, but that cloud looms on the horizon.”

When an anesthesiology professional is required to administer sedation, it can add substantial cost to screening colonoscopy.

“The way you measure the value of preventive care is the cost per life–year gained,” he explained. “Colonoscopy has measured well compared with mammography” in those terms. “But it’s still very expensive as a preventive strategy. The more you layer cost on top of screening, the less economical it becomes.”

This may be why, in many parts of the world, sedationless colonoscopy is a fairly common option.

“Sedation [for colonoscopy] is almost more of a cultural expectation than a clinical requirement,” said Katherine Pope, MD, an anesthesiologist with the Spectrum Medical Group, in Portland, Me. “We’re concerned about patient experience and quality of care, but the resource issue is not insignificant. I think, as responsible practitioners, we have to consider whether or not it is medically necessary to have sedation on every colonoscopy case, and I would say no,” Dr. Pope said.

Limiting Pain Most of the discomfort in colonoscopy occurs during insertion.

“The loop formation, traction on the mesentery and stretching of the bowel wall or excessive air distention are the main problems,” Dr. Howell said. “Once you’re in the cecum and beginning to withdraw, colonoscopy is virtually painless. So preventing and controlling looping might be a way to increase comfort and reduce the need for sedation.”

Technology has certainly played a role in controlling looping, from earlier versions of magnetic endoscope imaging to variable-stiffness colonoscopes to, most recently, the 2011 FDA approval of Olympus’ ScopeGuide digital version with internal colonoscope magnets, which allows for real-time visualization of the colonoscope’s position. During the colonoscopy, the magnetic detector hand coil can then be used to apply effective counter-pressure where it is needed.

Although ScopeGuide is relatively rare in the United States, it has been around in prototype form for about 20 years.

“Originally it was meant to be for training,” Dr. Howell said, but he envisions the instrument serving a bigger

role in sedationless endoscopy. “It may fit in here better than anywhere else; it allows you to deal with loops in the colon that you could not otherwise easily manage.”

Other advances, improvements or novel applications of technology, such as carbon dioxide insufflation, clear cap endoscopy, water infusion colonoscopy and improvements in colonoscopy insertion technology may enable sedationless colonoscopy to gain traction in the United States.

Although it may be difficult to imagine the acceptance of sedationless colonoscopy in a population accustomed to sedation, for some the advantages are readily apparent.

“I like to avoid medication if I can, and also I’m a busy person,” said Dr. Pope, who chose to go without sedation during her own colonoscopy. “I had things to do that day; I didn’t want to be unable to drive; and I wanted to get in and out quickly. It’s certainly quicker with fewer side effects, and that’s why I chose it.”

Patient acceptance may come down to how sedationless colonoscopy is presented.

“If it’s offered to the right patient as an option, with the pros and cons well explained, and with the endoscopist and staff sensitive to helping the patient through the procedure and offering to convert to sedation, it’s a wise and sensible option,” Dr. Pope said.

There is still work to be done before sedationless colonoscopy becomes a widely offered option.

“We need a pediatric, variable-stiffness colonoscope with incorporated magnetic technology for ScopeGuide to better manage loops on demand, and we must preserve the ability to perform endotherapy,” Dr. Howell said. “Industry is interested in this [development] and there are a variety of things on the horizon that may make this more feasible.”

■ Dr. Howell receives consulting fees from Olympus America.

Dr. Pope reported no relevant conflicts of interest.

50

GI Roundtable continued from page 1

Wash., to give leaders in gastroenterologyy practice an opportunity to discuss and nd exxplore issues of the day in a platforrm th hat facilitates discussion between facu ulty an nd attendees and among the attendeees th hemselves.

This year’s conference, which at timees had the feeling of a high-energy brainsttorming session, focused mainly on conceerns surrounding the potential effect of health care reform and what it will take too remain strong, independent and succeessful in today’s challenging health care en nvironment. The following round table discussion attempts to capture the essence of the 2012 conference, which was held at th he end of March in Knoxville.

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012 GASTRO

Reed Hogan, MD

Lawrence Kosinski, MD, MBA

Jackson GI Ass soc ciates and Endoscopyy Center C Jackson, Missis ssippi

Managing Partner Elgin Gastroenterology Elgin, Illinois

Scott Ketover President and CEO Minnesota Gastroenterology Minneapolis, Minnesota

Chal Nunn, MD

James Weber, MD

CE EO Ga astroenterology Associates of Central Virginia Lyn nchburg, Virginia

President and CEO Texas Digestive Disease Consultants Southlake, Texas

How has thinking about quality in gastroenterology changed in the last decade?

Dr. Nunn: First of all, we’re actuallly coming up with process measures th hat can give us an idea of what quality in n gastroenterology is. About 10 years aggo we didn’t have anything, soo I give i people l lik like Irr ving Pike, MD, and th he folks who have done GIQuIC [GI Quality ‘I give people like Irving Improvement Consortium] Pike, MD, and the folks a lot of credit for leading the who have done GIQuIC quality movement. I think [GI Quality Improvement it’s hard for a typical practice to pull it off because we don’t Consortium] a lot of credit for have the infrastructure that leading the quality movement.’ a health system has to do —Chal Nunn, MD quality measurement. Also, I don’t think that all gastroenterology doctors are embracing [quality measurement] yet.

Even within my own group, when I raised Dr. Weber: Ten years ago I think we the issue of participating in GIQuIC and just assumed we provided quality care and other registries, I got a big pushback. it wasn’t really questioned. Now it’s very much in the forefront of our minds. Not Dr. Kosinski: The great thing is that only do we want to practice quality mediwe’re actually thinking about quality. cine, we want to prove it to ourselves and In The Discipline of Market Leaders, the to our partners; we want to use quality authors stated that to be a market leader parameters to compare ourselves to othyou can only focus on one of three things: ers; and we want to justify to our patients, a superior product, impeccable customer the payers and the government that we are service or operational excellence with the practicing the highest-quality medicine lowest cost. Until now, we have not been that we can. able to measure quality, and we really have not been in control of our costs, so Dr. Hogan: There have been local and customer service was a proxy for qual- national shifts to try and push quality to ity for many years in health care. Then the forefront. Our group has been lookwe went through a phase where process ing at adenoma detection rates for about management became the proxy for qual- five years, benchmarking with some large ity. Today, for the first time, because of the groups, trying to make sure we have a stanrevolution in electronic health records, we dard of care. We also benchmark against finally have the ability to come up with ourselves. If we identify underperformers, measurements of what a quality product we try to counsel them and pull them up really is. to the level of others.

Dr. Ketover: The major change is the acceptance p byy gastroenterologists g g and physicians in general that we need to measure ourselves and our performance to demonstrate the quality we are all convinced we already provide.

What do you think will be the biggest challenges to your practice, or gastroenterology practices in general, in the next five years?

Dr. Nunn: Expenses continue to rise but reimbursement does not. Looking at my expenses as a percentage of revenue, seven years ago, we were at 50%; now we’re at 60%. So we keep grabbing more sources of revenue, such as ancillary services. But with ancillaries, you’re always at risk that the insurance companies will shut it out. For example, one of our small payers said they’re no longer going to pay for office-based pathology. The other biggest challenge for us is the uncertainty.

We don’t know what our health systems are actually going to be—whether more people will be covered or not.

Dr. Kosinski: We are trying to build a building on top of the San Andreas Fault.

We have no idea which way that fault is going to go, which side of that fault our building will be on or whether it’s going to fall into the abyss between. Despite this, we’re investing a lot in this building. With

the influence of cost control and the tremendous pressure p the federal government g is under, our landscape is changing. Our biggest challenge is to prove the value of our services to the payers who are taking the risk paying for health care despite the uncertainty of our future.

Dr. Weber: I think the biggest challenge is consolidation—consolidating as gastroenterology practices, perhaps as multigroup practices or across regions we didn’t do before. I think we are going to need to work better, smarter and more efficiently to provide high-quality care in a cost-effective manner. And we will need to do that collegially with one another so we get the outcomes we need, not just each man for himself.

Dr. Hogan: It depends on the health care instrumentation by the government. If we’re pushed toward the accountable care organization (ACO) concept, that will require significant reengineering in how we approach individual patients and how we stay profitable and independent of hospital systems or large health care systems. What we’d like to try to do is be a focus factory for gastroenterology health care, where we concentrate on what we do best, prove our outcomes are better, and prove we can do it cheaper than in hospital settings.

Dr. Ketover: I anticipate we will see further pricing pressure on see GI Roundtable, page 52

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GI Roundtable continued from page 50

gastroenterology procedures in the outpatient arena. As that occurs, there will probably be more non-gastroenterology providers performing gastroenterologytype procedures. The gastroenterologist’s practice will shift from the high percentage of procedures that are done today to more cognitive clinical work. A lot of the outpatient procedures we do will become a commodity and be performed by the lowest cost providers. Gastroenterologists may argue that we’re better endoscopists than others, but the quality argument may fall flat, whereas the money argument will win.

Is it possible to reduce cost and improve quality and efficiency at the same time?

Dr. Nunn: Definitely. I’ve seen dramatic improvements at the hospital over 18 years by standardizing care and reducing variation. I’m trying to do it in my gastroenterology practice now with electronic medical records, building standard templates, and building checklists and order sets for the common diseases that we treat. The thing that keeps us from going even farther with quality is the way we are paid: fee-for-service. We get paid to treat people when they’re sick. We’re not paid to keep people well and keep them out of the hospital. To take quality to the next level, we need to be rewarded for doing those kinds of things.

Dr. Kosinski: The three things we have to do are reduce cost, improve quality and maintain patient satisfaction.

Because of information technology, we will be able to focus on quality, which will cause cost to go down. I do believe that if you focus on quality you can improve your efficiency concurrently, but if you f focus on cost and d efficiency, ff you may lose your quality focus.

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

we get better outcomes quicker, thus saving patients and payers money and time.

I don’t necessarily mean doing cheaper studies, but doing them properly on the right people at the right time in the right way so that we can accomplish the outcomes we want. So I think it is possible, but I think we have to practice smarter.

be working with less available funds. We are going to see falling reimbursements and consolidation across our industry.

We know that there will be new models of care delivery—whether the PPACA is in existence or not—and we know that if Gordon Gekko was giving his lecture today, he wouldn’t say “greed is good,” he would say “risk is back.”

skeptical and more minimalist are going to win—those who can collaborate and manage people cost effectively, and typically those people will get into groups. Taking care of patients now is a team sport involving multiple people—advanced nurse practitioners, nurses, case managers, social workers. The doctor who can work with all those people is going to win.

Dr. Hogan: Absolutely. At the national level we’re seeing small groups Dr. Weber: Everything. I think Dr. Kosinski: With monumental coalesce into larger groups, which achieves PPACA is a misnomer. I don’t believe it change, sometimes those entities that were the economy of scale to provide a special- is really going to be affordable to anyone. the previous market leaders have the hardized focus on your disease process. When If it is carried out the way I understand est time maintaining their competitive you’re focusing on one thing, like doing it, it is going to cost more people more balance, while smaller players that weren’t endoscopy or taking care of able to compete wind up hepatitis C correctly, if you becoming the new standard. can achieve volumes such that I think the winners are going ‘My fear is that the care of the patient is efficiency works correctly, you to be those who can adapt and going to be depersonalized, also can drive down cost at the embrace change. Those who and I’m afraid that the quality and same time. can’t change will suffer.

compassion that we have worked to attain for our patients is going to be lost in this type of system.’

Dr. Ketover: That’s a great question. I think that in order to do that you have to own or manage a lot of different aspects of gastroenterology care. It will be challenging for the solo and very small independent groups to possess enough of the diversity in service lines to reduce cost and improve quality and efficiency simultaneously, whereas large, single- or multispecialty clinics will have the breadth of resources to approach efficiency and quality at the same time.

What are your biggest concerns about the Patient Protection and Affordable Care Act (PPACA)?

Dr. Nunn: Number 1: Whether it will even exist. Number 2: The push to consolidate everything. Gastroenterologists, in general, are very independent-minded people, so I think it’s going to be a major cultura cultural challenge for us to figure out wheere to fit into the integrated health systems that PPACA is going to bring about. Play‘Gastroenterologists, in general, ing well with others is are very independent-minded a problem for doctors in general. And then people, so I think it’s going to be there will be further a major cultural challenge for us revenue loss, too, with more patients in govto figure out where to fit into the ernment paid plans, integrated health systems that PPACA which don’t pay as is going to bring about.’ well as private plans.

—Chal Nunn, MD Dr. Kosinski: My biggest concern is I don’t know how Dr. Weber: I think if we work to plan because I don’t know what the together and work under best practice final version of this is going to look like. scenarios in a high-quality environment, There is one given: We are all going to

Dr. Weber: I’m not sure if there are any winners. My fear is that the care of the patient —James Weber, MD is going to be depersonalized, and I’m afraid that the quality and compassion that we money. There will be more people have worked to attain for our involved in health care, more bureaucracy, patients is going to be lost in more frivolous oversight. My big concern this type of system. I guess the in all this is that patient care is going to winners could be successful big ACOs— be compromised at no real savings. perhaps the big hospital systems, perhaps some of the big organized medical groups.

Dr. Hogan: If the PPACA is rejected, I think that the smaller medical groups I have significant concerns about cover- are going to be losers, and I think that age of the uninsured. We all share that patients are going to be potential losers, concern. But we have significant con- which would be a real crime. cerns about health care rationing if it passes. We want to see the best care done Dr. Hogan: If it’s quality-based we in an efficient model in a financial man- should all be winners in the long run. ner that makes sense. The problem we The losers will be those who provide poor have with big government is that we see a quality care, who were running people lot of decisions made on health care that through just to generate fees. Patient-care actually drive the prices up. wise, it will be good for all the consumers.

And most of us who care about health Dr. Ketover: Some regulations in the care and care about our patients want PPACA that are probably meant to protect quality-based medicine. patients or help with cost efficiency seem to be counterintuitive to having interoper- Dr. Ketover: The losers will be pracability between systems and institutions. I titioners who try to hold on to fee-for-serthink a fair amount of the regulation will vice forever without building new systems make it difficult to meet goals of improv- to look at population management or ing quality while lowering cost. some form of capitation. The winners will be those single- or multispecialty clinics or systems that can approach the delivery of Who will be the winners and gastroenterology care as population-based losers as health care delivery rather than on a one-on-one, fee-for-sermodels change from fee-forvice basis. I think these small groups will service to quality-based? find that they’ll need to be absorbed into a bigger structure in order to achieve those Dr. Nunn: The physicians who are efficiencies.

■ good collaborators and not maximizers of health care will be the winners. Some The GI Roundtable 2013 will be gastroenterologists believe in scoping held March 15-17 in Boston; for everything that walks. Overutilization of endoscopy, overutilization of treating reservation information, visit patients—I would consider those doctors www.giroundtable.com. maximizers. I think people who are more

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55

GASTROENTEROLOGY & ENDOS SCOPY NEWS • OCTOBER 2012

Money for Drugs

Part 3 of a 3-Part Series

Should Ph Physicians Be Paid for Pharmaceutical Development and Clinical Investigations?

[Editor’s Note: The following article was originally published in Missouri Medicine, September/October 2011;108:321.

It has been edited slightly for in-house style.]

YES

Yes, Physicians Must Interact With Pharma

Charles Van Way III, MD Professor of Surgery Sosland/Missouri Endowed Chair of Trauma Services University of Missouri Kansas City, Missouri Congratulations on well-reasoned commentaries from all of the authors in this debate. Because I agree substantially with Ms. Powell (“Money for Drugs,” Gastroenterology & Endoscopy News August 2012;63:42,44-47), let me address the arguments of Drs. Bohigian (“Money for Drugs,” Gastroenterology & Endoscopy News May 2012;63:44,4950) and Gale (August 2012).

Dr. Bohigian has focused largely on the support of physician speakers on behalf of pharmaceutical companies. I have little disagreement with him. This area has great potential for abuse. Indeed, I cited speakers’ bureaus as the “most troublesome facet of this issue.” It is in this particular area that we must be the most careful, both as

speakers and as audiences. And Dr. Bohigian’s comments on the need for physician-researchers to be independent of the company sponsoring a research project are exactly correct.

I have a bit more concern about Dr. Gale’s comments, which are unremittingly negative. He cites extensively the books by Drs. Angell and Kassirer, but he fails to mention their substantial conflicts of interest. Both of these authors were editors of a highly respectable journal that derives a great deal of its income from pharmaceutical advertising. One is tempted to speculate that their books derive from a feeling of guilt, but perhaps that goes too far. The important point, as Dr. Gale notes, is that both of their books are directed to the public, not physicians. Simply repeating these well-known arguments adds little to this discussion. In short, his passion for morality on this issue is clear. But while moral outrage may be admirable, it provides few guidelines for our conduct in the future.

■

NO No, Physicians Must Remain Independent of Pharma George Bohigian, MD Professor of Clinical Ophthalmology Department of Ophthalmology and Visual Sciences Washington University St. Louis, Missouri Transparency and common sense are the keys to solving the dilemma “that physicians must remain independent of the pharmaceutical industry.”

Furthermore, physicians should not profit from drug companies, medical device makers, lectures or continuing medical education efforts. I do agree in part with my colleague, Dr. Charles Van Way (“Money for Drugs,” Gastroenterology & Endoscopy News May 2012;63:44,49-50), when he states, “We are having a national discussion over the propriety of the physician relationship with industry and that we need more transparency.”

Our trade journals are filled with biased articles written by physicians with pharmaceutical companies. In contrast,

well-recognized peer-reviewed journals are more scientifically based, but are supported by advertisements from drug companies.

This conflict is apparent and transparent to any journal reader.

Frequently, the response to new public policy tends to allow the pendulum to swing too far to one side. Common sense is essential. One of the potential impending problems with the new pharmaceutical rules is the lack of samples for indigent patients, especially at university clinics. As stated, all information should be transparent. Honesty and openness by the pharmaceutical industry and physicians are the keys.

The guiding principle should be that physicians always act as whatever is in the best interest of the patient. Ethical collaboration between physicians and the pharmaceutical industry is essential for the development of new treatments. Transparency is an integral component of ethical collaboration. Hopefully, common sense will prevail in the future evolution of new state and federal rules and regulations. However, as Mark Twain said, “Common sense is not that common.” ■

FDA Denies Report that Agency Is To Blame for Drug Shortages

By George Ochoa The FDA rebutted charges that it is largely to blame for the drug shortage crisis in a July 23 letter to the House Committee on Oversight and Government Reform. The FDA was responding to the committee’s June report, “FDA’s Contribution to the Drug Shortage Crisis,” which claimed that overzealous regulatory actions by the FDA were the primary reason for the crisis.

The committee’s report did not place sole blame for the crisis on the FDA, noting other factors such as market concentration. But the FDA’s role, according to the report, could be traced to the arrival in 2009 of Obama appointee Margaret Hamburg as FDA commissioner.

According to the committee, chaired by Rep. Darrell Issa (R-Calif.), the drug shortage crisis began shortly afterward, in 2010. The committee noted that the number of warning letters issued by the FDA increased 42% from 2009 to 2010

and then climbed 156% from 2010 to 2011. In many cases, the report stated, companies that received the letters took their manufacturing offline to address the FDA criticisms. Four of the five largest U.S. manufacturers of generic injectable products have curtailed manufacturing in response to FDA action, the report claimed.

In the FDA’s response, signed by Jeanne Ireland, assistant commissioner for legislation, and addressed to Rep. Elijah E. Cummings (D-Md.), the committee’s ranking member, the agency asserted, “FDA is not the root cause of this serious public health problem.” The FDA stated that the number of drug shortages began to rise steadily in 2005, well before Ms. Hamburg’s appointment, and that most of the drug shortages were attributable to manufacturing production problems, such as qualityrelated issues and delays. The rest of the shortages were due to such factors as business decisions to discontinue products, difficulty obtaining raw materials

and increased demand.

The FDA claimed that the steep increase in warning letters alleged in the report was misleading because most of the letters were unrelated to drug manufacturing; they were related to the new Center for Tobacco Products. From 2008 to 2011, the level of drug manufacturing warning letters “remained relatively flat,” according to the FDA. Furthermore, according to the agency, the warning letters issued to drug manufacturers involved serious defects that posed a safety risk. Defects serious enough to require stopping production included glass shards in injectable products and fungal contamination of products, the FDA said.

The committee suggested that the FDA’s field force, which performs site inspections and issues citations, is insufficiently concerned about the implications of their actions, even if the result is a shortage. But the FDA said it is committed to working with manufacturers to resolve problems and avoid shortages.

The FDA reported that it has prevented

or mitigated drug shortages by taking steps such as expediting reviews, identifying additional manufacturers who may be able to produce scarce drugs, helping firms qualify new sources of a raw materials and allowing temporary importation of a non-U.S. product.

Commenting on the committee’s charges in an interview, Erin R. Fox, PharmD, director of the Drug Information Service at the University of Utah Hospitals & Clinics, in Salt Lake City, said, “I was very surprised. There was no mention of quality and manufacturing problems, no mention of the scary things going on in factories. I’ve read the inspection forms that document what the FDA found in its inspections. The FDA wasn’t saying, ‘We found uncrossed t’s and undotted i’s, and that’s why we’re mad at you.’ In injectables, they found glass shards and mold contamination, nonsterile products.” Noting that she considered the FDA’s actions “correct,” she said, “It’s hard to comply, but high quality is first priority.”

■

56

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Excise Tax Looms for Medical Device Industry Manufacturers Cry Foul, Saying Tax Will Cause Layoffs, Stifle Innovation n

By George Ochoa Barring a major political shift, medical device manufacturers will face a new 2.3% excise tax on their products beginning in 2013, which is expected to raise $29 billion over 10 years.

Enacted in 2010 as part of the Patient

Protection and Affordable Care Act (PPACA), the tax has drawn fire from the medical device industry, which predicts, despite some counterclaims, that the tax will result in lost profits, vanishing jobs, relocation overseas and a decline in innovation.

There is even a Web site supported by Cook Medical, with the message, “No

2.3%: Kill the med device tax!” (www. no2point3.com).

In June, the House passed a bill (H.R. 436) to repeal the tax. The bill is not generally expected to pass the Senate or survive a threatened presidential veto, but the future of the medical device tax may be decided on Election Day. “The overall fate of health [care] reform

How the device tax will affect the medical device industry depends on whom you ask.

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NO REFUNDS will be given after this date.

Hits Expected on Profits and Jobs “The medical device tax is just bad policy,” said Wanda Moebius, spokeswoman for AdvaMed, a medical device industry trade association in Washington, D.C., in an interview. “It will have a very damaging effect on our industry’s ability to hire and advance medical innovation, and it does nothing to make health care more accessible.”

The industry widely expects the tax to have a disproportionate effect on small to mid-sized companies. Because the tax equals 2.3% of total revenues, not profits, even a company that is not profitable or has relatively low profits will have to pay.

According to literature from the Medical Device Manufacturers Association (MDMA), another industry trade association, the medical device industry makes a profit of 3.4 % on sales. Therefore, says MDMA, the tax of 2.3% could consume more than 65% of a typical company’s profits.

But not everyone agrees with that estimation.

57

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Effects on Global Competitiveness and Innovation Other criticisms of the tax concern global competitiveness and innovation.

Mr. Ferguson said the main reason the tax should be repealed “is the industrial impact on one of the strongest industries we have, in terms of balance of payments and innovation.” Whether at the

level of startups, growing companies like Cook, or very large companies, the tax, he said, “is driving jobs outside the United States.”

Cook is already an example. Although not contemplating layoffs, the company has shelved plans to build five new manufacturing plants over five years in the Midwest. John Eckberg, director of

media relations, Cook Group, Inc., wrote by email, that “that action is directly related to the imposition of the medical device tax.”

Kem Hawkins, president of Cook Medical, said that as a result of the medical device tax, “we have plans to grow our production overseas; that is, our growth see Device Tax, page 58

DIFICID® (fidaxomicin) tablets Awarded New Technology Add-on Payment (NTAP)1 —Paul N. Van de Water, PhD, senior fellow, Center on Budget and Policy Priorities

“That sounds like a pretty big exaggeration,” said Jeff Jonas, CFA, research analyst, Gabelli & Co., in Rye, N.Y, in an interview. “For large companies like Medtronic and Stryker, there may be a 3% or 4% hit to profit. For small companies that are barely profitable, 65% could be correct.”

To pay the tax, many companies are expected to cut jobs, although here again, there is dispute.

A study financed by AdvaMed found that more than 43,000 jobs in the medical device industry would be lost as a result of the new tax.

“That seems on the high side,” retorted Mr. Jonas. “There will definitely be layoffs and other cost cuts, but I don’t have a total number for the industry.”

But according to Stephen L. Ferguson, JD, chairman of the Board of Directors, Cook Group Inc., in Bloomington, Ind., “Forty-three thousand is a minimal figure. I think it’ll be much larger than that,” he said in an interview.

“You have to put the tax in the context of the overall federal budget,” Dr. Van de Water explained. “If the tax is repealed, the loss in tax revenues will have to be made up from another tax or from cutting federal spending. Either alternative would offset whatever effect on jobs the tax repeal would have. From a macroeconomic perspective, there wouldn’t be much of an effect on jobs at all.”

CMS* has granted a NTAP for DIFICID administered in the inpatient hospital setting to treat Clostridium difficile-associated diarrhea (CDAD) CMS will reimburse hospitals an additional amount of up to $868 in fiscal year 2013, not for every case involving DIFICID, but only where the costs of the entire case exceed the MS-DRG† payment amount The CMS NTAP policy is designed to support timely access to innovative therapies used to treat Medicare beneficiaries in the inpatient setting that provide a substantial clinical improvement over existing therapies DIFICID is the first oral medication ever approved for a NTAP *Centers for Medicare & Medicaid Services. † Medical severity diagnosis-related groups.

For more information about DIFICID, please visit DIFICID.com.

For a copy of the CMS final rule regarding FY2013 Add-On Payments, please visit http://federalregister.gov/a/2012-19079.

Indications and Usage DIFICID is a macrolide antibacterial drug indicated in adults ≥18 years of age for treatment of Clostridium difficileassociated diarrhea To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile

Important Safety Information DIFICID should not be used for systemic infections Only use DIFICID for infection proven or strongly suspected to be caused by C. difficile. Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria The most common adverse reactions are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%) Please see brief summary of full prescribing information for DIFICID on following page.

Reference: 1. Department of Health and Human Services, Centers for Medicare and Medicaid Services, Medicare Program; Hospital Inpatient Prospective Payment Systems for Acute Care Hospitals and the Long-Term Care Hospital Prospective Payment System and Fiscal Year 2013 Rates, 77 Fed. Reg. 53258-53750 (August 31, 2012).

© 2012 Optimer Pharmaceuticals, Inc. San Diego, CA 92121 5124 September 2012

58

Device Tax continued from page 57

will be overseas but we have decided not to put our employees at risk. That is one of the benefits of being a private company: We can sacrifice a little of the bottom line to do the right thing.”

The tax also will hurt innovation, said Mr. Ferguson. “If you take development outside the United States, venture capitalists will take the good ideas of inventors overseas.”

But Dr. Van de Water countered. “The

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

argument on competitiveness is off base because the tax is carefully structured so it in no way disadvantages American firms.

Both U.S. and foreign firms pay the tax on devices sold in this country—it’s evensteven. And it doesn’t apply to U.S. products sold overseas.

“The tax will also have little effect on innovation in the medical device industry,” Dr. Van de Water added. “To the contrary, health [care] reform may well spur medical device innovation by promoting more cost-effective ways of delivering care.”

In a CBPP publication that he authored, Dr. Van de Water argued that health care reform, on balance, may benefit the medical device industry by extending coverage to 33 million more Americans, thus boosting demand for medical devices.

Mr. Ferguson responded, “I have seen absolutely no evidence to support that statement. … Most of the new patients will be voluntarily uninsured, basically healthy people who don’t need medical devices. This doesn’t generate more device usage.”

DIFICID™ (fidaxomicin) tablets Brief Summary of Prescribing Information 1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile.

1.1 Clostridium difficile-Associated e Diarrhea DIFICID is a macrolide antibacterial drug indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD).

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Not for Systemic Infections Since there is minimal systemic absorption of fidaxomicin, DIFICID is not effective for treatment of systemic infections.

5.2 Development of Drug Resistant Bacteria Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice.

The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment.

Thirty-three patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase 3 studies.

Table 1. Selected Adverse Reactions with an Incidence of ≥2% Reported in DIFICID Patients in Controlled Trials

System Organ Class Preferred Term

DIFICID (N=564)

Vancomycin (N=583)

n (%)

n (%)

Blood and Lymphatic System Disorders Anemia

14 (2%)

12 (2%)

Neutropenia

14 (2%)

6 (1%)

Physicians’ Perspective Asked for a physician’s perspective, John Maa, MD, assistant professor, Division of General Surgery, University of California, San Francisco, said, “Most surgeons are likely unaware of this tax, but should educate themselves about [its] implications. … Front-line surgeons are often the first to design new devices. The way the tax is constructed, it may provide a barrier to introducing new technologies.

It will likely stifle innovation.”

Dr. Maa voiced his views at the AdvaMed meeting in Washington, D.C.,

7 DRUG INTERACTIONS Fidaxomicin and its main metabolite, OP-1118, are substrates of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the gastrointestinal tract.

7.1 Cyclosporine Cyclosporine is an inhibitor of multiple transporters, including P-gp.

When cyclosporine was co-administered with DIFICID, plasma concentrations of fidaxomicin and OP-1118 were significantly increased but remained in the ng/mL range [see Clinical Pharmacology (12.3) in the full prescribing information].] Concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e., gastrointestinal tract) via P-gp inhibition; however, concomitant P-gp inhibitor use had no attributable effect on safety or treatment outcome of fidaxomicin-treated patients in controlled clinical trials.

Based on these results, fidaxomicin may be co-administered with P-gp inhibitors and no dose adjustment is recommended.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/kg, respectively. The plasma exposures (AUC0-t) at these doses were approximately 200- and 66-fold that in humans, respectively, and have revealed no evidence of harm to the fetus due to fidaxomicin. 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.

8.3 Nursing Mothers It is not known whether fidaxomicin is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when DIFICID is administered to a nursing woman.

8.4 Pediatric Use The safety and effectiveness of DIFICID in patients <18 years of age have not been established.

8.5 Geriatric Use Of the total number of patients in controlled trials of DIFICID, 50% were 65 years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of fidaxomicin compared to vancomycin were observed between these subjects and younger subjects.

In controlled trials, elderly patients (≥65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years of age) [see Clinical Pharmacology (12.3) in the full prescribing information].] However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.

10 OVERDOSAGE No cases of acute overdose have been reported in humans. No drug-related adverse effects were seen in dogs dosed with fidaxomicin tablets at 9600 mg/day (over 100 times the human dose, scaled by weight) for 3 months.

Manufactured for Optimer Pharmaceuticals, Inc., San Diego CA 92121 by Patheon, Inc. DIFICID™ is a trademark of Optimer Pharmaceuticals, Inc.

Gastrointestinal Disorders Nausea

62 (11%)

66 (11%)

Vomiting

41 (7%)

37 (6%)

Abdominal Pain

33 (6%)

23 (4%)

Gastrointestinal Hemorrhage

20 (4%)

12 (2%)

The following adverse reactions were reported in <2% of patients taking DIFICID tablets in controlled trials: Gastrointestinal Disorders: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolon Investigations: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count Metabolism and Nutrition Disorders: hyperglycemia, metabolic acidosis Skin and Subcutaneous Tissue Disorders: drug eruption, pruritus, rash

Product protected by US Patent Nos. 7,378,508; 7,507,564; 7,863,249; and 7,906,489 Optimer Pharmaceuticals, Inc. 10110 Sorrento Valley Road, Suite C San Diego, CA 92121 (858) 909-0736 © 2011 Optimer Pharmaceuticals, Inc. All rights reserved.

59

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

‘It will have a very damaging effect on our industry’s ability to hire and in 2010, where he said, “I believe that the medical device industry has been misunderstood in the crafting of the PPACA. I think this is most clearly reflected in the imposition of a blunt, flat tax of medical devices.”

In an interview with Gastroenterology & Endoscopy News, Dr. Maa argued that a progressive tax would likely have been fairer, and that it might have been preferable to distribute the tax across the supply chain.

Charles T. McHugh, MD, a retired general surgeon now in family practice in Baileyville, Me., said, “I find the arguments of device manufacturers—that the tax will raise health care costs, reduce sales and push manufacturing out of the United States, thus costing jobs—not meritorious.”

Although Dr. McHugh acknowledged that the tax would probably raise the costs of medical devices, he said, “In some cases, the discouragement to purchase, with its attendant pressure for hyper-utilization, may be a very good and effective means to reduce overall health care costs.”

advance medical innovation, and it does nothing to make health care more accessible.’

—Wanda Moebius, spokeswoman for AdvaMed

The Little Guy Weighs In

GO BEYOND INITIAL RESPONSE DELIVER 25 DAYS OF SUSTAINED EFFICACY DIFICID provided powerful efficacy that extended through 25 days post treatment for adult patients ≥18 years of age with Clostridium difficile-associated diarrhea (CDAD)1 DIFICID delivered: Comparable clinical response rate at the end of 10-day treatment versus vancomycin 125 mg four times daily (primary endpoint)1 DIFICID

Superior sustained response rate through 25 days beyond the end of treatment versus vancomycin 125 mg four times daily1

Vancomycin Difference (95% CI)* P value

Trial 1 88% (N=289) 86% (N=307) 2.6% (-2.9%, 8.0%) Trial 2 88% (N=253) 87% (N=256) 1.0% (-4.8%, 6.8%)

DIFICID

Vancomycin Difference (95% CI)* P value

NS

Trial 1 70% (N=289) 57% (N=307) 12.7% (4.4%, 20.9%)

0.0011

NS

Trial 2 72% (N=253) 57% (N=256) 14.6% (5.8%, 23.3%)

0.0004

Similar rates of clinical response at the end of treatment and proven or suspected CDAD during the follow-up period were seen in DIFICID-treated and vancomycin-treated patients infected with a BI isolate. However, DIFICID did not demonstrate superiority in sustained clinical response compared with vancomycin in these patients1 Sustained response rate was an additional efficacy endpoint defined as clinical response at the end of treatment and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment1 STUDY DESCRIPTION: Two phase 3, randomized, double-blind, non-inferiority studies (N=1105) comparing the efficacy and safety of oral DIFICID 200 mg twice daily versus oral vancomycin 125 mg four times daily for 10 days in the treatment of adults (aged ≥18 years) with CDAD (defined by >3 unformed bowel movements in the 24 hours before randomization and presence of either C. difficile toxin A or B in the stool within 48 hours of randomization). Enrolled patients received no more than 24 hours of pretreatment with vancomycin or metronidazole and had either no prior CDAD history or only one prior CDAD episode in the past 3 months. Subjects with life-threatening/fulminant infection, hypotension, septic shock, peritoneal signs, significant dehydration, or toxic megacolon were excluded.1 *Confidence interval was derived using Wilson’s score method. Approximately 5% to 9% of the data in each trial and treatment arm were missing sustained response data and were imputed using a multiple imputation method.1

Indications and Usage DIFICID is a macrolide antibacterial drug indicated in adults ≥18 years of age for treatment of Clostridium difficile-associated diarrhea To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile

Important Safety Information DIFICID should not be used for systemic infections Only use DIFICID for infection proven or strongly suspected to be caused by C. difficile.

Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefi fit to the patient and increases the risk of the development of drug-resistant bacteria The most common adverse reactions are nausea (11%), vomiting g (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%) Please see brief summary of full prescribing information for DIFICID on adjacent page.

For more information, please visit DIFICID.com.

Reference: 1. DIFICID [package insert]. San Diego, CA: Optimer Pharmaceuticals, Inc; May 2011.

© 2012 Optimer Pharmaceuticals, Inc. San Diego, CA 92121 5124 September 2012

Lev Melinyshyn knows firsthand what the cost of the medical device tax is. As president of a small medical device firm, UreSil, LLC, in Skokie, Ill., he said, “We did go through a layoff, beginning at 52 employees and going down to 46. Six people were laid off. The layoff was predominantly related to preparation for the tax.”

As for the effect on innovation, he said “Before we spent on new product development. Now all technical resources are directed to cost reduction. We’re quite concerned about the impact of the medical device tax. Based on future projected sales and actual net income of 2011, it will increase our tax by 26% of net income.”

Mr. Melinyshyn summed it up: “I don’t like the tax. From our perspective, it’s going to be very harmful to our industry.”

■

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60

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

New Pharmaceutical Tracking Registry Could Help Expedite Drug Recalls, Curb Shortages

By Al Heller A new global drug safety registry launched this summer to help track and trace drugs will offer several advantages over existing systems, according to its developers Leavitt Partners and Park City Group.

The registry, named ReposiTrak, is designed to pinpoint exact locations of every batch of pharmaceutical products in the supply-chain pipeline, from manufacturers to pharmacies.

This would bring three practical benefits to hospital, specialty and retail pharmacies and their prescription drug suppliers. First, it could expedite recalls by reducing tracking times from weeks to minutes, so affected products could be identified quickly and removed from distribution. Already, dozens of pharmaceutical and over-the-counter drug manufacturers have listed their products in the registry. Second, the registry could “help mitigate” critical drug shortages—which multiplied from 61 in 2005 to more than 250 in 2011, according to FDA figures—by “giving a virtual view of where product is anywhere in the United States,” said Kristina Lunner, a senior adviser to Leavitt Partners. Third, ReposiTrak could make it tougher to push counterfeit medications through the supply chain because “it has the capacity to examine inventories and know when irregularities come into the system,” noted Rich McKeown, president and CEO of Leavitt Partners, who served as chief of staff to former Health and Human Services Secretary Michael O. Leavitt, the firm’s founder.

“The ability to help manage all these areas of need is a major step forward,” said Mr. McKeown. Global counterfeit drug sales were estimated to be a $75 billion problem in 2010, up 92% from 2005, according to the Center for Medicines in the Public Interest.

At press time, Mr. McKeown said that pilot trials under way indicate that the registry will monitor the supply chain efficiently, effectively and economically, using the following features: • The ability to create an e-pedigree, with complete backward and forward visibility; this includes foreign imports entered into the system by manufacturers (when permitted by FDA to help alleviate a shortage). FDA defines pedigree as “a statement of origin that identifies each prior sale, purchase or trade of a drug, including the date of those transactions and the names and addresses of all parties to them.”

• ReposiTrak’s Universal Translator—a key simplifier for users of the registry, especially pharmacies dealing with multiple sources. “Think of it as the United Nations,” Ms. Lunner said. It has standard identifiers for products and synchronizes information technology communications for all parties in the pipeline, regardless of the language or technology used. It accepts data in any format.

• The ability to function with specialty, hospital and retail pharmacies’ existing technology. By contrast, radiofrequency identification and bar coding could potentially require hardware.

• No start-up or connect fees for pharmacies, just a $10 monthly maintenance fee.

Pharmaceutical tracking is a sister application to food tracking by the registry. Both build on the viaLink technology used to synchronize retailers with suppliers. Supply chain participants register products with the ReposiTrak engine at every point in the shipping process; ReposiTrak can validate each lot as it is received into a location. Valid lots are certified, security signed and authorized. The registry also compares distributed quantities with quantities received by lot number, and issues alerts when information doesn’t match, is missing or isn’t authenticated.

The initial mplementations of the registry include a global grocery retailer that operates 1,500 pharmacies and a major grocery wholesaler that distributes pharmaceuticals to more than 1,000 pharmacies. “The initial response to ReposiTrak from retailers, suppliers, wholesalers and other participants in the global food and drug supply chain has been very encouraging,” said Randall K. Fields, chairman and CEO of Park City Group. “The solution offers an easy-to-implement and cost-effective way to address very real safety problems. In very short order, we have progressed to the point of implementation with our first customers and have several more in the pipeline.”

could help immensely in preventing drug diversion and simplifying the drug recall process.” However, he added, “good technology is not always the answer. Too often we find that political issues affect the market. It is all too rare for the best technology to win over those that have the connections.”

A year-and-a-half in development, the registry will arrive on the market as Congress discusses two bills to reauthorize the Prescription Drug User Fee Act. At press time, the House and Senate were in negotiations about how to reconcile their respective approaches (Senate bill S.3187 and House bill H.R. 5651) to requiring tighter tracking of the drug pipeline and notifications by manufacturers of potential drug shortages, said Ms. Lunner, a former vice president of government affairs for the American Pharmacists Association. “With so much FDA funding tied to the legislation, most consider this a must-pass piece of legislation. Add industry support of the bill [to] … bipartisan Congressional support, and it’s very likely the bill will pass,” she predicted.

“Assuming the final bill includes a national standard, it would be beneficial because stakeholders feel the patchwork of state regulations [presents] an operational challenge,” according to Ms. Lunner. “FDA and Congress have tried before to establish track-and-trace and pedigree requirements but faced various barriers to implementation.”

According to the Healthcare Distribution Management Association, 20 states had no pedigree legislation or regulation, whereas 18 had adopted final rules as of June 2012 (Figure). Moreover, two states had proposed legislation, eight had enacted it, and another two had enacted it and were developing final rules.

■

A ‘Simple, Comprehensive’ Tool Commenting on the ReposiTrak system, Bruce Kneeland, a pharmacy industry consultant based in Royersford, Pa., said that based on the information from Leavitt, it appears that they “have created a way to accomplish what has eluded the industry for years—a simple, comprehensive and practical way to keep track of pharmaceuticals from the [active pharmaceutical ingredient] stage to the will-call bin of the pharmacy.”

Mr. Kneeland predicted, “If the system finds traction …

20 No legislation or regulations Enacted legislation; rules pending

2

2

Proposed legislation

8

Enacted legislation

18

Final rules adopted

0

Legislation vetoed

0

Rules pending; no legislation

WA ME ND

MT OR

MN ID

SD

NY

WI

WY

MI

NV

PA

IA

NE

IL

UT CA

OH

VT

IN WV

CO

KS

MO

VA

KY TN

OK

NM

SC

TK

AL

CT NJ

AR MS

MA RI

NC AZ

NH

DE MD

GA

DC

LA

AK FL

HI

Figure. Pedigree legislation for pharmaceutical products varies by state.a a

Current as of June 21, 2012; source: Healthcare Distributon Management Association

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62

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

Undisclosed Use of Supplements Poses Threat to Cancer Patients

By Kate O’Rourke Orlando, Fla.—Almost one-third of cancer patients taking supplements did not have them listed on their medication history or had only a partial list of what they were taking, according to a study presented at the 2012 annual meeting of the Hematology/Oncology Pharmacy Association (HOPA; poster T05).

“It is very important that we specifically

ask patients whether they are taking supplements,” said Christan Thomas, PharmD, who led the study when she was a pharmacy student at Gatton College of Pharmacy at East Tennessee State University in Johnson City. “Consumers need to disclose supplement use to their pharmacists so they can manage those interactions and side effects.”

In 2011, researchers at the Regional Cancer Center in Johnson City interviewed 99 cancer patients who had

been seen at the center and explicitly asked them about supplement use. They compared these results with the drug information in the patient charts. The researchers found that 27% of patients taking supplements either had no supplements listed on their medication histories or had only a partial list. The most commonly reported supplements were a multivitamin (54%), vitamin B12 (22%), potassium (22%), fish oil (20%), iron (17%), calcium plus vitamin D (17%),

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vitamin D alone (14%) and calcium alone (8%). Other supplements included red yeast rice and vitamin E. No potential chemotherapy–supplement interactions were specifically identified in the study population, but several supplements reportedly taken by patients have been shown to have adverse effects in cancer patients, the researchers noted. If taken in high doses, fish oil, for example, can reduce platelet aggregation and increase risk for bleeding. Calcium and iron can cause constipation, which is often already a problem with cancer patients on opioids. Red yeast rice and vitamin E can increase liver enzymes and cause fatigue and weakness.

Dr. Thomas believes that although a reminder to ask about supplements was at the top of the patient history form, nurses or other health care professionals just forgot to ask and patients didn’t connect the dots. “I think a lot of patients don’t consider supplements to be drugs because they are natural and you can get them over the counter,” said Dr. Thomas.

A More Holistic Approach Cathy Rosenbaum, PharmD, MBA, RPh, a clinical effectiveness and safety officer at Bethesda North Hospital in Cincinnati, said that disclosure of supplement use to health care professionals is not the only problem. Overuse of supplements, without the advice and consent of a physician, also is a concern.

A better approach to achieving holistic health, she noted, would be to adopt an optimal nutrition plan that embraces the use of locally grown, organic whole foods—“as much as one can afford,” noted Dr. Rosenbaum, who also is the founder and CEO of Rx Integrative Solutions, a private consulting practice in holistic medicine located in Cincinnati.

“For cancer patients trying to use vitamins, minerals and protein supplements who are having difficulty eating due to side effects from chemotherapy, nutrition in the form of a smoothie might be a more appropriate solution,” she added.

According to the National Center for Health Statistics, more than half of all Americans use some kind of vitamin or supplement (Gahche J et al. NCHS Data Brief 2011;61:1-8). A recent study of cancer patients in the Veterans Administration medical system found that 25% of patients who were using supplements did not tell their physicians about them ( Jazieh AR et al. J Altern Complement Med 2004;10:560-564).

■ Drs. Thomas and Rosenbaum reported no relevant financial conflicts of interest.

63

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

From the Literature

Use of Dietary Supplements May Raise Cancer Risk

By George Ochoa Dietary supplements have little to no effect in preventing cancer and may actually increase cancer risk, according to a review published in the Journal of the National Cancer Institute (Martínez ME et al.

2012;104:732-739).

Restricting their review to supplements that have been researched in sufficiently powered clinical trials or large observational studies, the authors focused on antioxidants, folate and folic acid, vitamin D and calcium.

Despite early evidence suggesting an anticancer benefit from antioxidants, clinical studies have not borne out that promise, the authors said. For example, β-carotene does not prevent recurrence of non-melanoma skin cancer (Greenberg ER et al. N Engl J Med d 1990;323:789-795); β-carotene and vitamin A do not protect against lung cancer (Omenn GS et al. N Engl J Med 1996;334:1150-1155); vitamins C and E do not protect against total cancer incidence (Gaziano JM et al. JAMA 2009;301:52-62); and α-tocopherol, vitamin C, and β-carotene do not protect against total cancer or cancer mortality (Lin J et al. J Natl Cancer Instt 2009;101:14-23).

However, several trials have shown evidence of an increased cancer risk

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from antioxidants, the review authors, led by María Elena Martínez, PhD, at the University of California, San Diego, reported. One such study, conducted in a population at high risk for lung cancer, found a 39% increase in lung cancer incidence in the β-carotene arm compared with the placebo arm (Omenn GS et al. N Engl J Med 1996;334:1150-1155).

Similarly, the authors did not find evidence that folic acid and folate

protect against cancer, whereas they did note evidence of increased risk for cancer from long-term folic acid supplementation. They found insufficient evidence to draw conclusions about vitamin D, and “diverse results” regarding calcium.

Many expert groups have reached a “general consensus” that “nutritional supplements have little to no benefit in preventing cancer,” the authors wrote.

Even so, much of the public continues to use dietary supplements, a fact that the authors attribute in large part to the marketing influence of supplement manufacturers. The authors call for “efforts by scientists and government officials to encourage the public to make prudent decisions based on sound evidence with respect to the use of dietary supplements for cancer prevention.”

64

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

FDA Approves Linzess To Treat IBS and Chronic Constipation

By Maureen Sullivan The FDA recently approved Linzess (linaclotide), a new drug to treat constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC) in adults who do not respond to standard treatments.

Linaclotide, the active ingredient in Linzess, is a first-in-class, guanylate

cyclase-C (GC-C) agonist that acts selectively within the intestine to accelerate gastrointestinal transit and reduce abdominal pain, according to the two companies co-marketing the drug, Forest Laboratories, Inc., and Ironwood Pharmaceuticals, Inc. An oral medication, Linzess is taken once a day on an empty stomach at least 30 minutes before the first meal of the day.

In the United States, an estimated

15.3 million people are affected by IBS (including IBS-C) and a further 63 million by chronic constipation, according to the National Institutes of Health.

“No one medication works for all patients suffering from these gastrointestinal disorders,” Victoria Kusiak, MD, deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research, said in a statement. “With the availability of new therapies, patients and their

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doctors can select the most appropriate treatment for their condition.”

The efficacy of Linzess for the management of IBS-C was established in two, double-blind, Phase III clinical studies. More than 1,600 patients were randomly assigned to take Linzess 290 mcg or placebo for at least 12 weeks.

Results showed that those taking the medication reported less abdominal pain and an increased number of complete spontaneous bowel movements than those on placebo.

Two additional double-blind, Phase III clinical studies were undertaken to evaluate Linzess as a treatment for CIC. More than 1,200 patients were randomly assigned to three groups, the first taking a daily dose of Linzess 290 mcg, the second a daily dose of Linzess 145 mcg and the third a placebo for a 12-week period. Patients taking Linzess reported having more complete, spontaneous bowel movements than those on placebo, according to results of these studies.

The FDA has approved a recommended daily dose of 290 mcg of Linzess for patients with IBS-C and 145 mcg for patients with CIC, as the studies did not show that the higher dose is more effective for patients with CIC. In the IBS-C clinical trials, the most common adverse events (AEs) in patients taking Linzess and placebo were diarrhea (20% vs. 3%), abdominal pain (7% vs. 5%), flatulence (4% vs. 2%), abdominal distension (2% vs. 1%), headache (4% vs. 3%) and viral gastroenteritis (3% vs. 1%).

AEs reported in the CIC clinical trials for Linzess versus placebo were diarrhea (16% vs. 5%), abdominal pain (7% vs. 6%), flatulence (6% vs. 5%), abdominal distension (3% vs. 2%), upper respiratory tract infection (5% vs. 4%) and sinusitis (3% vs. 2%).

Linzess is approved with a boxed warning that it should not be given to pediatric patients aged 6 through 17 years. It is contraindicated in pediatric patients up to 6 years of age and also in patients with known or suspected mechanical gastrointestinal obstruction.

The manufacturers expect to launch Linzess before the end of 2012.

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66

F D A U P D AT E & P R O D U C T N E W S

Abbott Launches Talking Pen To Assist Patients In the Administration of Humira

By Maureen Sullivan Abbott Laboratories has created a new training tool to teach patients the proper technique for self-injection of its drug, Humira (adalimumab).

Launched this summer, the Humira Talking Training Pen is a replica of the single-use pen that is used to inject the medication subcutaneously.

Although it does not contain needles, drugs or liquid, the training pen simulates each step of the actual drug administration process, thus allowing the user to practice and reinforce the injection technique.

Using a toggle button on the side of the training pen, users can choose to hear instructions in English or Spanish and can rewind and repeat the instructions up to 50 times before the pen becomes redundant. An accompanying booklet that contains step-by-step images of the injection process provides users with a visual aid.

“The multisensory approach to learning provides the opportunity for patients to use repetition to help them better understand how to take their medication,” said Phyliss Milligan, manager of immunology

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

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According to Abbott, the Humira Talking Training Pen “provides an important bridge from the doctor’s office to the patient’s home and a new advancement for patient education.” It is not designed to replace communication between doctor and patient but to reinforce and supplement doctors’ instructions.

The training pen is provided free of charge as part of the myHumira patient support program and is available from doctors and pharmacists, and online at www.humira.com/ myhumira/injection-training-kit.aspx.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2012

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MoviPrep®

USE IN SPECIFIC POPULATIONS

(PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid for oral solution) The following is a brief summary only; see full Prescribing Information for complete product information.

Pregnancy: Pregnancy Category C. Animal reproduction studies have not been performed with MoviPrep. It is also not known if MoviPrep can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. MoviPrep should be given to a pregnant woman only if clearly needed.

INDICATIONS AND USAGE MoviPrep is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older.

CONTRAINDICATIONS

MoviPrep is contraindicated in patients with the following conditions: gastrointestinal (GI) obstruction, bowel perforation, gastric retention, ileus, toxic colitis or toxic megacolon, or hypersensitivity to any components of MoviPrep.

WARNINGS AND PRECAUTIONS Use with caution in patients using concomitant medications that increase the risk of electrolyte abnormalities (such as diuretics, angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs), patients with known or suspected hyponatremia), patients at increased risk of cardiac arrhythmias, patients with a history of seizures or at increased risk of seizures such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with impaired renal function or patients taking concomitant medications that affect renal function (such as diuretics, ACE inhibitors, ARBs, or non-steroidal anti-inflammatory drugs), patients with severe ulcerative colitis or inflammatory bowel disease, patients with impaired gag reflex or patients prone to regurgitation or aspiration, patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization.

Concurrent use of stimulant laxatives and MoviPrep may increase the risk and is not recommended. The potential for mucosal ulcerations resulting from the bowel preparation should be considered when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease.

If gastrointestinal obstruction or perforation is suspected, appropriate diagnostic studies should be performed to rule out these conditions before administering MoviPrep. If a patient experiences severe bloating, abdominal distension, or abdominal pain, administration should be slowed or temporarily discontinued until symptoms abate.

Patients with electrolyte abnormalities should have them corrected before treatment with MoviPrep. Patients should be advised to hydrate adequately before, during, and after the use of MoviPrep. If a patient develops significant vomiting or signs of dehydration after taking MoviPrep post-colonoscopy lab tests (electrolytes, creatinine, and BUN) should be considered. Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias, seizures and renal impairment.

MoviPrep contains phenylalanine (233 mg per treatment).

ADVERSE REACTIONS

In clinical trials, the most common adverse reactions for split dosing regimen (incidence 5%) were malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing regimen (incidence 5%) were abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness.

Isolated cases of urticaria, rhinorrhea, dermatitis, and anaphylactic reaction have been reported with PEG-based products and may represent allergic reactions.

Published literature contains isolated reports of serious adverse events following the administration of PEG-based products in patients over 60 years of age.

These adverse events included upper gastrointestinal bleeding from a MalloryWeis tear, esophageal perforation, asystole, and acute pulmonary edema after aspirating PEG-based preparation.

In addition to adverse reactions reported from clinical trials, the following adverse events have been identified during post-approval use of MoviPrep: hypersensitivity reactions including anaphylaxis (some of which were severe, including shock), rash, urticaria, pruritis, lip, tongue and facial swelling, dyspnea, chest tightness and throat tightness. Fever, chills and dehydration.

DRUG INTERACTIONS Use caution when prescribing MoviPrep for patients with conditions, or who are using medications that increase the risk for fluid and electrolyte disturbances or may increase the risk of adverse events of seizure, arrhythmias, and prolonged QT in the setting of fluid and electrolyte abnormalities. Consider additional patient evaluations as appropriate.

Oral medication administered within 1 hour of the start of administration of MoviPrep may be flushed from the gastrointestinal tract and the medication may not be absorbed.

Nursing Mothers: Because many drugs are excreted in human milk, caution should be exercised when MoviPrep is administered to a nursing woman.

Pediatric Use: The safety and effectiveness of MoviPrep in pediatric patients has not been established.

Geriatric Use: Of the 413 patients in clinical studies receiving MoviPrep, 91 (22%) patients were aged 65 or older, while 25 (6%) patients were over 75 years of age. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients, and other reported clinical experience has not identified differences in responses between geriatric patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

OVERDOSAGE There have been no reported cases of overdose with MoviPrep. Purposeful or gross accidental ingestion of more than the recommended dose of MoviPrep might be expected to lead to severe electrolyte disturbances, including hyponatremia and/or hypokalemia, as well as dehydration and hypovolemia, with signs and symptoms of these disturbances. The patient who has taken an overdose should be monitored carefully, and treated symptomatically for complications.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Long-term studies in animals to evaluate the carcinogenic potential have not been performed with MoviPrep. Studies to evaluate potential for impairment of fertility or mutagenic potential have not been performed with MoviPrep.

STORAGE Store carton/container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

When reconstituted, store upright and keep solution refrigerated. Use within 24 hours.

PATIENT COUNSELING INFORMATION s Advise patients to read the Medication Guide included in the full prescribing information. s Advise patients who require a diet low in phenylalanine that MoviPrep contains phenylalanine. s Ask patients to inform you if they have trouble swallowing or are prone to regurgitation or aspiration. s Instruct patients that each pouch needs to be diluted in water before ingestion and that they need to drink additional clear liquid (e.g., water, clear soup, fruit juice without pulp, soft drinks, tea and/or coffee without milk) according to instructions. s Inform patients that oral medications may not be absorbed properly if they are taken within one hour of starting each dose of MoviPrep. s Tell patients not to take other laxatives while they are taking MoviPrep. s Tell patients that MoviPrep produces a watery stool (diarrhea) which cleanses the colon before colonoscopy. Advise patients receiving MoviPrep to adequately hydrate before, during, and after the use of MoviPrep. Patients may have clear soup and/or plain yogurt for dinner, finishing the evening meal at least one hour prior to the start of MoviPrep treatment. No solid food should be taken from the start of MoviPrep treatment until after the colonoscopy. s Tell patients that the first bowel movement may occur approximately 1 hour after the start of MoviPrep administration. Abdominal bloating and distention may occur before the first bowel movement. If severe abdominal discomfort or distention occurs, stop drinking MoviPrep temporarily or drink each portion at longer intervals until these symptoms diminish. If severe symptoms persist, notify your health provider.

Rx only

Manufactured by: Norgine B.V. Hogehilweg 7 1101 CA Amsterdam Zuidoost Netherlands For: Salix Pharmaceuticals, Inc. Raleigh, NC 27615 © 2012 Salix Pharmaceuticals Inc. Feb 12

Web site: www.salix.com E-mail: customer.service@salix.com 8510 Colonnade Center Drive Raleigh, NC 27615 Tel. 866-669-SLXP (7597) All rights reserved.

MoviPrep® #1 prescribed branded purgative in the United States

1

Seeing is believing MoviPrep has proven 89% excellent or good cleansing when used as a split dose2 ° Low-volume PEG-3350 provides consistent, clear visibility of the entire colon ° FDA approved for PM|AM Split Dosing™ ° Osmotic laxative with electrolytes ° In clinical trials, no differences in safety and tolerability between younger and geriatric patients -Most common adverse reactions for split dosing (incidence ⱖ5%) are malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing (incidence ⱖ5%) are abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness.

Please see Brief Summary of full Prescribing Information on reverse.

References: 1. Medi-Span® Price Rx® [database online]. Indianapolis, IN: Wolters Kluwer Health. http://www.medispan.com/drug-pricing-analysis-pricerx.aspx. Accessed July 13, 2012. 2. MoviPrep [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012.

Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel·866.669.SLXP (7597) MoviPrep® is a registered trademark and PM | AM Split Dosing™ is a trademark of Salix Pharmaceuticals, Inc. © 2012 Salix Pharmaceuticals, Inc. All rights reserved. MOV11/41-3

www.MoviPrep.com

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OCTOBER 2012

REPORT The Benefits of Dietary Fiber for Public Health and Wellness Introduction

Faculty The US Department of Agriculture’s recommended dietary fiber intake for Dietary fiber remains an evolving and Robynne Chutkan, MD adults is 14 g per 1,000 calories, or important topic. Although the effort Medical Director about 25 g per day in women and 38 g to understand the functional role of Digestive Center for Women per day in men.1 The average daily intake dietary fiber has now yielded a variety of significant subcategories that allow among adults in the United States, Assistant Professor detailed analyses of its physiologic which was relatively steady between Division of Gastroenterology roles, the underlying concepts remain 1999 and 2008, currently is 14.8 g per Georgetown University simple. The low consumption of fiber day—less than half of the recommended Washington, DC in the American diet has contributed to daily value.3 the increased incidence of preventable The Benefits of Dietary Fiber diseases.1,2 Clinicians who can effectively encourage patients to increase their dietary fiber intake are in a According to the Academy of Nutrition and Dietetics, position to change the trajectory of the risk for and manthe currently recommended daily values for dietary fiber agement of several diseases. Engaging patients to conintake are appropriate and reasonable. Epidemiologic sume more fresh fruits and vegetables can be a major studies have shown a correlation between inadequate step forward, but a more regimented approach has the dietary fiber intake and increased rates of cardiovascular potential to yield benefits, particularly for those in which disease (CVD).2 But data also have shown a link between a proper diet may not be feasible on a daily basis. low dietary fiber intake and an increase in several of the In many patients, an increase in dietary fiber is an indicated risk factors for CVD, including hypertension,4 hyperlipidtherapeutic intervention. “Dietary fiber still does not receive emia,5 diabetes,6 and metabolic syndrome.7 The ability of the attention it deserves. Even some gastroenterologists do fiber to regulate motility and induce immunomodulatory not fully recognize that increased dietary fiber is medicine. effects may explain its benefits for irritable bowel synThere needs to be a level of urgency in addressing dietary drome,2,8 and studies have linked high-fiber diets with a fiber in patients with health risks that can be modified with a reduced risk for colorectal cancer.2,9 systematic approach,” said Robynne Chutkan, MD, medical Another benefit of a high-fiber diet is improved weight director, Digestive Center for Women, assistant professor, regulation. Dietary fiber has been shown to influence hunDivision of Gastroenterology, Georgetown University, Washger, satiety, energy intake, and body composition, and ington, DC. Guiding individuals toward a diet high in fiber epidemiologic studies associate low-fiber diets with an has potential health benefits, but “the level at which one increased risk for obesity.10,11 There is speculation that the intervenes needs to be intensified as the expected health persistent paucity of fresh fruits and vegetables and other benefits for the patient in front of you increase.” sources of fiber have contributed to the ongoing obesity

Supported by

REPORT Table 1. Characteristics and Benefits of Fiber Supplements Product

Active Ingredient

Form, Amount of Active Ingredient Per Dose

Fiber Type

Active Bulks Stools

Lowers Lowers Lowers Cholesterol Blood Blood Sugar Pressure

Powder, 3.4 g; Capsule, 0.525 g (5 capsules/dose)

70% viscous, soluble; gel forming; holds water; 30% insoluble

Yes

Yes

Yes

Yes

Methylcellulose Powder, 2 g; Citrucel®, Citrucel® Caplet, 0.5 g swallowable (2 caplets/dose) caplets

100% soluble; holds some water

Partially

No

ND

ND

BeneFiber ®

Powder, 3 g

100% soluble

No

No

ND

ND

Caplet, 0.625 g (2 caplets/dose)

100% insoluble; Yes gel forming; holds water after being broken down in the stomach

No

ND

ND

Tablet, 2 g/tablet (2 tablets/dose)

100% soluble

No

ND

ND

Metamucil®, Psyllium husk Metamucil® capsules

Wheat dextrin

®

FiberCon Calcium swallowable Polycarbophil caplets

FiberChoice®

Inulin

No

ND, no data available Adapted from reference 14.

epidemic in the United States and other industrialized countries.10,12 The benefits of a high-fiber diet likely exert a cumulative effect and are most effective when initiated in children.13 But certain benefits, such as reductions in blood pressure, have been observed within several weeks.4 “Diets low in fiber accelerate age-related processes; autopsy studies in children as young as 10 [years old] with a history of high-fat, low-fiber diets show early stages of atherosclerosis.

Cases of diverticulosis, which were once largely confined to individuals over the age of 50 years, are now being observed among patients in their 20s. This is a significant public health problem as well as an identifiable contributor to health problems in individual patients,” said Dr. Chutkan.

Clinical Effect of Fiber Sources Progress in understanding the function of dietary fiber in normal physiology suggests that specific sources can be linked to unique health benefits. Fiber was once defined as the nondigestible carbohydrates and lignin in plants.13 However, a breakdown of the physiologic effects of fiber has led to the identification of several important distinctions, particularly insoluble and soluble fibers.13 Insoluble fiber, such as cellulose, wheat bran, and resistant starches, provides the bulk needed for a favorable consistency of gastric contents and effective stool formation.2,8 Following ingestion, insoluble fibers trap water and pass through the digestive system mainly intact. This helps to increase stool bulk and colonic motility, which promotes regularity.14 Soluble fiber includes a viscous and nonviscous subtype.15 Viscous, soluble fiber, such as that provided by oats, apples, bananas, and psyllium husk, is important for a variety of health conditions.2,13 Following ingestion, these fibers absorb water; once in the stomach, they mix with stomach fluids and partially digested food, forming into a gel.14 As they pass through

2

the small intestine, viscous, soluble fibers bind with sugars, cholesterol, and fats, which slows their absorption into the bloodstream. As they move through the large intestine, these fibers promote regularity and exert a favorable effect on the balanced absorption of nutrients.2,14 “In counseling patients about a healthy diet, it can be helpful to make a distinction between ‘live’ fiber sources, such as fruits, vegetables, and legumes, and ‘dead’ fiber sources, which often include those advertised on packaged foods.

When patients are trying to increase fiber intake, the live fiber sources should be emphasized,” Dr. Chutkan suggested.

This advice is useful for achieving a healthy diet, but recognizing differences between specific types of soluble fiber may be important when intervening in patients who are at risk for or have a disease that is exacerbated by a low-fiber diet.

In these patients, fiber supplements are often appropriate, particularly during the difficult lifestyle changes that can be an obstacle to an immediate increase in fiber consumption. The differences in benefits derived from specific fiber supplements illustrate the need for clinical distinctions. Importantly, each commercial supplement employs a different fiber source with unique labeling.

“Fiber sources are not the same. When prescribing a highfiber diet to improve bowel function or to reduce cardiovascular risk, it is important to be specific about the need for viscous, soluble fiber sources relative to insoluble [or nonviscous] fibers.

It is easy to be misled by labels. Health bars advertising highfiber content often are a relatively poor source of the types of fiber that patients need,” noted Dr. Chutkan.

Among the 5 most commonly prescribed fiber supplements, wheat dextrin and inulin do not have an indication for improving regularity despite being soluble fibers (Table 1).14 Another supplement, methylcellulose, does have utility for improving bowel

REPORT Table 2. Research on Clinical Benefits of Dietary Fiber Investigators

Purpose

Therapy

Outcome

Anderson et al, 1999

Safety and efficacy of psyllium husk fiber in conjunction with a traditional diet for diabetes in the treatment of men with type 2 diabetes and hypercholesterolemia

5.1 g psyllium or cellulose placebo bid for 8 wk. Results were taken at baseline and at week 8

Psyllium group had an 11% reduction in all-day postprandial serum glucose concentrations compared with placebo (–4.2% vs 6.8%, respectively; P<0.05) and a 19.2% reduction in post-lunch serum glucose concentrations compared with placebo (–6.5% vs 12.7%, respectively; P<0.01)

Montonen et al, 2003

Relationship between intake of whole grains and fiber on the incidence of type 2 diabetes

None, patients were studied based on normal dietary habits

Investigators reported an inverse relationship between whole grain intake or cereal fiber intake and the risk for type 2 diabetes

Whelton et al, 2005

A meta-analysis of randomized controlled trials to examine the effects of dietary fiber intake on blood pressure

Fiber intake for hypertensive patients ranged from 7 to 13.3 g/d

Results of 25 trials suggest that an increase in dietary fiber consumption may provide a safe and acceptable means of reducing blood pressure in patients with hypertension

Anderson et al, 2000

Efficacy and safety of psyllium in addition to a low-fat diet in men and women with hypercholesterolemia compared with cellulose placebo

10.2 g/d of psyllium for ≥8 wk

Psyllium reduced serum TC levels by 4% (P<0.0001) and LDL-C by 7% (P<0.0001) compared with placebo

Pal et al, 2011

Randomized, single-blind, parallel-design study to investigate the effect of additional dietary fiber intake through a healthy diet or dietary supplement on risk factors for metabolic syndrome in overweight and obese patients

Patients were placed into 4 groups: placebo with normal diet; fiber supplement (12 g psyllium tid) with normal diet; healthy diet plus placebo; and healthy diet plus fiber supplement (12 g psyllium tid)

Psyllium plus normal diet led to improvements in TC, LDL-C, body weight, BMI, and percent body fat compared with placebo.

Psyllium plus a healthy diet led to even greater improvements in these parameters compared with the other 3 interventions

bid, twice daily; BMI, body mass index; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; tid, three times daily Adapted from references 4, 6, 7, 17, and 18.

function. But this soluble, viscous fiber has not provided a positive effect on weight management.15 In contrast, psyllium, a viscous, soluble fiber, improves bowel function and has shown benefits for a variety of conditions, including CVD, diabetes, obesity,13 and potentially, colorectal cancer.9 Psyllium also decreases hunger through satiation and reduces the absorption of fats; thus, it may help individuals manage their weight.16 As a result, psyllium supplementation may have an important role in the management of metabolic syndrome.16 A randomized, placebo-controlled study found that the addition of a psyllium fiber supplement (12 g taken 3 times daily) to the normal diets of overweight and obese individuals led to improvements in total cholesterol (TC), serum lowdensity lipoprotein cholesterol (LDL-C), body weight, body mass index, and percent body fat compared with controls.7 A previous meta-analysis of 8 clinical studies showed that for patients already consuming a low-fat diet, psyllium fiber supplementation provided additional benefits to both TC levels (4% reduction) and serum LDL-C levels (7% reduction) compared with placebo.17 In a randomized, placebo-controlled trial of men with type 2 diabetes, patients assigned to the psyllium supplement group had an 11% reduction in all-day postprandial serum

glucose concentrations compared with placebo (–4.2% vs 6.8%, respectively; P<0.05).18 Additionally, patients who received psyllium had a 19.2% reduction in their post-lunch serum glucose concentrations (–6.5% vs 12.7%, respectively; P<0.01).18 Patients assigned to the psyllium group also had a 9% reduction in serum TC concentrations compared with placebo (–2.1 vs 6.9%, respectively; P=0.068).18 The authors concluded that the use of psyllium, in combination with a traditional diet, improves metabolic control in individuals with type 2 diabetes and high cholesterol.18 Table 2 presents an overview of studies on the clinical benefits of fiber.4,6,7,17,18 Overall, patients should seek an array of fiber sources to gain the full spectrum of health benefits, but it is important to consider the unique characteristics of fiber in both food and supplements when treating or preventing specific diseases. Fiber sources are not interchangeable, whether the goals include a reduction in risk factors for CVD, weight management, or controlling constipation. In those who require fiber supplements, the relative characteristics of current options can be compared in published charts (Table 1). “It is important for clinicians to be aware of the different types of fiber. This is true both for counseling patients about food and when considering supplements,” advised Dr. Chutkan.

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REPORT Strategies for Effective Patient Counseling Fiber supplements are an effective way to accelerate fiber intake for individuals with a specific indication, but such prescriptions should always be coupled with counseling that is designed to produce a successful transition to a high-fiber diet.

As a part of regular health maintenance, the value of highfiber diets should repeatedly be reinforced. Patients should be reminded that achieving recommended levels of fiber intake has the potential to reduce the risk for diabetes and CVD while improving bowel function and potentially avoiding certain cancers. However, in those who already have risk factors for these diseases, the intensity of counseling and the degree of intervention should be adjusted accordingly.

“It is important to be sensitive to where the patient is regarding their interest and ability to adopt the changes in diet required to improve fiber intake,” said Dr. Chutkan. “Some patients are ready to hear the message, others less so. Most people will substantially overestimate their fiber intake, so it is often helpful for patients to keep a food journal so that they can recognize their own eating patterns.”

There are online tools and software programs that can help patients organize and track food and fiber consumption, but clinicians should not hesitate to refer patients to experts who can design menus and programs that are palatable to the specific patient. For patients accustomed to high-salt, high-fat diets, some retraining of food preferences will be necessary.

Patients should incorporate dietary changes with other lifestyle modifications, such as exercise, in a broader effort to change the patient’s orientation to healthy choices.

Although it is important for patients to understand that the increase in dietary fiber is a medical intervention, “It is also important to take this out of the office setting,” suggested Dr. Chutkan. “You need to get them to bring these concepts home by engaging in activities, such as cooking classes, which will help them make real change.”

Follow-up is an essential component of these changes to encourage compliance and to make further adjustments to help patients reach their target fiber intake. Documenting the health benefits of increased fiber intake, such as blood pressure reductions, can further reinforce compliance. For patients who remain compliant, an improvement in their sense of well-being also may provide an important reinforcement of these lifestyle changes; in turn, this produces lasting improvements in fiber intake and patients’ overall quality of life.

Conclusion The large body of evidence linking high-fiber diets with health benefits has been accompanied by an improved understanding of the roles that specific types of fiber perform in mediating nutrient absorption. This has enabled a refinement of high-fiber diets to adapt them to specific health issues. Although improved bowel function can be anticipated from a well-balanced diet that is high in fiber, the inclusion of viscous, soluble fibers, which are provided by certain fresh fruits (eg, apples and bananas), legumes, oats, and certain fiber supplements (eg, those containing psyllium husk), is particularly relevant to reducing the

risk for CVD. Clinicians have an opportunity to substantially improve patients’ health by understanding the specific functions of dietary fiber. Recognizing that many patients cannot reach the recommended daily values for fiber should encourage health care practitioners to adopt effective strategies for success.

References 1. US Department of Agriculture. Dietary Guidelines for Americans, 2010.

7th ed. Washington, DC: US Government Printing Office; 2010.

2. Slavin JL. Position of the American Dietetic Association: health implications of dietary fiber. J Am Diet Assoc. 2008;108(10):1716-1731.

3. King DE, Mainous AG, Lambourne CA. Trends in dietary fiber intake in the United States, 1999-2008. J Acad Nutr Diet. 2012;112(5):642-648.

4. Whelton SP, Hyre AD, Pedersen B, Yi Y, Whelton PK, He J. Effect of dietary fiber intake on blood pressure: a meta-analysis of randomized, controlled clinical trials. J Hypertens. 2005;23(3):475-481.

5. Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr. 1999;69(1):30-42.

6. Montonen J, Knekt P, Jarvinen R, Aromaa A, Reunanen A. Whole-grain and fiber intake and the incidence of type 2 diabetes. Am J Clin Nutr. 2003;77(3): 622-629.

7. Pal S, Khossousi A, Binns C, Dhaliwal S, Ellis V. The effect of a fibre supplement compared to a healthy diet on body composition, lipids, glucose, insulin and other metabolic syndrome risk factors in overweight and obese individuals. Br J Nutr. 2011;105(1):90-100.

8. Petruziello L, Iacopini M, Bulajic M, Shah S, Costamagna G. Uncomplicated diverticular disease of the colon. Aliment Pharmacol Ther. 2006;23(10): 1379-1391.

9. Park Y, Hunter DJ, Spiegelman D, et al. Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies.

JAMA. 2005;294(22):2849-2857.

10. Howarth NC, Saltzman E, Roberts SB. Dietary fiber and weight regulation.

Nutr Rev. 2001;59(5):129-139.

11. Slavin JL. Dietary fiber and body weight. Nutrition. 2005;21(3):411-418.

12. Liu S, Willett WC, Manson JE, Hu FB, Rosner B, Colditz G. Relation between changes in intakes of dietary fiber and grain products and changes in weight and development of obesity among middle-aged women. Am J Clin Nutr.

2003;78(5):920-927.

13. Anderson JW, Baird P, Davis RH, et al. Health benefits of dietary fiber.

Nutr Rev. 2009;67(4):188-205.

14. National Fiber Council. A fresh look at fiber. http://www.nationalfibercouncil. org/pdfs/FINAL_FINAL%20NFC%20Brochure4.6.07.pdf. Accessed August 24, 2012.

15. Anderson JW. All fibers are not created equal. J Med. 2009;2(2):97-91.

16. Giacosa A, Rondanelli M. The right fiber for the right disease: an update on the psyllium seed husk and the metabolic syndrome. J Clin Gastroenterol.

2010;44(suppl 1):S58-S60.

17. Anderson JW, Allgood LD, Lawrence A, et al. Cholesterol-lowering effects of psyllium intake adjunctive to diet therapy in men and women with hypercholesterolemia: meta-analysis of 8 controlled trials. Am J Clin Nutr. 2000; 71(2):472-479.

18. Anderson JW, Allgood LD, Turner J, Oeltgen PR, Daggy BP. Effects of psyllium on glucose and serum lipid responses in men with type 2 diabetes and hypercholesterolemia. Am J Clin Nutr. 1999;70(4):466-473.

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Proctor & Gamble, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

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Copyright © 2012, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

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Financial Disclosure: Dr. Chutkan reported that she has served as a consultant for Given Imaging, Inc.