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Volume 63, Number 8 • August 2012 40th ANNIVERSARY 1972–201 2
Rising Prevalence of Pediatric NAFLD a ‘Major Health Problem’
Quality Initiatives, Benchmarking in Gastroenterology: Is It Worth It? One Expert Says ‘ Yes,’ Explains Why
BY DAVID WILD BY CAROLINE HELWICK SAN DIEGO—The prevalence of pediatric nonalcoholic fatty liver disease (NAFLD) is rising at an alarming rate and has implications for liver-related morbidity and mortality later in life, said researchers at the 2012 see NAFLD, page 28
Colonoscopy in Elders Yields ‘Shocking’ Rate Of Curable Cancers BY CAROLINE HELWICK SAN DIEGO—Researchers reported a high rate of curable colorectal cancers among elderly patients undergoing screening colonoscopy for the first time. Therefore, advanced age should not be a reason not to screen, they told attendees of the 2012 Digestive Disease Week meeting.
SAN DIEGO—Gastroenterologists who are procrastinating about participating in quality initiatives need to get on board now, according to Irving M. Pike, MD, who laid out his reasons in a lecture at the 2012 Digestive Disease Week meeting. Although there may be reimbursement advantages associated with quality reporting, that should not be the incentive, Dr. Pike said. “We should be doing it anyway,” he told colleagues at the meeting. Participation in quality initiatives “could positively impact your practice reputation if you do it, and negatively if you don’t,” said Dr. Pike, chief medical officer of John Muir Health in Walnut Creek, Calif. “Initially, it may cost you money nott to,” he added.
Incentives and Penalties During 2012, physicians have their last chance to receive the full $44,000 per physician for attesting to “meaningful use” grants. Penalties for not meeting the meaningful use definition come into play after 2016 and escalate over time. Quality reporting is one of the criteria for attesting to “meaningful use.” see Quality Initiatives, page 20
see Elderly Colonoscopy, page 36
I N S I D E
How To Become a Five-Star GI Practice
Experts share their favorite abstracts from the 2012 DDW meeting....................page 7
BY MO ONICA J. SMITH
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D I C A L P R AC T I C E
EXPERTS’ PICKS Best of Digestive Disease Week (DDW): Part 2
KNOXVILLE, TENN.—Whatever changes health care reform brings, it is likely tthat the shift toward value-based reimbursement will have a significant influence on the relationships between health care organizations and gastroenteroloogists, as the battle continues over who controls the health care dollar. “Your referrals are going to be based on the quality of care you deliver and on the see Five-Star Practice, page 14 PRODUCT ANNOUNCEMENT see page 49 for product information
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EXPERTS’ PICKS Best of European Association for the Study of the Liver/International Liver Congress Hepatologists Nezam Afdhal, MD, Stuart C. Gordon, MD, and Ira Jacobson, MD, share their favorite abstracts ..................................page 22
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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
Vol. 63, No. 8 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD
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LETTER TO THE EDITOR
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
Long Live Private Practice Medicine! Re: “The Private Practice Model of Medicine Must Survive,� by Roseman B, Flake T, Kopen D. Gastroenterology & Endoscopy News June 2012;63:40,44-46. To the Editor:
To the Editor:
Thanks for that excellent article on this topic. I have been in private practice for 24 years, and I fully agree that this model provides the best care of the patient. I have patients for whom I have cared for more than 20 years who have changed primary care doctors several times because of insurance reasons, and many times I know these patients better than the new primary care physician. They continue to see me for their care and I end up seeing their families and friends because I always try to provide great care and put the patient’s interest first. My income has been steadily dropping over the past 15 years, but I’m still working for the patient! I dread the death of the private practitioner and the ability to see my doctor of choice who I know and trust. Thanks again! Dan Acosta, MD Gastroenterologist Corpus Christi, Texas
I am in agreement with everything said in the recent article on saving fee-for-service medicine. I would add, however, that physicians helped create the ever-expanding and largely physician-unfriendly regulated environment Patients Prefer GI Quality Improvement Consortium Colonoscopy Catching on Across the Country that we have today, and physicians will have to get themProgram a Win-Win-Win for Physicians, Patients, Payers selves out of it. What began as an acceptance of small discounts in a supposed exchange for more patients (that never happened) and exploded into huge discounts; multiple, Fly and Flare Air Travel Linked to IBD Flares unfunded mandates by independent practice associations, health maintenance organizations, insurance companies and state and federal governments; markedly lower payments; and increased overhead has led to an overworked Physician n Rallie es Colleagues To Help and underpaid U.S. physician aggregate. Shape Fu uture off Health Care Reform We physicians are the only essential part of medical care and the ultimate advocates for our patients. We need to look in the mirror and ask ourselves why we sign inadequate contracts and don’t have the pricing power in the market to cover our costs and a reasonable profit. It’s time for physicians to say, “We’ve had enough.� As the current scheme du jour—now, accountable care organizations—fails to produce results and lowers our pay even more, we need to make better business decisions in the best interests of ourselves, our families and our patients. Ronald Feldman, MD Correction: Gastroenterologist The article “Investigational Agent, Teduglutide, Reduces Parenteral Volume Escondido, Calif. Needs in Patients With Short Bowel Syndrome,� which appeared on page 42 of the July 2012 issue of Gastroenterology & Endoscopy News, was incorrectly attributed to Monica J. Smith. The article was written by Ted Bosworth. gastroendonews.com
The Independent Monthly Newspaper for Gastroenterologists
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BY DAVID WILD
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
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.
“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 see GIQuIC, page 24
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The Use of JCV Antibody Assay in Treating Patients With Crohn’s Disease .................. >}iÊ££
BY KATE O’ROURKE
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
Stephen B. Hanauer, MD
Uma Mahadevan, MD
David T. Rubin, MD
see Health Care, page 38
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Cut and Paste the computer-generated and template-driven approach to medicine. Think back to when you were a medical student. You rotated on a service as a third-year clinical clerk and began to use some of the principles you learned in physical diagnosis class. We all were excited about putting on that white coat and showing up on the inpatient floor with the idea that now we could be part of the team that takes care of patients and could feel what it was like to be a doctor. One of our duties was to take a good history and physical on a patient and provide that write-up to our mentors who were directing the outpatient and inpatient care. The other important issue was to follow a patient on a daily basis in order to see the positive progression of someone who was benefiting from good medical care and, on the surgical service, recuperating from an operation that we had the privilege to witness. We were taught to write progress notes in the patient’s chart,
Frederick L. Greene, MD Chairman, Department of General Surgery Carolinas Medical Center Charlotte, North Carolina This editorial is stimulated by the rollout of the computerized physician order entry (CPOE) portion of our electronic medical records (EMR) system this week at my institution. I am sure that discussions of the role of the EMR and CPOE have been ongoing at your location. Obviously, a great deal of work and planning has gone into this next phase of the “meaningful use� of the EMR and all attending physicians, trainees, nurses, mid-level providers and so on, have spent hours getting ready for this evolution. It is unclear to many whether the EMR will, in fact, increase the overall quality of care and reduce the opportunities for misadventure. I also have concerns about the unintended consequences of
Rather than spend time at the bedside analyzing the actual patient, the temptation will be to rely on inputting clinical information to satisfy templates that have been created to populate the cyber-chart. and these were dutifully countersigned by our residents and ultimately perhaps by the attending physician. This routine also allowed us to learn how to function as physicians and incorporate laboratory data, intake and output information, patient-related symptoms and other meaningful criteria into a progress note. It gave us the opportunity to feel that we were part of the team. Sadly, I have a feeling that this important rite of passage for students may be lost in the template-driven, cut-andpaste world of electronic records keeping. In teaching institutions, one of the
byproducts of introducing the EMR is that the medical student has been marginalized from the record-keeping queue. The template-driven progress notes are now, in many teaching institutions, solely in the purview of the attending physician, mid-level providers and the residents caring for the patient. At many institutions, the medical student does not play a role in developing a progress note or placing see Cut and Paste, page 11
DDW 2012
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
7
Experts’ Picks:
The Best of Digestive g Disease Week 20122: Part 2 COMPILED AND WRITTEN BY DAVID WILD
Gastroenterology & Endoscopy Newss asked the experts: What were your favorite abstracts presented at this year’s Digestive Disease Week meeting? Following is a collection of selected abstracts and comments on the meeting as provided by three experts in the field. Stay tuned for moore expert commentary on this year’s DDW meeting in the September issue of Gastroenterology & En ndoscopy News.
Prateek Sharma, MD Professor of Medicine University of Kansas Medical School Kansas City, Kansas
570.
Real-Time Diminutive Polyp Diagnosis Accurately Determines Colonoscopy Surveillance Interval in Clinical Practice (Heiko P et al)
they accurately diagnosed 88.1% of diminutive polyps in real time, with a 95.4% negative predictive value for these polyps. Surveillance interval recommendaations based on real-time diagnoses and supplementary patthology reports agreed with pathology reports in 96.4% % of cases, the researchers found. Dr. Sharma: The results from this study are impressive and could lead to a paradigm shift in how we approach small/diminutive polyps in the colon. Detection of several diminutive hyperplastic-app pearing polyps in the left side of the colon during colonooscopy leads to multiple biopsies, which is a significant bu urden in terms of financial costs and resources. As the ASGE’s PIVIs recommend, if we can accurately distingguish between hyperplastic and adenomatous polyps and predict an appropriate surveillance colonoscopy in nterval using a given technology, we can improve the efficciency of colonoscopy and reduce these costs. Given the large number of polyps evaaluated in this study, the extremely high net negative prredictive value of 95% in diagnosing small rectosigmoid polyps, as well as the impressive accuracy of predictin ng surveillance intervals, the findings show that a “resectt-and-discard” approach using cap-assisted HDNBI reeaches the set thresholds.
In 2011, the American Society of Gastrointestinal Endoscopy (ASGE) issued Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) guidelines suggesting diminutive colonic polyps 5 mm or less can be resected and discarded without undergoing pathological analyses if clinicians can make real-time diagnoses in concordance with pathology assessment at least 90% of the time (Rex D et al. Gastrointest Endosc 2011;73:419-422). The current study set out to document the predictive Decreasing Rates of value of real-time diminutive polyp diagnosis and surveilEsophageal Adenocarcinoma lance interval recommendations made using cap-assisted (EAC) in Patients with colonoscopy with high-definition narrow band imaging Persistent Nondysplastic Barrett’s Esophagus (HDNBI). To this end, a group of 10 experienced endos(NDBE): Results from a Large Multicenter Cohort copists trained to conduct real-time diagnoses of colonic (Gaddam S et al) polyps with HDNBI performed 608 cap-assisted colonoscopies. Endoscopists were asked to determine whether Although recent research has suggested patients with a polyp was adenomatous and how confident they were nondysplastic Barrett’s esophagus (NDBE) are at low in their diagnosis, both in real time. All real-time diag- risk for developing high-grade dysplasia (HGD) (Hvidnosed polyps were also excised and examined patho- Jensen F et al. N Engl J Med 2011;365:1375-1383), the logically. Endoscopists likelihood of prowere asked to recomgression to EAC in ‘The results from this study are impressive mend surveillance those patients with colonoscopy intervals persistent NDBE and could lead to a paradigm shift in how we based on their highhas not been estabapproach small/diminutive polyps in the colon.’ est-confidence diaglished. This multi—Prateek Sharma, MD noses along with any center cohort study supplemental patholexamined data from ogy findings. Biopsy 1,401 patients with diagnoses and surveillance intervals were compared with persistent NDBE who underwent a mean 5.6 years pathology data and surveillance recommendations. of surveillance endoscopies following initial diagnosis Analyses showed 80.6% of the 1,001 detected polyps (standard deviation [SD], 3.8 years), for a total of 7,845 were diminutive. Pathological findings showed 54.4% patient-years of surveillance. HGD or EAC that develof all polyps and 49.2% of diminutive polyps were oped within one year of NDBE were considered to have adenomatous. Clinicians’ diagnoses fell in line with been missed at the time of diagnosis and were excluded pathology reports 85.2% of the time for all polyps and from the analysis. Nearly all patients were white males 83.6% of the time for diminutive polyps. Clinicians were and were a mean age of 59 years. Forty-six percent had highly confident of 81.3% of the diagnoses they made a history of smoking. The mean length of BE was 4 cm for all detected polyps and 79.9% of their diagnoses for (SD, 3.2 cm). diminutive polyps. For rectosigmoid polyps specifically, The researchers found 25 patients developed EAC
962.
after their first index endoscopy, yielding an annual risk for EAC of 0.32%. H ow e v e r, t h e risk for EAC decreased with each subsequent surveillance endoscopy with persistent NDBE, to 0.25% at the third endoscopy, 0.16% at the fourth endoscopy, 0.15% at the fifth and 0.09% a t the sixth endoscopy (P=0.005 P for trend). Similarly the combined annual risk for EAC or HGD during the first surveillance interval was 0.75%, with the likelihood lik lih d off either ith d decreasing i significantly i ifi tl over ti time tto 0.54% by the third endoscopy, 0.38% by the fourth, 0.4% by the fifth and 0.36% by the sixth surveillance endoscopy (P=0.046). P Dr. Sharma: The low risk for adenocarcinoma associated with NDBE has brought into question the role of continued surveillance endoscopy in these patients. When and how often should we examine these patients? When is it safe to stop surveillance? It would be helpful to risk-stratify our Barrett’s patients so that we can make use of health care resources more efficiently. This is an important study because it suggests that patients with NDBE have a continued decrease in their progression rates to cancer if they continue to have consecutive surveillance endoscopies with biopsies showing nondysplastic tissue. Gastroenterologists have a similar experience in practice; if a patient has persistent NDBE over several years, we rarely see those patients developing cancer. These results argue that maybe in patients with persistent NDBE, surveillance intervals can be lengthened to perhaps 10 years or even discontinued in some cases.
Tu1635.
Multimodality Endoscopic Therapy for Early Barrett’s Cancer: A Single-Center Experience (Sandhu DK et al) Although combined endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) is becoming the standard of care for treating high-grade dysplasia see Best of DDW, page 8
8
DDW 2012
Best of DDW continued from page 7
(HGD) in patients with Barrett’s esophagus (BE), data on the real-world outcomes of this approach are lacking. This retrospective analysis included 82 patients with BE who underwent endoscopic treatment for HGD at the University of Washington, Seattle, between June 2002 and November 2011. Most patients were men, with a mean age of 66 years. The mean BE segment length was 51 mm (range, 5-150 mm) and the mean size of hiatal hernia was 4 cm (range, 1-10 cm). The first session of treatment included EMR alone for 54% of patients, RFA alone in 38%, photodynamic therapy (PDT) alone in 5% and combined PDT and EMR in 4%. Subsequent treatments for those who required it included RFA alone in 40% of patients, EMR alone in 3% and combination RFA and EMR in 58% of patients.
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
Nirmal Mann, MD, PhD, DSc Professor of Medicine and Gastroenterology University of California Davis School of Medicine Senior Consultant in Gastroenterology-Hepatology University of California Davis Medical Center Sacramento, California
1041.
Efficacy of Rifaximin for IBS Without Constipation in Men and Women (Pimentel M et al)
Gender is thought to play a role in the pathophysiology and natural history of irritable bowel syndrome (IBS) (see “The Best of Digestive Disease Week: Part 1,” Gastroenterology & Endoscopy Newss July 2012;63:9. Abstract Su1016). To identify any differences in drug treatment response among men and women, investigators conducted a subgroup analysis of data from two Phase III trials (TARGET 1 and TARGET 2 [Targeted, non-systemic antibiotic rifaximin gut-selective evaluation of treatment]), both of which compared rifaximin 550 mg thrice daily
Inadequate Bowel Preps: A Problem With Potentially Serious Consequences
‘This abstract provides a snapshot of real-world scenarios. It shows that eradication rates for BE are not as high as we’ve suspected.’ —Prateek Sharma, MD
The researchers found 69.5% of patients achieved complete eradication (95% confidence interval [CI], 59.3%-79.7%) after a mean 23 months of follow-up (range six to 112 months). Furthermore, 54.9% of patients with metaplasia achieved complete eradication (95% CI, 43.9%-65.9%). Multivariate analyses determined that each 1 cm of Barrett’s length decreased the likelihood of complete dysplasia eradication by 2% (95% CI, 0.5%-2.9%). Increasing age and larger hiatal hernias also lowered the chances of complete dysplasia eradication with endoscopic therapy, the investigators found. Dr. Sharma: Most data on the efficacy of endoscopic therapies have derived from large clinical trials. In contrast, this abstract provides a snapshot of real-world scenarios. It shows that eradication rates for BE are not as high as we have suspected. These eradication rates are in contrast to previous efficacy trials showing eradication rates of 85% to 90% (Shaheen NJ et al. N Engl J Med 2009;360:2277-2288). Furthermore, recurrence after successful eradication also have been reported, emphasizing the need to continue following these patients carefully even after successful eradication.
Colonoscopic view of cecum in patient using a split-dose bowel prep1
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 • AUGUST 2012
with a placebo for the treatment of nonconstipation IBS. Patients in both studies received the drug or placebo for 14 days
The data revealed that 39.8% of women who received rifaximin experienced relief of daily global IBS symptoms,
‘The study provides a rationale for the use of rifaximin in nonconstipated IBS patients, particularly female patients.’ —Nirmal Mann, MD, PhD, DSc
and were followed for an additional 10 weeks. This subgroup analysis included 909 women and 349 men.
compared with 30.2% of women given a placebo (P=0.0026). P Furthermore, 41.8% of female rifaximin recipients reported
significant improvements in daily bloating, compared with 31.5% of female placebo participants (P=0.0015). P Among men, 41.4% of rifaximin recipients and 27.8% of placebo patients reported relief in daily global IBS symptoms (P=0.0054). Although the number of men reporting improvements in daily bloating was numerically greater in the rifaximin group than in the placebo group, the difference was not statistically significant, the researchers found (40.1% vs. 32.1%; P=0.1192). Dr. Mann: There are gender
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
* 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.
SU-12873RV
March, 2012
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differences in the symptomatology of IBS. In this study, the investigators found that in 1,258 patients with nonconstipation IBS, rifaximin relieved global symptoms and abdominal bloating in a significantly larger number of women than men compared with placebo. Rifaximin relieved global IBS symptoms in more men than did placebo. Rifaximin also seemed to be effective in relieving abdominal bloating in men but the effect was not statistically significant. It may be that larger numbers of men need to be studied to evaluate the effect of rifaximin on abdominal bloating. In summary, the study provides a rationale for the use of rifaximin in nonconstipated IBS patients, particularly female patients.
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The Twelve-Hour Battery Given Wireless PillCam Sb2ex Improves Overall Cecal Intubation Rate and Increases the Positive Yield (Mann K et al) Standard eight-hour wireless capsule endoscopy (WCE) is associated with an 80% cecal intubation rate, leaving this area of small bowel unexamined in approximately 20% of patients. This single-center retrospective chart review documented cecal intubation rates in 108 patients who underwent 12-hour WCE (Pillcam 2B2EX; Given Imaging) and 147 who received eight-hour WCE. One experienced clinician read all endoscopy videos. Results showed all 12-hour WCEs performed in outpatients reached the colon, compared with 83% of eighthour WCEs. Among inpatients, 85% of 12-hour WCEs reached the colon, compared with approximately 64% of eighthour procedures. The median time for orocecal transit for the 12-hour Pillcam 2B2EX was 389 minutes, compared with 276 minutes for the eight-hour PillcamSB2. The 12-hour WCE required an average of 282 minutes to reach the colon in the outpatient group, falling well within an eight-hour window, but reached the colon after an average of 463 minutes in the inpatient group. Among inpatient 12-hour WCEs that did not reach the colon, mean time to the duodenum was 117 minutes. Orocecal transit time differed among outpatients with a history of small bowel surgical resection (348 minutes for 12-hour vs. 310 minutes for eight-hour; P=0.017). P The researchers found 9% of 12-hour WCEs yielded at least one positive finding beyond an eight-hour time frame. These findings included small bowel lesions, bleeding anastomotic varices, heme at the distal small bowel and ulcerated mucosa at the terminal ileum, as well as heme in the colon, “suggesting a see Best of DDW, page 10
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Best of DDW continued from page 9
missed colonic lesion or ulcer in patients with IBD,” the effect in facilitating complete and less painful colonosauthors wrote. copy ((Am J Gastroenterol 2011;106:S562-S566). Dr. Mann: This research comes from a group at There is a significant adenoma miss rate in the proxiCedars-Sinai in Los Angeles that has accumulated exten- mal right colon with conventional air-insufflation colosive experience in evaluating noscopy. The dye spray method the small bowel with doublehas been advocated to increase balloon enteroscopy (DBE) and adenoma detection rate, but this ‘If a long orocecal transit time is WCE. Here they examined the method can be cumbersome. wireless PillCam sb2ex, which In this randomized study, the suspected, 12-hour WCE should has a 12-hour battery life and authors added 0.008% indigo be used.’ may improve small bowel visucarmine to water and compared alization in patients with proit with a water method with —Nirmal Mann, MD, PhD, DSc longed small bowel transit time. localized dye spray. These were The retrospective study showed all screening colonoscopies and that for both inpatients and outthe groups were comparable patients, a larger number of 12-hour WCEs reached the in mean age, gender distribution and body mass index. cecum, compared with eight-hour WCE. This difference Notably, there were more smokers in the dyed water was more marked in the case of outpatients, although the group. reasons for this are not known. In 95 cases of 12-hour The authors found an increased overall adenoma WCE, at least one positive finding was encountered detection rate in the dyed water group, most significantly beyond the eight-hour time frame. Therefore, if a long with regard to polyps in the proximal colon in general orocecal transit time is suspected, 12-hour WCE should and polyps smaller than 10 mm in the proximal colon. be used. Although the authors concluded that the dyed water method increased the adenoma detection rate, I am not a Combined Dye (Indigo car- hydromaniac and wonder if dyed water might interfere in mine) and Water Method vs. the evaluation of colonic inflammation. Water Alone Further Enhanced Proximal Adenoma Detection Rate (ADR) in Screening Colonoscopy—an RCT (Leung JW et al)
795.
Franklin Kasmin, MD
Colonoscopy using chromoendoscopy with dye spray and water increases the proximal colon adenoma detection rate, but “dye spray is considered cumbersome.” In this study, researchers examined the adenoma detection rate of colonoscopy using chromoendoscopy with water dyed with indigo carmine, obviating the need for dye spray. To this end, the investigators randomized 92 patients to undergo screening colonoscopy with chromendoscopy with water and dye spray and 92 to undergo chromoendoscopic colonoscopy with dyed water. Two endoscopists with experience in both techniques performed the procedures. Patients in the dye spray group were more likely to be active smokers and had a higher rate of family history of colon cancer, although these differences were not statistically significant. Data revealed an overall 62% adenoma detection rate with dyed water chromoendoscopy, compared with a 44.6% overall detection rate with water and dye spray (P=0.0264). The adenoma detection rate in the proximal colon specifically was 53.3% in the dyed water group, in contrast to 34.8% in the dye spray group (P=0.0172). P Almost all adenomas detected in the proximal colon were smaller than 10 mm. Five sessile serrated polyps were detected in the proximal colon in the dyed water group, compared with two detected in the dye spray group (P-value not significant). One cancer in each group was detected as well. “We demonstrated that indigo carmine at 0.008% concentration, added to the water [is a] simple, easy-to-learn method [and] significantly enhanced the effectiveness of the water method in detecting overall, proximal and proximal <10 mm adenomas in patients undergoing screening colonoscopy,” the researchers concluded. Dr. Mann: This group from the VA Medical Centers in Sacramento and Sepulveda, Calif., has been using water-immersion and water-exchange methods to good
Assistant Professor of Medicine Albert Einstein College of Medicine of Yeshiva University New York, New York
compared with 9.2% of all indomethacin subjects, conferring a relative risk reduction of 46% (95% confidence interval [CI], 17%-65%; P P=0.005). Moderate to severe post-ERCP pancreatitis occurred in 8.8% of those in the placebo group, compared with 4.4% of indomethacin recipients (P=0.034). P Among stent recipients, 16.1% of the placebo group developed pancreatitis compared with 9.7% of the indomethacin group (P=0.04). P Pancreatitis occurred in 20.6% of placebo recipients who did not receive stents compared with approximately 6.3% of indomethacin recipients not administered a stent (P=0.049). P There were no differences in the efficacy of indomethacin between those who did or did not have sphincter of Oddi dysfunction and indomethacin did not increase the risk for adverse events. The trial was terminated early because of “an overwhelming benefit of indomethacin compared to placebo.” Dr. Kasmin: Perhaps most surprising here was the pancreatitis rate in the placebo patients who received pancreatic stents. Although this represents a 4% reduction from the pancreatitis rate among placebo patients who did not receive a stent, the rate is much higher than expected. Indomethacin had an important additive effect to pancreatic stenting, reducing the rate of pancreatitis, but the lowest pancreatitis rate was in those patients who received indomethacin but not a stent. This might be explained by the fact that many of those not stented were felt to be at lowest risk for developing pancreatitis. The study demonstrates that combination stenting and indomethacin is much more effective than stenting alone, which suggests that indomethacin use should perhaps become standard practice. Although it is possible that NSAIDs administered either intravenously or orally also have the same protective benefit, rectal administration provides the drug immediately and locally.
A Randomized Controlled Trial of Rectal Indomethacin for the Prevention of PostERCP Pancreatitis (Elmunzer BJ et al)
720.
‘The study demonstrates that
Pancreatitis is the most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP) and is associated with significant morbidity, occasional mortality and increased financial costs. This trial followed on the heels of previous research, which suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) can decrease the rate of this complication (Bhatia V et al. J Clin Gastroenterol 2011;45:170-176). In the current study, investigators at several sites randomized 607 patients at risk for post-ERCP pancreatitis to receive either two indomethacin 50 mg suppositories or two placebo suppositories immediately following ERCP, both in a double-blinded fashion. Eighty percent of patients considered at highest risk for post-ERCP pancreatitis also received a pancreatic stent. Risk factors for the complication included clinical suspicion of sphincter of Oddi dysfunction (suspected in 82% of all patients), a history of post-ERCP pancreatitis, difficult cannulation, precut access sphincterotomy or pancreatic sphincterotomy. Subjects were followed for 30 days post-ERCP and examined for pancreatitis as well as indomethacinrelated adverse events. Researchers found 16.9% of all placebo recipients developed post-ERCP pancreatitis,
alone, which suggests that indomethacin
combination stenting and indomethacin is much more effective than stenting use should perhaps become standard practice.’ —Franklin Kasmin, MD
Su1491.
Underwater Endoscopic Mucosal Resection (UEMR) Without Submucosal Injection for Large Sessile Colorectal Polyps (Binmoeller K et al) Investigators in San Francisco developed a technique to replace submucosal injection of large sessile colorectal polyps—a practice that aids endoscopic mucosal resection (EMR) of large sessile polyps but can also make snare capture of flat polyps more difficult. In a prospective study, the investigators performed the new EMR technique in 109 patients who underwent resection of 112 large sessile colorectal polyps that were a median size of 30 mm. The technique involved placing a colonoscope mounted with a translucent cap on its tip and
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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
performing polypectomy with the colon distended by water. Following full water immersion of the colon and prior to resection, lack of submucosal invasion using probe endoscopic ultrasound was confirmed. The perimeter of the adenoma was then marked underwater using an argon plasma coagulation probe and the adenoma was resected with a 15-mm “duck bill” snare. Resections required a median 16 minutes. The researchers found no perforations and no cases of post-polypectomy syndrome. Three patients did experience delayed bleeding but were managed conservatively and did not require transfusion. Follow-up surveillance colonoscopies in 67 patients revealed adenomatous tissue at or near resection sites in two patients, each of whom had polyps between 6 and 8 cm in size prior to initial resection.
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Dr. Kasmin: Resecting large tumors is very cumbersome and somewhat dangerous, given the possibility of also removing underlying muscularis layer. Submucosal injection is used when the colon is insufflated with air because the air flattens out the polyps. However, the problem with injection is that it shapes the polyp into a large bleb, making it difficult to snare. The method developed here is based on the hypothesis that while air distention thins the submucosal and muscularis layers of the colon, water distention allows the thick submucosal layer to follow the contour of the mucosa, leaving the muscularis layer circular. By not distorting the shape of the polyp, it is easier to resect and the likelihood of snaring the muscularis layer is
The investigators reported accomplishing total visualization of the small bowel in all patients, with procedures requiring an average of 58 minutes (range, 43-98 minutes). The antegrade portion of the procedure reached an estimated average depth of 530 cm past the LigaEndoscopic Visualization ment of Treitz while the retrograde portion reached an of the Entire Small Intestine average of 310 cm. in 27 Consecutive Patients The last three patients in the series underwent enterUsing Novel Motorized Spiral Endoscope oscopy by one of three experienced enteroscopists who (Akerman PA et al) were first-time users of the motorized spiral instruExisting spiral endoscopy consists of overtubes that are ment, and in these patients total small bowel visualfitted on to the exterior of an endoscope. In this trial, ization was achieved with antegrade insertion alone. researchers examined the visualization capabilities of an Time to cecum in these patients required 18 to 22 integrated motorized spiral enteroscope. The investiga- minutes. No serious complications occurred and findtors wrote that they developed the device “to improve ings revealed colon polyps in two patients, colon cancer the technique and performance of spiral enteroscopy.” in one patient, three arteriovenous malformations and One operator controls the enteroscope and the spiral one small bowel mass. is moved clockwise or counter-clockwise using a foot Dr. Kasmin: This is a seminal study and I believe pedal. The rate of rotation and torque is electronically this device will make routine and complete small bowel controlled according to visualization a common the rate of resistance. The reality in our practice. enteroscope measures 160 The device overcomes a ‘I believe this device will make routine cm in length and 11.5 fairly common problem and complete small bowel visualization a mm in diameter and has a that occurs with con2.8-mm working channel ventional spiral entercommon reality in our practice.’ and an integrated motoroscopy, namely that the —Franklin Kasmin, MD ized spiral on the distal enteroscope gets caught end. Once the endoscope in the spiral overtube. reaches the small bowel, The integrated system the rotating spiral pleats the intestine to propel itself. smoothly and quickly navigates the enteroscope down The current single-center retrospective study through the small bowel. This was demonstrated in included 27 consecutive patients who underwent ante- the last three cases of the series, where the enteroscope grade deep small bowel enteroscopy with the device. reached the cecum within an unheard-of 20 minutes. Patients who did not have cecal visualization with Endoscopists with no prior experience using this device antegrade enteroscopy had the maximum insertion site performed the last three procedures, thus there may be marked with injected India ink and underwent sub- a short learning curve. ■ sequent retrograde insertion. Total enteroscopy was defined as either antegrade cecal visualization or retroDr. Sharma has received grant funding from Barrx Medigrade visualization of the India ink spot placed during cal, Cook Medical, Olympus and Takeda Pharmaceuticals. the antegrade insertion. Drs. Kasmin and Mann reported no relevant disclosures.
Cut and Paste
The use of templates
‘It was a groundbreaking study that I believe will change how many of us practice.’ —Franklin Kasmin, MD
continued from page 6
a written history and physical into the chart. The more serious consequence of this EMR system is that students cannot develop their own methods of creating documents because they are not allowed to participate in the activity. The repercussions of this revolution in documentation are not limited to medical students; they involve all physicians who now are exposed only to templatedriven documentation, which may circumvent the “thought process” that is so important in developing one’s approach to patient care. Rather than spend time at the bedside analyzing the actual patient, the temptation will be to rely on inputting clinical information to satisfy templates that have been created to populate the cyber-chart. It will be a great temptation to “cut and paste” rather than “inquire and examine”! I recognize all of the positive attributes of having good documentation, especially in a computerized format. I also recognize that it would make the collection of data much easier and reduce the time that many of us spend in the futile exercise of searching for laboratory
reduced. This very large study demonstrated the success of this approach in reducing perforation risk. It was a groundbreaking study that I believe will change how many of us practice.
285.
and static outlines could potentially minimize the traditional need to assess patients, answer their questions and provide physical diagnostic confirmation of findings on rounds. information, I’s and O’s, drain output, pathology reports and so forth. My concern is that perhaps we have not given enough thought to the consequences of this electronic revolution on medical education and the personal daily involvement with the patient. Hopefully, we can overcome this by discovering ways to integrate the needs of our students into these formats. The greater challenge is to avoid the temptation to let record keeping become the goal of our medical care.
The use of templates and static outlines could potentially minimize the traditional need to assess patients, answer their questions and provide physical diagnostic confirmation of findings on rounds. One could propose a future scenario in which “the team” could sit around a table some distance from the inpatient venue, manipulate a robot with video and audio capability (already marketed!) to visit our patient and then have all of the data transcribed to us on our electronic tablet, allowing us to create a note that could go seamlessly into the EMR— all of this obviating any need to ever go into the patient room or lay hands on anyone. I think we are at a great tipping point in medicine as a consequence of the technical advances in monitoring patient care. For those who have been involved in medical student and resident education, the EMR and newer methods of data collection must not be a barrier to involvement with patients. Only time will tell how all of this will affect the interface between patients and their physicians. We all need to avoid a “cut-and-paste” mentality and the potential that this would lead to high tech, but low touch. ■
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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
Not All Endoscopists Adhere to Recommendations For Duodenal Biopsy in Patients With Celiac Disease May Explain Underdiagnosis of Celiac Disease BY CHRISTINA FRANGOU SAN DIEGO—Practice characteristics of endoscopists predict their adherence to recommended guidelines for specimen retrieval during duodenal biopsy, according to a new study presented at the 2012 Digestive Disease Week meeting (abstract 396). High-volume endoscopists are less likely to adhere to guidelines, whereas those who work in endoscopy suites with five or more gastroenterologists are more likely to observe recommended guidelines.
physician characteristics influenced rates of adherence to recommendations. They identified 92,580 patients (67% female, mean age 53.5 years) who underwent duodenal biopsy with specimens submitted to Miraca Life Sciences (formerly Caris Life Sciences) between 2006 and
2009. Specimens were submitted by 669 gastroenterologists from 200 endoscopy sites, located in 191 zip codes around the country. Data from gastroenterologists who performed procedures during at least three of the four years were analyzed, and patients with known celiac disease prior
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—Benjamin Lebwohl, MD
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➢ Go to www.gastroendonews.com/apps and click on the "Available on the App Store" icon. “Individual provider procedure volume and proximity to other gastroenterologists influence adherence,” said lead author Benjamin Lebwohl, MD, assistant professor of clinical medicine and gastroenterologist at the Celiac Disease Center of Columbia University, New York City. A 2006 technical review from the American Gastroenterological Association recommended that endoscopists retrieve four to six biopsy specimens from the proximal small intestine to make a diagnosis of celiac disease (Rostom A et al. Gastroenterology 2006;131:1981-2002). Yet three years after the review was published, Dr. Lebwohl and colleagues found that only 37% of patients who underwent duodenal biopsies had an adequate number of specimens retrieved (Gastrointest Endoscc 2011;74:103-109). The same study found celiac disease diagnosis doubled when biopsies met the recommended guidelines. In their recent study, Dr. Lebwohl and colleagues examined a large national pathology database to determine whether
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to the endoscopy were excluded. Endoscopist procedure volume had a significant effect on adherence. Endoscopists in the lowest volume quartile had the highest adherence at 43%, whereas those in the highest quartile had the lowest adherence at 32%. For every additional 100
DDW 2012
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
procedures performed by a gastroenterologist, the odds of retrieving four or more specimens dropped by 7% (odds ratio [OR] for each additional 100 procedures, 0.93; 95% confidence interval [CI], 0.88-0.98; P=0.01). On multivariable logistic regresP sion, two patient factors—older age and male gender—also were associated with a decreased likelihood of submitting four or more specimens. Investigators also evaluated the influence of proximity to other gastroenterologists. Those practicing in endoscopy suites with five or more gastroenterologists had
higher rates of adherence, at 40%, compared with sites with fewer gastroenterologists. Each additional gastroenterologist practicing in an endoscopy suite was associated with a 9% increased chance of adherence (OR for each additional gastroenterologist, 1.09; 95% CI, 1.05-1.12; P<0.0001). But increased density of gastroenterologists in the surrounding area had no benefit. Investigators found similar adherence rates between gastroenterologists practicing in zip codes with the highest physician density and areas of the lowest
physician density. Limitations of the study include a lack of clinical details regarding the individual risk for celiac disease in patients and inadequate information on physician volume outside the database of duodenal biopsies. Dr. Lebwohl said it was impossible to determine from this study why endoscopists who work in a suite with more endoscopists are more likely to adhere, whereas those with higher volumes are less likely to meet retrieval standards. “It may be a function of increased time pressure for high-volume endoscopists,”
he suggested. And physicians who practice in multi-endoscopist suites may have better access to peer education or experience more peer pressure to meet practice standards. Marjorie M. Walker, BM, BS, reader in gastrointestinal pathology, Imperial College, London, noted that increased specimen retrieval would improve diagnosis of celiac disease. “As a histopathologist, I truly appreciate adhering to guidelines for biopsies. If we don’t get biopsies, we can’t make a diagnosis,” she said. ■
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Five-Star Practice continued from page 1
ME
D I C A L P R AC T I C E ‘Your referrals are going to be based on the
quality of care you deliver and on the price of that care.’
price of that care,” which also will in nfluence “your relationships with third-p party institutions—hospitals, insurance com mpanies, the government,” said Bergein Overholt, MD, at the 2012 GI Roundtab ble, a meeting organized by Dr. Overholt and Klaus Mergener, MD, PhD, MBA A, of Digestive Health Specialists in Tacooma, Wash. “I think the best way to deal with that is to become the go-to, five-star GI practice.”
—Bergein Overholt, MD
To a large degree, becoming the favored practice requires adhering tto th the fundamental f d t l principles i i l off quall ity patient care, Dr. Overholt explained.
“Things that we all know, but sometimes have let slip a little bit.” Drawing D i on 40 years off experience i as the managing partner of Gastrointestinal
Associates in Knoxville, Tenn., as well as from lessons learned from his physician father, Dr. Overholt elucidated these basicc principles, starting with the definition of a “five-star” practice. “Itt means providing high-quality care with a high level of efficiency. It means comp passion to the patient from all staff and physicians, and it means providing that care at a fair and competitive price,” Dr. O Overholt said. “You can wrap that up into just saying, ‘the best patient experience.’ ” Of course, the various players have
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GASTROENTEROLOGY & ENDOSCOPY NEWS • AU U GUST 2012
different concerns about what they get out of your practice. Patients care aboout their experience; referring physicians waant timely, quality care and a quick repoort; insurance companies and governmeent agencies are concerned about the cost. “But the one who really determin nes whether you’re a five-star practice is you— what you do to reach that goal, and how you get there,” Dr. Overholt said.
Five-star ‘means providing high-quality care with a high level of efficiency. It means compassion to the patient from all staff and physicians, and it means
Leadership
M
providing that care at a fair and competitive price.’
“Of the five stars, the single moost important, the brightest, is leadersh hip.
E D I—Bergein Overholt, MD I C E C A L P R AC T
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An nd that is leadership of all people,” Dr. O verholt said. The major task of leadership falls to th he managing partner who is the physiccian willing to take the time to learn, traavel, establish the vision of the practice, sett quality standards, recruit new doctors an nd negotiate new deals. “An essential part of any successful prractice has got to be the leadership of th he practice, which involves both the key peerson running the practice, the other ph hysician partners who step up to contriibute and help, and the governance strructure that determines how decisions are made,” said Arnold G. Levy, MD, president and CEO of Capital Digestive Care LLC, in the Washington D.C./ metro Maryland area. Both the leadership arrangement and governance structure evolve from how the practice itself was formed. When practices build from within, the key leader often is easy to identify. “The physicians in that group work within the same culture, grow together and learn to trust each other. One of them always rises to the top as the one who has the ability to direct and lead the group,” Dr. Levy said. When practices grow by merger, selecting the leader can be a bit more of a challenge, as each group had a preferred way of doing things before coming together under one umbrella. “In a setting such as this, there often will be two or three point physicians who will lead the groups into discussion. Usually one of these physicians becomes the ad hoc leader while ideas are developing. That person has to be willing to listen to input from everybody, analyze and organize all ideas and demonstrate leadership by being inclusive as he or she provides guidance and direction for the entire group,” Dr. Levy said. “In this position, there is no room for ego,” he continued. “You have to recognize what you do and do not know, and you have to be able to assemble a team that can manage the finances, billing, services, information technology [IT] and all the day-to-day aspects of running the business. Also, as the leader of the organization, you have to keep your eyes and ears open all the time: read, travel, network and be able to listen to and learn from everybody else.” As far as governance structures go, different practices use different models, but the idea is to establish a clear line of communication and make sure that the ideas, thoughts and opinions of all parties are represented fairly. Capital Digestive Care, a merger of seven competing practices, now includes 56 gastroenterologists and pathologists and uses a “federated” model. see Five-Star Practice, page 16
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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
Five-Star Practice continued from page 15
“This organizational model is like having a cen- does not end, with competitive salary and benefits. Physician competence, of course, is essential, and is tral government with seven separate states,” Dr. Levy “A big part of motivation is how you deal with them, measurable by such things as board certification and explained. “Everyone is under the same tax ID number how you respect them and how you thank them for a job participation in ongoing continuing medical education. and functions—such as billing, collections, payroll and well done,” Dr. Overholt said. But other qualities, such as the ability to get along well health insurance, contracting, marketing, pension plan, A ticket to the theater, a birthday cake, a day off for and work with others, and to make patients feel cared and malpractice and health insurance—are handled at a job well done and heartfelt thanks can go a long way for, also are deeply important. the central, or federal, level.” toward making staff feel appreciated. The power of the “Without compatibility, you’re not going to get Each practice, or division, receives the revenue it handwritten note should not be underestimated. there. And compassion, not just toward your patients, has generated, minus the federal overbut toward your staff, is an important head, “and can make its own decisions characteristic of physician excellence,” on operations, such as specific practiceDr. Overholt said. “You need physi‘From the time they pick up the phone to make an appointment, related overhead choices and its own cians who are willing to do their share, from the receptionist to the doctor’s office, to the ASC, walk in formula for physician compensation,” but beyond that, to help a colleague, a Dr. Levy said. staff member or particularly a patient.” the shoes of the patient and ask, “Is this what I consider a fiveCapital Digestive Care has a presiInfrastructure star experience?” ’ dent/CEO, vice president, secretary and treasurer (the executive commitThe underpinnings of a practice are —Bergein Overholt, MD tee), and a board comprising represencritical to achieving five-star quality. tatives from each division. The number A five-star practice should have phone of representatives is determined by the and Internet capabilities sufficient to size of that division, that is, one rephandle patient communication; sysresentative for every five physicians in tems designed to reduce patient wait the division. time; a comfortable, attractive setting; “That makes representation fair, and and up-to-date materials from office everyone knows they have a say,” Dr. Levy equipment to endoscopes. said. “Developing a strong committee Peter Donaldson, CEO of Digesstructure is important, as it allows t i v e Health Specialists, PA, in the organization to tap the talWinston-Salem, N.C., knew ent of its other physician memthe moment he walked in the bers.” The board makes decisions door of that practice that IT after hearing recommenwas going to be a key facdations from the various tor to moving ahead in committees. health care. Other practice types may “I thought, how in the have one partner serving as presiworld are physicians supposed dent, with several officers who act like to remember 10,000 ICD-9 [Interthe executive committee. “They handle a national Classification of Diseases] lot of decisions of operations, but bring codes and 5,000 CPT [Current Prothings back to the partners for major cedural Terminology] codes? So we growth,” Dr. Levy said. “They discuss it, have been very progressive in moving come to a vote and make a decision. But ahead with EMR [electronic medical very specifically, you have to have somerecords] systems and understanding one elected as leader.” IT.” The practice will need to figure out a In his 21 years with Digestive way to compensate the key leader, as the Health Specialists, Mr. Donaldson demands of running the practice likely has seen it grow from three to 17 prowill necessitate seeing a smaller percentviders, and considers the IT systems age of patients. essential to boosting efficiency and “The way we approach that is equal reducing waste. time, equal pay,” Dr. Overholt said. “If it “Health care is complicated, and ‘Always remember the bottom line is takes one day a week, you pay that physiso is health care infrastructure and patient care, not profits.’ technology,” he said. “This is a small cian the average revenue for that group per day. Physician leadership is probably —Bergein Overholt, MD business. We don’t have a large IT one of the best investments a practice can department to rely on, so it requires make.” practice leadership to understand what’s out there.” Office Staff Physicians To streamline patient check-in, the practice will soon Although one might assume the second of the five Leadership of the practice is not restricted to the key implement an automated system. “Instead of handing stars to be the doctors taking care of patients, Dr. Over- manager, but includes all physicians, each of whom is a the patient a piece of paper to fill out again for the 15th holt actually listed staff next. leader in his or her own way. time, we’ll hand them an iPad-like device with their “You want to get the best staff that’s possibly avail“They set the attitude of the practice with staff and information. They’ll be able to view it online, sign off able; they will reflect the physician, they will bring qual- patients, and they determine the quality of care that’s on their documents and view and pay their account bality, friendliness, efficiency and compassion. They will administered and delivered by the practice,” Dr. Over- ance,” Mr. Donaldson said. “We think that will greatly represent you,” he said. holt said. “Each physician needs to assume the respon- enhance the customer’s experience.” To attract and keep this kind of staff, you need to sibility of being a leader because [he or she is] a part of The practice has used an EMR system for the past provide motivating incentives. That starts, but certainly the success of the practice.” see Five-Star Practice, page 18
ME
D I C A L P R AC T I C E
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
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continued from page 16
11 years. This ensures that patients get the information they need when they call for it. “Patients call in, and the nurse can pull their chart up instantaneously on the computer screen. No one waits for charts to be pulled and reviewed before calling the patient back,” Mr. Donaldson said. They also invested in a high-quality Web site. “We have a number of patients who
come to us because they found our Web site,” Mr. Donaldson said. “A professionallooking Web site gives patients the sense that you’re technologically advanced, staying on the forefront of what’s happening in the world rather than being buried in a room with a stack of charts. Not that it’s a fool-proof test, but it does point to the practice being a progressive one.” Digestive Health Specialists built a new office 14 years ago, and they take the effort to keep it looking new. “We just got new carpet and paint— it’s attractive,” Mr. Donaldson said.
M EDIC
“In so many places, aces,, you walk into a tiny waiting room with chairs jammed around the outside wall, wa causing you to wonder what’s going on in the doctor’s mind and what type of care car you might receive. You take care of thee patient pa and everything else—money, success— ess—will follow along.”
The five-star practice will
Quality and Value
be attractive to all who are
“Value” can be a somewhat slippery term, and its meaning varies depending on who is measuring it: the patient, the payer, the government, the referring physician
involved with it, but what
AL
PR
AC
TI
EC
Five-Star Practice
GASTROENTEROLOGY & ENDOSCOPY E NEWS • AUGUST 2012
really drives it is the patient experience: Any questions remaining about what it takes
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
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.
to have a five-star practice may best be answered by considering the patient’s perspective.
and so on. But in the often-quoted equation, it equals quality over cost. Quality can be measured to some degree by benchmarking to national standards and meeting patient satisfaction. Digestive Health Specialists began benchmarking internally years ago, comparing adenoma detection rates (ADR) on a peer-to-peer basis—an exercise they found useful. They also participate in regular meetings with other small practices to compare how they are doing. “There are national benchmarking tools [you can use to] compare yourself with your peers, but one of the frustrations with those tools is that you never know what’s in the numbers,” Mr. Donaldson said. “For years, half of those surveys included academic practices, half of them included private practices, but those practices are
Sunny Forecast… Re: “Stormy Forecast: Seven Changes That Will Affect Your Practice,” by Caroline Helwick. Gastroenterology & Endoscopy News July 2012;63:1,24. For those of you who are wondering what [No. 7] is, it is [the] consolidation of many aspects of the health care system. Hospital systems, payers, insurance risk pools, independent practices—all are consolidating to get bigger and capture more market share, negotiating clout or patients. While all this sounds disturbing and “stormy,” there are certain steps that practices can take to improve their position. These will be outlined
19
GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ AUGUST 2012
totally different in terms of how we handle things.â&#x20AC;? Mr. Donaldson and several colleagues affiliated with the Medical Group Management Association began sharing data ass part p of an email listserv, asking â&#x20AC;&#x153;what are you doing for this, how are you hanar dling that?â&#x20AC;? These discussions evolved into a formal semi-annual live meeting. â&#x20AC;&#x153;We call ourselves the Gastroenterology Best Practices Group. There are currently six groups, small enough that we can really know each other,â&#x20AC;? he said. The groups compile a spreadsheet that includes patient and physician information, data on such metrics as ADR and other quality indicators they want to examine. The meetings also give them an opportunity to teach and learn from each other. â&#x20AC;&#x153;Weâ&#x20AC;&#x2122;ve shared marketing ideas, policies, procedures, accreditation, things we all go through,â&#x20AC;? Mr. Donaldson said. The meetings include administrators and physicians, one from each group. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s a safe environment for them to speak their mind to each other without needing to prove themselves to their partners,â&#x20AC;? Mr. Donaldson said. â&#x20AC;&#x153;These meetings bring it down to where we really live. We all go to seminars and meetings, which challenge and inspire our overall goals, but this small group gets into the practical detail of â&#x20AC;&#x2DC;When the patient walks in your door, what really happens? Walk us through your door.â&#x20AC;&#x2122; â&#x20AC;? His practice also is dedicated to cost containment. â&#x20AC;&#x153;We have focused on quality and value, but being very cost-conscious to the patient,â&#x20AC;? Mr. Donaldson said. â&#x20AC;&#x153;With increasing high-deductible health plans, itâ&#x20AC;&#x2122;s just not â&#x20AC;&#x2DC;business as usualâ&#x20AC;&#x2122; anymore. Patients will drive out of their way for
Web Comment in the American Gasttroenterological Associationâ&#x20AC;&#x2122;s i initiative called â&#x20AC;&#x153;The Road Ahead.â&#x20AC;? There is a new series in Clinical Gastroenterology and Hepatologyy called â&#x20AC;&#x153;Practice Management, The Road Aheadâ&#x20AC;? (see Allen JI. Clin Gastroenterol Hepatol 2012;10:692-696). In this section of Clinical Gastroenterology and Hepatology, we will be outlining some areas where practices should focus their strategy and management efforts. Independent practice will not go quietly into the nightâ&#x20AC;&#x201D;we still have much to offer our patients. â&#x20AC;&#x153;jalleâ&#x20AC;? Via Web site on July 18, 2012
a colonoscopy if they can save $100 or more.â&#x20AC;? Mr. Donaldson added, â&#x20AC;&#x153;We try to understand all the nuances of the insurance processes and eligibilities so that when the patient comes in, we can tell them in advance what theyâ&#x20AC;&#x2122;re going to pay. I think folks really appreciate us walking them through the maze of health care billing.â&#x20AC;?
Summary The five-star practice will be attractive to all who are involved with it, but what
really drives it is the patient experience: Any questions remaining about what it takes to have a five-star practice may best be answered by considering the patientâ&#x20AC;&#x2122;s perspective. â&#x20AC;&#x153;From the time they pick up the phone to make an appointment, from the receptionist to the doctorâ&#x20AC;&#x2122;s office, to the ASC [ambulatory surgery center], walk in the shoes of the patient and ask, â&#x20AC;&#x2DC;Is this what I consider a five-star experience?â&#x20AC;&#x2122; â&#x20AC;? Dr. Overholt said. â&#x20AC;&#x153;Always remember the bottom line is patient care, not profits.â&#x20AC;? â&#x2013;
what is your
opinion?
Gastroenterology & Endoscopy News is now accepting opinion pieces. Send your thoughts to the editor at: mail: 545 West 45th Street, 8th Floor New York, New York 10036 fax: 212.957.7230 email:
cgordon@mcmahonmed.com
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Gottumukkala S. Raju MD, FASGE The University of Texas MD Anderson Cancer Center Houston, TX
Michael J. Levy, MD Mayo Clinic Rochester, MN
This course is designed for practitioners in gastrointestinal endoscopy, especially gastroenterologists, gastrointestinal surgeons, gastrointestinal nurses and fellows in training.
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20
DDW 2012
Quality Initiatives continued from page 1
“But more specifically, what about your reputation?” Dr. Pike offered. By 2013, the Centers for Medicare & Medicaid Services will publish quality measures on a Web site, including a listing of physicians who participate in the Physician Quality Reporting System (PQRS). “This will be transparent for all, and one quality measure is whether you are participating in the PQRS program, which raises the question to the public: If you are not, why aren’t you?” By 2015, Medicare reimbursement will be reduced by 1.5% for providers not participating in PQRS. After that, a 2% cut looms in 2016 and 2017. Together with penalties for not attesting to meaningful use, reimbursements to practices could fall by 10%. “And 10% of millions of dollars in a gastroenterology practice gets to be a real number,” Dr. Pike quipped. Another reason to “bother” to participate, Dr. Pike said, is to retain patients. For example, in 2013, gastroenterologists participating in Blue Cross Blue Shield of North Carolina (BCBSNC) will be required to submit quality data from a gastroenterology specialty registry in order to be included in the network. BCBSNC represents approximately 70% of the state’s commercial health insurance market. Should the company decide to expand its program in the future, gastroenterologists will have little choice about participating. For the current program, participation in at least some of the measures will be sufficient in order to allow a one-year “ramp-up to readiness,” but eventually more will be required. This could be the beginning of a trend. The best reason for participating in quality initiatives, however, may be that measuring and reporting quality does improve patient care, he said. This was eloquently shown by Douglas Rex, MD, and colleagues who secretly videotaped endoscopists performing colonoscopies, then later informed the endoscopists that they were going to bee videotaped to assess the attainment of five quality measures. Compared with the stealth baseline videos, measurable improvements were demonstrated for all endoscopists on all parameters. The investigators attributed the improvements to the endoscopists’ anticipation of being observed and measured. “The fact of measuring quality moves the quality curve to the right,” Dr. Pike pointed out. Because of the trend toward benchmarking, he added, it is not uncommon today for the lowest performer in an endoscopy practice to have an adenoma detection rate of 40% and the highest to reach 60%.
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
• Percentage of patients aged 18 years and older with documented CRC risk assessment prior to the CRC screening procedure • Percentage of patients aged 18 years and older receiving colonoscopy with the appropriate follow-up interval based on postprocedure CRC risk assessment • Percentage of patients aged 18 years and older receiving a colonoscopy with American Society of Anesthesiology (ASA) class 1 or 2 status when an anesthesia professional was used • Percentage of colonoscopy patients experiencing an adverse event (AE) within two days of the procedure • Percentage of patients who received a complete colonoscopy • Adenoma detection rate
Benchmarking reports are generated in a standard format and can be customized by data managers at each participating facility, greatly increasing the number of measures that can be analyzed. The tool also offers separate evaluation of trainees in order to follow their endoscopic skill development. Still evolving, at press time the GIQuIC tool had 84 data points and 11 measures, including medical history and physical documentation, informed consent documentation (including potential AEs), adequacy of bowel preparation, written discharge instructions for outpatients, ASA risk stratification, withdrawal time, documentation of indication, cecal intubation with photo documentation, adenoma detection rate and immediate AEs. Other quality measures are in development. “GIQuIC will keep abreast of all third party–devel-
Participation in quality initiatives ‘could positively impact your practice reputation if you do it, and negatively if you don’t. Initially, it may cost you money not to.’ —Irving M. Pike, MD
‘One quality measure is whether you are participating in the PQRS program, which raises the question to the public: If you are not, why aren’t you?’ —Irving M. Pike, MD
GI Registries for Reporting Quality Currently, two gastroenterology registries are available for measuring quality: the American Gastroenterological Association’s (AGA) Digestive Health Outcomes Registry and the GI Quality Improvement Consortium (GIQuIC), available through a partnership of the American College of Gastroenterology and the American Society for Gastrointestinal Endoscopy. The AGA registry allows data to be entered electronically for users of gMed version 4 or others via interfacing with FIGMD at an additional cost. The FIGMD registry includes quality measures for colorectal cancer (CRC) screening, hepatitis C and inflammatory bowel disease, among other things. For example, to demonstrate quality in CRC prevention, providers need to show the following:
The GIQuIC registry offers a direct “endowriterto-database” upload system. Currently, nine endowriter software vendors are certified to submit data to the registry and several other vendors are in the process of becoming certified; therefore, with this system, a third-party vendor interface is not required. Manual data entry also is available for facilities not using an electronic report writer; these practices can submit data via an electronic data collection form. Providers using the GIQuIC registry receive an immediate report and can benchmark their performance on a daily, weekly, monthly, quarterly or annual basis.
oped measures and be prepared to include them in the registry,” Dr. Pike said. Dr. Pike concluded by urging physicians to get more involved in quality initiatives and to take advantage of these registries to their fullest extent. “Maintaining autonomy as a specialty is very important,” he said. “If we don’t decide on these measures ourselves, most assuredly third-party payers will be handing us measures—and they may not be the measures we find important.” ■ Dr. Pike serves on the advisory committee/review panel for Validare and is a consultant for Olympus.
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For further information call 1-866-GET-VSL3 (438-8753) or visit www.vsl3.com Made in the USA Distributed by Sigma-Tau Pharmaceuticals Inc., Gaithersburg MD © 2012 Sigma-Tau Pharmaceuticals, Inc. All rights reserved. 1
Study Suggests Familial Aggregation of IBS,” MedScape Medical News, December 17, 2003 2 Based on IRI retail data ending week of 12.25.11. 3 Guandalini S et al. J Pediatr Gastroenterol Nutr. 51:24-34 (2010).
22
H E PAT O L O G Y I N F O C U S
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
Experts’ Picks:
Best of the EASL/International Liver Congress 2012 COMPILED AND WRITTEN BY DAVID WILD
Gastroenterology & Endoscopy Newss asked several hepatology experts to seleect their favorite abstracts from this year’s European Association for the Studyy of the Liver/International Liver Congress, held in Barcelona. Following is a collection of their selected abstracts and comments.
Nezam Afdhal, MD Director of Hepatology Beth Israel Deaconess Medical Center Boston, Massachusetts Associate Professor of Medicine Harvard Medical School Boston, Massachusetts
8.
Safety of Telaprevir or Boceprevir in Combination with Peginterferon alfa/ Ribavirin in Cirrhotic non-Responders: First Results of the French Early Access Program (ANRS C020-CUPIC) (Hezode C et al) French investigators set out to investigate the safety of these two drugs, given that prior Phase III trials of boceprevir and telaprevir included few cirrhotic patients. To this end, they assigned patients with genotype 1 hepatitis C virus (HCV) infection with compensated child A cirrhosis who had relapsed or partially responded to previous pegylated interferon (PEG-IFN) and ribavirin (RBV) treatment to receive either telaprevir with PEGIFN-alfa2a/RBV for 12 weeks followed by PEG-IFNalfa2a/RBV for 36 weeks (N=169) or PEG-IFN-2b/ RBV for four weeks followed by boceprevir, PEG-IFNalfa2b/RBV for 44 weeks (N=138). Median treatment duration in the two groups was approximately 16 weeks at the time of abstract submission. The researchers found 51% of telaprevir recipients experienced a serious adverse event (AE), with 12% discontinuing drug treatment. Serious AEs occurred in 30% of the boceprevir group, with 7% discontinuing treatment. Grade 2 anemia occurred in 32% and 28% of the telaprevir and boceprevir groups, respectively, and grade 3 to 4 anemia occurred in 14% and 6% of the two groups, respectively. More than half of the patients in either group required treatment with erythropoietin and 19% and 6% of telaprevir and boceprevir subjects, respectively, were given blood transfusions. Treatment led to grade 3 to 4 neutropenia in 12% and 10% of telaprevir and boceprevir recipients, respectively, with some requiring granulocyte-colony stimulating factor. Furthermore, telaprevir led to grade 3 to 4 thrombocytopenia in 22% of subjects, and boceprevir was associated with this AE in 7% of subjects. Seven percent
of telaprevir recipients experienced a grade 3 rash compared with 1% of boceprevir patients. Two percent and 1% of patients in the telaprevir and boceprevirr groups, respectively, died. The researchers noted that the lack of randomization in the study “precludes any comparison between th he two molecules.” Dr. Afdhal: The findings heree illustrate the significant safety issues associated with the treatment of HCV patients with cirrhosis. With both agents, we see that anemiaa is the defining side effect with significant use of erythropoietin and transfusion. However, no information was given on RBV dose reduction, which we recommend as firstline treatment for anemia. Even more worrying was the rate of infections, liver decompensation and mortality. Treatment of patients with cirrhosis using triple therapy requires careful consideration of the costs and benefits of treatment and careful patient monitoring if the decision is made to go ahead.
1162.
Ribavirin Dose Modification in Treatment-Naive and Previously Treated Patients who Received Telaprevir Combination Treatment: No Impact on Sustained Virologic Response in Phase 3 Studies (Sulkowski MS et al) This was a retrospective analysis of more than 1,000 patients with HCV genotype 1 infection in two Phase III, randomized placebo-controlled trials of telaprevir. In the ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir)/ILLUMINATE (Illustrating the Effects of Combination Therapy with Telaprevir) trial, treatment-naive subjects received 12 weeks of telaprevir with 24 or 48 weeks of PEG-IFN-alfa2a and RBV 1,000 to 1,200 mg/day (N=885) or placebo with PEG-IFN-alfa2a/RBV for 48 weeks. A second study, REALIZE (Re-treatment of Patients with Telaprevirbased Regimen to Optimize Outcomes), included previously treated patients who were randomized to receive 12 weeks of telaprevir with 48 weeks of PEGIFN/RBV (N=259) or a placebo with PEG/RBV for 48 weeks. Half of the ADVANCE/ILLUMINATE telaprevir
recipients required RBV dose reduction for anemia management, including 45% whose RBV dose was reduced to 600 mg/day or lower. In the REALIZE study, RBV dosage was reduced in 39% of telaprevir recipients who had relapsed with prior treatment, in 31% of telaprevir subjects who had a prior partial response and in 18% of telaprevir-treated prior null responders. Significantly more telaprevir recipients than placebo subjects required RBV dose reductions.
‘Both … studies demonstrate that RBV dose reduction in HCV protease inhibitor recipients is effective as an anemiamanagement strategy and does not affect SVR rates.’ —Nezam Afdhal, MD
Data showed 74% and 75% of ADVANCE/ILLUMINATE telaprevir subjects whose RBV dose was reduced to 600 mg/day or lower or 800 to 1,000 mg/ day, respectively, had an SVR following dose reduction, compared with 79% of telaprevir-treated subjects whose RBV dose was not lowered. In the REALIZE study, SVR rates among telaprevir-treated prior relapsers were 90% and 84% with RBV dose reductions to 600 mg/day or lower and 800 to 1,000 mg/day, respectively, and 82% among those who did not undergo RBV dose reduction.
H E PAT O L O G Y I N F O C U S
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
In prior partial responders, SVR rates were 62% for an RBV dose or 600 mg/day or lower, 50% for RBV 800 to 1,000 mg/day and 62% for non-reduced RBV, with no statistically significant difference. Finally, SVR rates in prior null responders were 22% for RBV 600 mg/day or lower, 50% for 800 to 1,000 mg/day and 31% for nonreduced RBV.
Stuart C. Gordon, MD Director of Hepatology Henry Ford Health Systems Detroit, Michigan
1419.
A Randomized Trial Comparing Ribavirin Dose Reduction Versus Erythropoietin for Anemia Management in Previously Untreated Patients with Chronic Hepatitis C Receiving Boceprevir Plus Peginterferon/RIBA (Poordad FF et al) This multinational, open-label trial investigated the efficacy of RBV dose reduction in managing treatmentrelated anemia while maintaining sustained virologic response (SVR) in patients treated with boceprevir, PEG-IFN and RBV. The study included 687 treatmentnaive patients with HCV genotype 1 infection who had baseline hemoglobin (Hb) levels of 12 to 15 g/dL among females and 13 to 15 g/dL in males. Subjects received PEG-IFN-2b and RBV 600 to 1,400 mg/day for four weeks, followed by boceprevir 800 mg three times daily with PEG-IFN-2b/RBV for 24 or 44 weeks, depending on the presence of SVR at eight weeks. Those whose Hb levels dropped to 10 g/dL or lower (N=500) were randomized to receive either subcutaneous erythropoietin 40,000 U weekly or to undergo RBV dose reduction by 200 to 400 mg/day. According to the researchers, 71.5% (178 of 249) of patients randomized to undergo RBV dose reduction experienced SVR following dose reduction compared with 70.9% (178 of 251) of erythropoietin recipients. However, 18% of the RBV dose reduction group required additional erythropoietin, and 38% of the erythropoietin arm also required further RBV dose reduction. Rates of treatment discontinuation were similar in the RBV dose-reduction and erythropoietin groups. Specifically, 11% and 13% of the RBV dose-reduction and erythropoietin groups, respectively, discontinued treatment due to any AE, and 2% and 2.4%, respectively, terminated treatment in light of persistent anemia. Rates of influenza-like symptoms, fatigue, depression or anxiety, dyspnea and cardiovascular events were similar in the two groups. Dr. Afdhal: Clinicians have always been frightened of the effects of RBV dose reduction on SVR rates in patients who develop treatment-related anemia. However, in the age of combination HCV protease inhibitor (PI) treatment, there is a safety net with the addition of either boceprevir or telaprevir. Both the Poordad (abstract 1419) and Sulkowski (abstract 1162) studies demonstrate that RBV dose reduction in HCV PI recipients is effective as an anemia-management strategy and does not affect SVR rates. Using a dose-reduction approach means we can avoid the risk for thrombosis and save the added costs associated with erythropoietin. Both these studies, therefore, suggest that first-line treatment for the management of anemia in this population should be RBV dose reduction, with erythropoietin use reserved for highly symptomatic patients who cannot otherwise be managed by RBV dose reduction alone.
106.
Efficacy and Safety of Anticoagulation in Patients with Cirrhosis and Portal Vein Thrombosis (Seijo S et al) This study examined the effects of anticoagulation therapy in cirrhotic patients with portal vein thrombosis (PVT), a frequent complication of liver cirrhosis.
‘Among these hypercoagulable cirrhotic patients, early, long-term and aggressive use of anticoagulation achieves recanalization of the portal vein in a substantial proportion of such patients, often with better clinical outcomes.’ —Stuart C. Gordon, MD
The analysis included data from 55 cirrhotic patients with non-neoplastic PVT treated between June 2003 and September 2010 who received anticoagulative therapy. They evaluated thrombosis and recanalization using Doppler ultrasound, angio-computer tomography and/ or angio-magnetic resonance imaging. Thirty-one patients received anticoagulation treatment for acute or subacute PVT while 24 had previously known PVT that was progressing. Twenty-six patients received low-molecular-weight heparin while 21 were administered low-molecular-weight heparin with subsequent vitamin K antagonists; eight received a vitamin K antagonist alone. Patients had similar baseline characteristics and none had portal cavernous transformation. The researchers found that 45% of patients treated with anticoagulation experienced complete recanalization and another 15% experienced partial recanalization. These patients developed less frequent portal hypertension–related complications than those who did not achieve recanalization, although the difference was not statistically significant. Thrombosis recurred after a median of 1.3 months in five of 13 patients who terminated anticoagulation after achieving complete recanalization. Five patients developed bleeding complications, which the researchers said were probably related to anticoagulation. They found a platelet count of less than 50 x 109/L was significantly associated with a risk for bleeding complications. No anticoagulation-related deaths occurred.
23
Dr. Gordon: One of the most vexing questions concerning the management of cirrhotic complications is the role of anticoagulation in the patient with PVT. It is becoming increasingly evident that despite decreased levels of most coagulation factors as well as thrombocytopenia as causes of innate coagulopathy in the patient with cirrhosis, advanced liver disease is actually a hypercoagulable state—with a subgroup of patients benefiting from anticoagulation. The overriding clinical concern with anticoagulation is that esophageal varices, should they bleed, could prove “more lethal” in such a situation. There are limited data on anticoagulation therapy in patients who develop PVT while waiting for liver transplantation. The results of the present study from a respected group of Spanish investigators advocate for the role of early anticoagulation in the case of cirrhotic patients who develop acute or subacute PVT, or experience progression of previously established PVT, and suggests that indefinite anticoagulation is actually beneficial. Notably, although severe thrombocytopenia was associated with a higher risk for bleeding, no deaths were attributed to anticoagulation. Emerging data, therefore, appear to validate that among these hypercoagulable cirrhotic patients, early, long-term and aggressive use of anticoagulation achieves recanalization of the portal vein in a substantial proportion of such patients, often with better clinical outcomes.
199.
The Effect of an ‘Alcohol Contract’ on Ethanol Consumption After Transplantation for Alcoholic Liver Disease (Kendrick S et al). In 2005, the United Kingdom Transplant Liver Advisory Group implemented a policy requiring liver transplant patients with alcoholic liver disease to sign contracts indicating their commitment to postoperative alcohol abstinence. The policy was aimed at reducing recidivism rates, estimated at 16%, following alcohol liver diseaserelated transplant, but the impact of this policy has not been examined to date.
‘The present report from the United Kingdom shatters any myth that the signing of an “alcohol contract” by a potential transplant recipient—with the intention of creating a legal obligation— has in any way diminished a return to alcohol consumption.’ —Stuart C. Gordon, MD
In this study, British researchers compared alcohol consumption between 32 patients who received a liver transplant for alcoholic liver disease after the “alcohol contract” policy was introduced and 68 patients transplanted prior to the policy’s implementation. According to the findings, 40.6% of patients who had signed an alcohol contract said they consumed alcohol see Best of EASL page 32
24
H E PAT O L O G Y I N F O C U S
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
CDC Proposes HCV Testing for All Baby Boomers ‘Long Overdue’ Recommendation for Group That Makes Up 75% of All U.S. Adults With HCV BY GEORGE OCHOA On May 18, the Centers for Disease Control and Prevention (CDC) announced draft recommendations proposing that all U.S. baby boomers—anyone born between 1945 and 1965—be tested for hepatitis C virus (HCV). This marks a change from the current CDC recommendation, which called only for the testing of individuals with certain risk factors for HCV infection, including IV drug use, blood transfusion or organ transplantation prior to July 1992, recognized exposure to HCV (e.g., health care workers experiencing a needle-stick injury) or infection with HIV. Paul J. Pockros, MD, called the draft recommendations “long overdue and vital to be adopted.” The recommendations have taken this long to be published because outcomes data published in the past year were necessary “to confirm that birth-cohort screening is cost-effective and valid,” explained Dr. Pockros, who is head of the Division of Gastroenterology/ Hepatology, director of the Scripps Clinic Liver Research Consortium and clinical director of research of the Scripps Translational Science Institute in La Jolla, Calif. According to the CDC, baby boomers are five times more likely to be infected with HCV than other adults. More than 2 million baby boomers are infected with HCV, which comprises more than 75% of adults with HCV in the United States overall. Most infected baby boomers do not know about their HCV status because the infection can remain asymptomatic for many years. “Identifying these hidden infections early will allow more baby boomers to receive care and treatment before they develop life-threatening liver disease,” said Kevin Fenton, MD, director of the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD and Tuberculosis Prevention in Atlanta, in a statement. “I think it’s great,” said Robert S. Brown Jr., MD, MPH, Frank Cardile Professor of Medicine, chief, Center for Liver Disease & Transplantation, Columbia University College of Physicians and Surgeons, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York City. “It recognizes that we have failed in our attempt to do risk factor–based screening, in part because patients don’t remember or don’t tell the truth, in part because visit times have gotten shorter.” The CDC draft recommendations also advised that individuals who test positive for HCV infection should receive
screening for alcohol abuse and counseling (as needed). The recommendation was open for public comment from May 22 to June 8, and comments received will be incorporated into the final version. Some physicians are baby boomers
themselves and may be concerned about being tested because of the possible effect of HCV status on their ability to practice. “All health care workers are a risk group that should be screened,” Dr. Brown said. Dr. Pockros added: “They may have
a concern, but they are better served by being diagnosed and treated than not being diagnosed and having a silent progressive disease.” ■ Drs. Brown and Pockros reported no relevant conflicts of interest.
Indication INCIVEK (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 naïve 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: INCIVEK must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin A high proportion of previous null responders (particularly those with cirrhosis) did not achieve a Sustained Virologic Response (SVR) and had telaprevir resistance-associated substitutions emerge on treatment with INCIVEK combination treatment INCIVEK efficacy has not been established for patients who have previously failed therapy with a treatment regimen that includes INCIVEK or other HCV NS3/4A protease inhibitors
Important safety information Contraindications
Contraindications to peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. INCIVEK combination treatment is contraindicated in women who are or may become pregnant. Ribavirin may cause fetal harm when administered to a pregnant woman. If ribavirin is used during pregnancy or in the event of a pregnancy while on treatment, inform the patient of the potential hazard to a fetus. INCIVEK combination treatment is also contraindicated in men whose female partners are pregnant. INCIVEK is contraindicated when combined with drugs that 1) are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events and 2) strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of INCIVEK. Contraindicated medications are alfuzosin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John’s wort, lovastatin, simvastatin, pimozide, sildenafil (Revatio®) or tadalafil (Adcirca®) for pulmonary arterial hypertension, oral midazolam, and/or triazolam.
Anemia has been reported with peginterferon alfa and ribavirin treatment. Adding INCIVEK is associated with an additional decrease in hemoglobin compared to peginterferon alfa and ribavirin alone. Hemoglobin values of ≤10 g per dL were observed in 36% of patients, and <8.5 g per dL in 14% of patients who received INCIVEK combination treatment compared to 17% and 5%, respectively, with peginterferon alfa and ribavirin alone. Hemoglobin should be monitored at baseline and at weeks 2, 4, 8, and 12, or as clinically appropriate. Use the labeled ribavirin dose modification guidelines to manage anemia; if ribavirin dose reductions are inadequate, consider discontinuing INCIVEK. If ribavirin is permanently discontinued, INCIVEK must also be permanently discontinued. The dose of INCIVEK must not be reduced and must not be restarted if discontinued
Warnings and precautions
Pregnancy: Ribavirin may cause defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained just before initiation of 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 combination treatment and for 6 months after all treatment has ended. Female patients should have monthly pregnancy tests during treatment and during the 6-month period after stopping all treatment. Female patients may continue hormonal contraceptives but they may not be reliable during INCIVEK dosing and for up to 2 weeks after stopping INCIVEK. During this time, female patients of childbearing potential should use 2 effective non-hormonal methods of contraception Serious skin reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson syndrome (SJS) were reported in <1% of patients receiving INCIVEK combination treatment compared to none with peginterferon alfa and ribavirin alone. These serious reactions required hospitalization and all patients recovered. Presenting signs of these reactions may include rash, fever, facial edema, target lesions, mucosal ulcerations, and evidence of internal organ involvement. If serious skin reactions occur, all components of INCIVEK combination treatment must be discontinued immediately and the patient referred for urgent medical care Rash developed in 56% of patients who received INCIVEK combination treatment compared to 34% with peginterferon alfa and ribavirin alone. Severe rash was reported in 4% of patients treated with INCIVEK combination treatment compared to <1% with peginterferon alfa and ribavirin alone. Severe rash may have a prominent eczematous component. Patients with mild to moderate rash should be followed for progression of rash or development of systemic symptoms. If rash becomes severe or systemic symptoms develop, discontinue INCIVEK. Peginterferon alfa and ribavirin may be continued.
Adverse reactions
The most common adverse reactions seen with an incidence ≥5% with INCIVEK over controls were rash (56% vs 34%), fatigue (56% vs 50%), pruritus (47% vs 28%), nausea (39% vs 28%), anemia (36% vs 17%), diarrhea (26% vs 17%), vomiting (13% vs 8%), hemorrhoids (12% vs 3%), anorectal discomfort (11% vs 3%), dysgeusia (10% vs 3%), and anal pruritus (6% vs 1%) Please see the Brief Summary on the adjacent pages to this ad. a
ADVANCE was a randomized, double-blind, parallel-group, placebo-controlled, Phase 3 trial in treatment-naïve patients with genotype 1 chronic HCV and compensated liver disease (N=1088). INCIVEK was given for the first 8 weeks of treatment (T8 arm) or the first 12 weeks of treatment (T12 arm) in combination with pegIFN-RBV for either 24 or 48 weeks. Patients who had undetectable HCV RNA (target not detected) at Weeks 4 and 12 (eRVR) received 24 weeks of pegIFN-RBV, and patients who did not have undetectable HCV RNA at Weeks 4 and 12 (no eRVR) received 48 weeks of pegIFN-RBV treatment. The control regimen had a fixed treatment duration, with telaprevir-matching placebo for the first 12 weeks and pegIFN-RBV for 48 weeks. SVR in all trials was defined as HCV RNA <25 IU/mL at 24 weeks after the planned end of treatment. b REALIZE was a randomized, double-blind, placebo-controlled, Phase 3 trial in patients with genotype 1 chronic HCV and compensated liver disease who were previously treated with pegIFN-RBV (N=662). The trial enrolled prior relapsers and prior nonresponders (including partial responders and null responders). Patients received INCIVEK combination treatment for 12 weeks (with and without a 4-week lead-in of pegIFN-RBV alone) followed by treatment with pegIFN-RBV alone for a total of 48 weeks. The control regimen received a telaprevir-matching placebo for the first 16 weeks followed by pegIFN-RBV alone for a total of 48 weeks. Immediate-start and lead-in arms delivered comparable rates of SVR, relapse, and virologic failure; therefore, data were pooled. SVR in all trials was defined as HCV RNA <25 IU/mL at 24 weeks after the planned end of treatment. c Adult patients with genotype 1 chronic hepatitis C virus and compensated liver disease. HCV = hepatitis C virus. INCIVEK combination treatment = INCIVEK + pegIFN-RBV for 12 weeks, and an additional 12 or 36 weeks of pegIFN-RBV alone. pegIFN = peginterferon alfa. RBV = ribavirin. SVR (virologic cure) = sustained virologic response; defined as HCV RNA <25 IU/mL at 24 weeks after the planned end of treatment. RVR = undetectable HCV RNA (target not detected) at Week 4; the first milestone toward eRVR. eRVR = undetectable HCV RNA (target not detected) at Weeks 4 and 12. Treatment-naïve = received no prior therapy for HCV, including interferon or pegylated interferon monotherapy. Partial responder = ≥2 log10 reduction in HCV RNA at Week 12, but not achieving undetectable HCV RNA at the end of a prior pegIFN-RBV therapy. Relapser = undetectable HCV RNA at the end of a prior pegIFN-RBV regimen, but detectable HCV RNA within 24 weeks of follow-up. Null responder = <2 log10 reduction in HCV RNA at Week 12 during a prior pegIFN-RBV therapy. References: 1. IMS Health, IMS NPA Market DynamicsTM, 05/2011 to 03/2012, extracted 04/2012. 2. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.
H E PAT O L O G Y I N F O C U S
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
25
Lowering Ribavirin Dose During Telaprevir Therapy Does Not Compromise SVR in Patients With HCV BY CHRISTINA FRANGOU SAN DIEGO—Patients infected with hepatitis C virus (HCV) who reduced their daily ribavirin dose during telaprevir-based triple therapy did not significantly decrease their odds for achieving a sustained virologic response (SVR),
according to a study presented at the 2012 Digestive Disease Week meeting (abstract 594). After analyzing data from several previously published Phase III trials, the investigators found that ribavirin dose reduction, to 600 mg per day or less, had no substantial effect on SVR rates. The results do not suggest that telaprevir
can or should be used without ribavirin; rather, they indicate that in cases where a patient is experiencing significant negative side effects from ribavirin, the dosage can be cut back in accordance with the package label without major consequence for SVR rates. “In treatment-naive patients, the timing, duration and degree of ribavirin
1
THE # PRESCRIBED
DIRECT-ACTING ANTIVIRAL
IN ADULTS WITH GENOTYPE 1 CHRONIC HEPATITIS C VIRUS 1
In adults with genotype 1 chronic hepatitis C virus (HCV) and compensated liver disease
POWERFUL RESULTS
RAPID VIROLOGIC RESPONSE
Superior SVR (virologic cure) rates across all patient types studied with INCIVEK combination treatment vs pegIFN-RBV alone
Rapid achievement of undetectable HCV RNA in treatmentnaïve patients—68% (246/363) of treatment-naïve patients achieved
79% (285/363) of treatment-naïve patients achieved SVR vs 46% (166/361) with pegIFN-RBV alonea 86% (246/286) of prior relapsers achieved SVR vs 22% (15/68) with pegIFN-RBV aloneb 59% (57/97) of prior partial responders achieved SVR vs 15% (4/27) with pegIFN-RBV aloneb 32% (47/147) of prior null responders achieved SVR vs 5% (2/37) with pegIFN-RBV aloneb – A high proportion of previous null responders (particularly those with cirrhosis) did not achieve SVR and had telaprevir resistanceassociated substitutions emerge on treatment with INCIVEK combination treatment
START TRIPLE THERAPY DAY 1 All patientsc start Day 1 with triple therapy for 12 weeks
undetectable HCV RNA at Week 4 (RVR) vs 9% (34/361) with pegIFN-RBV alonea,2 12 weeks of triple therapy and an additional 12 or 36 weeks of pegIFN-RBV alone is required
Majority of treatment-naïve patients and prior relapsers achieved eRVR—58% (212/363) of treatment-naïve patients and 76% (218/286) of prior relapsers achieved eRVR in the ADVANCE and REALIZE trials, respectivelya,b In the ADVANCE trial, 8% (29/361) achieved eRVR with pegIFN-RBV alone 24-week total treatment duration is recommended in treatment-naïve patients and prior relapsers who achieve eRVR – Treatment-naïve patients with cirrhosis who have undetectable HCV RNA at Weeks 4 and 12 may benefit from a total treatment duration of 48 weeks A confirmed “detectable but below limit of quantification” should not be considered equivalent to an “undetectable” (target not detected) result
An additional 12 or 36 weeks of pegIFN-RBV alone is required
SAFETY PROFILE 1797 patients were included in safety evaluations Most common adverse reactions with an incidence ≥5% with INCIVEK over controls were rash, fatigue, pruritus, nausea, anemia, diarrhea, vomiting, hemorrhoids, anorectal discomfort, dysgeusia, and anal pruritus Rash, anemia, fatigue, pruritus, nausea, and vomiting were the most frequent adverse drug reactions leading to discontinuation of INCIVEK 14% of patients overall discontinued INCIVEK due to adverse drug reactions INCIVEK and the Blue Arrow logo are trademarks of Vertex Pharmaceuticals Incorporated. The brands listed are trademarks of their respective owners. ©2012 Vertex Pharmaceuticals Incorporated | All rights reserved | VX12-3593 | 5/12
dose reduction did not substantially affect SVR achievements with a telaprevir-based regimen,” said study co-author Stuart K. Roberts, MD, of the Department of Gastroenterology, Alfred Hospital, Melbourne, Victoria, Australia. “This study gives us some degree of confidence that we can reduce ribavirin. see Ribavirin Dose, page 26
H E PAT O L O G Y I N F O C U S
be used without ribavirin; rather, they indicate that in cases where a patient is experiencing significant negative side effects from ribavirin, the dosage can be cut back in accordance with the package label without major consequence for SVR rates.
Drugs within Class that are Contraindicated with INCIVEK
Clinical Comments
"MQIB BESFOPSFDFQUPS BOUBHPOJTU
"MGV[PTJO
Potential for hypotension or cardiac arrhythmia
"OUJNZDPCBDUFSJBMT
3JGBNQJO
3JGBNQJO TJHOJGJDBOUMZ SFEVDFT UFMBQSFWJS QMBTNB concentrations.
Ergot derivatives
Dihydroergotamine, ergonovine, ergotamine, methylergonovine
Potential for acute ergot toxicity characterized by peripheral vasospasm or ischemia
GI motility agent
Cisapride
Potential for cardiac arrhythmias
)FSCBM QSPEVDUT
St. John's wort (Hypericum perforatum)
Plasma concentrations of telaprevir can be reduced by concomitant use of the herbal preparation St. Johnâ&#x20AC;&#x2122;s wort.
).( $P" SFEVDUBTF JOIJCJUPST
Lovastatin, simvastatin
Potential for myopathy including rhabdomyolysis
Neuroleptic
Pimozide
Potential for serious and/or life-threatening adverse reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics
PDE5 inhibitor
4JMEFOBGJM 3FWBUJPÂŽ PS UBEBMBGJM "EDJSDBÂŽ) [for Potential for PDE5 inhibitor-associated treatment of pulmonary arterial hypertension] adverse events, including visual abnormalities, a hypotension, prolonged erection, and syncope
Sedatives/hypnotics
Orally administered midazolamb, triazolam
Prolonged or increased sedation or respiratory depression
Peginterferon alfa and ribavirin
3BTI
56%
34%
Fatigue
56%
Pruritus
47%
Nausea
39%
"OFNJB
36%
17%
Diarrhea
26%
17%
Vomiting
13%
)FNPSSIPJET
12%
3%
"OPSFDUBM EJTDPNGPSU
11%
3%
Dysgeusia
3%
"OBM QSVSJUVT
6%
1%
N=493
3BTI BOE BOFNJB CBTFE PO 44$ 4QFDJBM 4FBSDI $BUFHPSZ HSPVQFE UFSNT Description of Selected Adverse Drug Reactions Rash. In controlled clinical trials, rash events (all grades) were reported in 56% of subjects who received INCIVEK combination treatment and in 34% of subjects XIP SFDFJWFE QFHJOUFSGFSPO BMGB BOE SJCBWJSJO 3BTI NPTU GSFRVFOUMZ CFHBO EVSJOH UIF GJSTU XFFLT CVU DPVME PDDVS BU BOZ UJNF EVSJOH */$*7&, DPNCJOBUJPO treatment. Improvement of rash occurs after INCIVEK dosing completion or discontinuation; however, rashes may take weeks for complete resolution. 3BTI FWFOUT MFE UP EJTDPOUJOVBUJPO PG */$*7&, BMPOF JO PG TVCKFDUT BOE EJTDPOUJOVBUJPO PG */$*7&, DPNCJOBUJPO USFBUNFOU JO PG TVCKFDUT Anemia. In controlled clinical trials, the overall incidence and severity of anemia increased with INCIVEK combination treatment compared to peginterferon alfa and ribavirin alone. The incidence of anemia adverse events was 36% with INCIVEK combination treatment compared to 17% with peginterferon alfa and SJCBWJSJO BMPOF " EFDSFBTF JO IFNPHMPCJO MFWFMT PDDVSSFE EVSJOH UIF GJSTU XFFLT PG USFBUNFOU XJUI MPXFTU WBMVFT SFBDIFE BUU UIF FOE PG */$*7&, EPTJOH )FNPHMPCJO WBMVFT HSBEVBMMZ SFUVSOFE UP MFWFMT PCTFSWFE XJUI QFHJOUFSGFSPO BMGB BOE SJCBWJSJO BGUFS */$*7&, EPTJOH XBT DPNQMFUFE Anorectal Signs and Symptoms. In the controlled clinical trials, 29% of subjects treated with INCIVEK combination treatment experienced anorectal adverse events, 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 count. More INCIVEK-treated subjects had decreases in lymphocyte counts to 499/mm3 or less (15% compared to 5%). Decreases in total white cell counts to 1,499/mm3 PS MFTT XFSF DPNQBSBCMF DPNQBSFE UP 5IF JODJEFODF PG EFDSFBTFT JO BCTPMVUF OFVUSPQIJM DPVOUT UP NN3 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 decreases in mean platelet values of all grades: 47% compared to 36% treated with peginterferon alfa and ribavirin alone. Three percent of INCIVEK combination treatment subjects had decreases to 49,999/mm3 or less compared to 1% of those treated with peginterferon alfa and ribavirin-treated alone. Bilirubin: 'PSUZ POF QFSDFOU PG */$*7&, USFBUFE TVCKFDUT DPNQBSFE UP : PG QFHJOUFSGFSPO BMGB BOE SJCBWJSJO USFBUFE TVCKFDUT IBE BMM HSBEF FMFWBUJPOT JO CJMJSVCJO levels; 4% and 2% of subjects, respectively, had greater than or equal to 2.6 x ULN elevations. Bilirubin levels increased mostt steeply during the first 1 to 2 weeks of INCIVEK dosing, stabilized and between Weeks 12 and 16 were at baseline levels. Uric Acid:: During the INCIVEK combination treatment period, 73% of subjects had elevated uric acid levels compared to 29% for those treated with peginterferon alfa and ribavirin alone. Shifts to greater than or equal to 12.1 mg per dL from baseline in uric acid levels were also more frequent among subjects treated with INCIVEK (7%) compared to peginterferon alfa and ribavirin (1%). Less than 1% of subjects had clinical events of gout/gouty arthritis; none were serious and none resulted in treatment discontinuation. DRUG INTERACTIONS Potential for INCIVEK to Affect Other Drugs */$*7&, JT BO JOIJCJUPS PG $:1 " $P BENJOJTUSBUJPO PG */$*7&, XJUI ESVHT UIBU BSF QSJNBSJMZ NFUBCPMJ[FE CZ $:1 " NBZ SFTVMU JO JODSFBTFE QMBTNB concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions. INCIVEK is also an inhibitor of P-gp. Co-administration of INCIVEK with drugs that are substrates for P-gp transport may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions. If dose adjustments of concomitant medications are made during INCIVEK treatment, they should be re-adjusted after administration of INCIVEK is completed. Potential for Other Drugs to Affect INCIVEK */$*7&, JT B TVCTUSBUF PG $:1 " BOE 1 HQ UIFSFGPSF ESVHT UIBU JOEVDF $:1 " BOE PS 1 HQ NBZ EFDSFBTF */$*7&, QMBTNB DPODFOUSB U UJPOT 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 USJBMT JOEJDBUFE 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: Drug Name
Effect on concentration of INCIVEK or Concomitant Drug
Clinical Comment
lidocaine (systemic), amiodarone, bepridil, flecainide, propafenone, quinidine EJHPYJO
ANTIARRHYTHMICS Co-administration with telaprevir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir. Concentrations of digoxin were increased when co-administered with telaprevir. The lowest dose of digoxin should be initially prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Concentrations of both telaprevir and the antibacterial may be increased during co-administration. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir. QT interval prolongation and Torsade de Pointes have been reported with clarithromycin and erythromycin. QT interval prolongation has been reported with telithromycin.
or warfarin
Concentrations of warfarin may be altered when co-administered with telaprevir. 5IF JOUFSOBUJPOBM OPSNBMJ[FE SBUJP */3 TIPVME CF NPOJUPSFE XIFO XBSGBSJO JT co-administered with telaprevir.
telaprevir carbamazepine or phenytoin or phenobarbital
Concentrations of the anticonvulsant may be altered and concentrations of telaprevir may be decreased. Caution should be used when prescribing carbamazepine, phenobarbital, and phenytoin. Telaprevir may be less effective in patients taking these agents concomitantly. Clinical or laboratory monitoring of carbamazepine, phenobarbital, and phenytoin concentrations and dose titration are recommended to achieve the desired clinical response.
telaprevir escitalopram
Concentrations of escitalopram were decreased when co-administered with telaprevir. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with telaprevir. Concomitant use of trazodone or desipramine and telaprevir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with telaprevir, the combination should be used with caution and a lower dose of trazodone or desipramine should be considered.
antiarrhythmics
digoxin
ANTIBACTERIALS clarithromycin erythromycin telithromycin
telaprevir antibacterials
ANTICOAGULANT warfarin
â&#x17E;&#x17E;
ANTICONVULSANTS
â&#x17E;&#x17E; â&#x17E;&#x17E;
carbamazepine phenobarbital phenytoin
â&#x17E;&#x17E;
ANTIDEPRESSANTS FTDJUBMPQSBN
â&#x17E;&#x17E;
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 has been obtained 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 period after stopping treatment. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male QBUJFOUT BT TJHOJGJDBOU UFSBUPHFOJD BOE PS FNCSZPDJEBM FGGFDUT IBWF CFFO EFNPOTUSBUFE JO BMM BOJNBM TQFDJFT FYQPTFE UP SJCBWJSJO 3FGFS BMTP UP UIF QSFTDSJCJOH information for ribavirin. Female Patients-)PSNPOBM DPOUSBDFQUJWFT NBZ CF DPOUJOVFE CVU NBZ OPU CF SFMJBCMF EVSJOH */$*7&, EPTJOH BOE GPS VQ UP UXP XFFLT GPMMPXJOH DFTTBUJPO PG INCIVEK. During this time, female patients of childbearing potential should use two effective non-hormonal methods of contraception. Examples may include barrier methods or intrauterine devices (IUDs). Two weeks after completion of INCIVEK treatment, hormonal contraceptives are again appropriate as one of the two required effective methods of birth control; however, specific prescribing information recommendations should be followed for the contraceptives. Serious Skin Reactions. 4FSJPVT TLJO SFBDUJPOT JODMVEJOH %SVH 3BTI XJUI &PTJOPQIJMJB BOE 4ZTUFNJD 4ZNQUPNT %3&44 BOE 4UFWFOT +PIOTPO 4ZOESPNF (SJS) were reported in less than 1% of subjects who received INCIVEK combination treatment compared to none who received peginterferon alfa and ribavirin BMPOF 5IFTF TFSJPVT TLJO SFBDUJPOT SFRVJSFE IPTQJUBMJ[BUJPO BOE BMM QBUJFOUT SFDPWFSFE 5IF QSFTFOUJOH TJHOT PG %3&44 NBZ JODMVEF SBTI GFWFS GBDJBM edema, and evidence of internal organ involvement (e.g., hepatitis, nephritis). Eosinophilia may or may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips). If a serious skin reaction occurs, all components of INCIVEK combination treatment must be discontinued immediately and the patient should be promptly referred for urgent medical care. Rash. 3BTI EFWFMPQFE JO PG TVCKFDUT XIP SFDFJWFE */$*7&, DPNCJOBUJPO USFBUNFOU 4FWFSF SBTI F H B HFOFSBMJ[FE SBTI PS SBTI XJUI WFTJDMFT PS CVMMBF PS ulcerations other than SJS) was reported in 4% of subjects who received INCIVEK combination treatment compared to less than 1% who received peginterferon alfa and ribavirin alone. 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 discontinuation, sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon alfa should be considered. If medically indicated, earlier interruption or discontinuation of ribavirin and peginterferon alfa should be considered. Patients should be monitored until the rash has resolved. INCIVEK must not be reduced or restarted if discontinued due to rash. Treatment of rash with oral antihistamines and/or topical corticosteroids may provide symptomatic relief but effectiveness 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 observed in 14% of subjects who received INCIVEK combination treatment compared to 5% of subjects receiving peginterferon alfa and ribavirin. In subjects receiving INCIVEK combination treatment, 4% discontinued INCIVEK, 1% discontinued INCIVEK combination treatment, and 32% underwent a ribavirin dose 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 FWFSZ XFFLT EVSJOH */$*7&, DPNCJOBUJPO USFBUNFOU 'PS UIF NBOBHFNFOU PGG BOFNJB SJCBWJSJO EPTF reductions should be used (refer to the prescribing information for ribavirin for its dose reduction guidelines). If ribavirin dose reductions are inadequate, discontinuation of INCIVEK should be considered. If ribavirin is permanently discontinued for the management of anemia, INCIVEKK must also be permanently EJTDPOUJOVFE 3JCBWJSJO NBZ CF SFTUBSUFE QFS UIF EPTJOH NPEJGJDBUJPO HVJEFMJOFT GPS SJCBWJSJO 5IF EPTF PG */$*7&, NVTU OPU CF SFEVDFE BOE */$*7&, NVTU OPU be restarted if discontinued. Drug Interactions. See the table under Contraindicationss for a listing of drugs that are contraindicated for use with INCIVEK due to potentially life-threatening BEWFSTF FWFOUT PS QPUFOUJBM MPTT PG UIFSBQFVUJD FGGFDU UP */$*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 B 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 PG 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 BU XFFLT BOE PS BT DMJOJDBMMZ BQQS U PQSJBUF UIFSFBGUFS $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 )$7 /4 " QSPUFBTF JOIJCJUPS CBTFE USFBUNFOU OPS BSF UIFSF EBUB PO SFQFBUFE DPVSTFT of INCIVEK. Hepatic Impairment. INCIVEK is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal UP PS QBUJFOUT XJUI EFDPNQFOTBUFE MJWFS EJTFBTF 3FGFS UP QSFTDSJCJOH JOGPSNBUJPO GPS QFHJOUFSGFSPO BMGB BOE SJCBWJSJO XIJDI NVTU CF DP BENJOJTUFSFE with INCIVEK. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: t 1SFHOBODZ 6TF XJUI 3JCBWJSJO BOE 1FHJOUFSGFSPO BMGB t 4FSJPVT 4LJO 3FBDUJPOT 3BTI t "OFNJB */$*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 493 who received peginterferon alfa and ribavirin. Serious adverse drug reactions occurred in 3% of subjects who received INCIVEK combination treatment compared to none of the subjects treated with peginterferon alfa and ribavirin. The most frequent serious adverse events in subjects treated with INCIVEK combination treatment were skin disorders (rash BOE PS QSVSJUVT BOE BOFNJB 'PVSUFFO QFSDFOU PG TVCKFDUT EJTDPOUJOVFE */$*7&, EVF UP BEWFSTF ESVH SFBDUJPOT 3BTI BOFNJB GBUJHVF QSVSJUVT OBVTFB BOE vomiting were the most frequent adverse drug reactions leading to discontinuation of INCIVEK. a
INCIVEK, peginterferon alfa, and ribavirin Combination Treatment N=1797
â&#x17E;&#x17E;
Drug Class
INCIVEK was administered in combination with peginterferon alfa and ribavirin. The following table lists adverse drug reactions that occurred in INCIVEK-treated subjects with an incidence at least 5% greater than in subjects receiving peginterferon alfa and ribavirin alone. Clinical Adverse Drug Reactions Reported with at Least 5% Higher Frequency Among Subjects Receiving INCIVEK
â&#x17E;&#x17E;
INCIVEKKTM (telaprevir) Tablets Brief Summary of Prescribing Information. See package insert for full prescribing information. INDICATIONS AND USAGE INCIVEKKTM (telaprevir), in combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis, who are treatment-naĂŻve or who have previously been treated with interferon-based treatment, including prior null responders, partial responders, and relapsers. The following points should be considered when initiating treatment with INCIVEK: t */$*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 resistanceâ&#x20AC;&#x201C;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 )$7 /4 " QSPUFBTF JOIJCJUPST CONTRAINDICATIONS Contraindications to peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. INCIVEK combination treatment is contraindicated in: t X PNFO XIP BSF PS NBZ CFDPNF QSFHOBOU 3JCBWJSJO NBZ DBVTF GFUBM IBSN XIFO BENJOJTUFSFE UP B QSFHOBOU XPNBO *G UIJT ESVH JT VTFE EVSJOH QSFHOBODZ or if the patient becomes pregnant while taking this drug treatment, the patient should be apprised of the potential hazard to a fetus. t NFO XIPTF GFNBMF QBSUOFST BSF QSFHOBOU */$*7&, JT DPOUSBJOEJDBUFE XIFO DPNCJOFE XJUI ESVHT UIBU BSF IJHIMZ EFQFOEFOU PO $:1 " GPS DMFBSBODF BOE GPS XIJDI FMFWBUFE QMBTNB DPODFOUSBUJPOT BSF associated with serious and/or life-threatening events (narrow therapeutic index). INCIVEK is contraindicated when combined with drugs that strongly JOEVDF $:1 " BOE UIVT NBZ MFBE UP MPXFS FYQPTVSF BOE MPTT PG FGGJDBDZ PG */$*7&, $POUSBJOEJDBUFE ESVHT BSF MJTUFE CFMPX G
â&#x17E;&#x17E; â&#x17E;&#x17E;
We saw good results even with the 400 and 200 [mg per day] patients, and still maintained high SVR rates.â&#x20AC;? Since telaprevir obtained the FDAâ&#x20AC;&#x2122;s go-ahead in May 2011, clinicians have struggled with how to manage patients who develop anemia, the key side effect associated with this protease inhibitor. In initial trials, hemoglobin values of 10 g/dL or less were observed in 36% of patients and of 8.5 g/dL or less in 14% of
The results do not suggest that telaprevir can or should
â&#x17E;&#x17E;
continued from page 25
patients who received telaprevir combination treatment compared with 17% and 5%, respectively, with peginterferon (peg/ IFN)-Îą and ribavirin alone. Although reducing the dose of ribavirin can ameliorate anemia, researchers did not know if and how a ribavirin decrease would influence SVR. The current findings help clarify this question. Dr. Roberts and colleagues examined data from three Phase III studies of telaprevir: REALIZE (Retreatment of Patients with Telaprevirbased Regimen to Optimize Outcomes),
â&#x17E;&#x17E; â&#x17E;&#x17E; â&#x17E;&#x17E;
Ribavirin Dose
GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ AUGUST 2012
desipramine trazodone
â&#x17E;&#x17E; â&#x17E;&#x17E;
26
desipramine trazodone
H E PAT O L O G Y I N F O C U S
GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ AUGUST 2012
â&#x20AC;&#x2DC;In treatment-naive patients, the timing, duration and degree of ribavirin dose reduction did not substantially affect SVR achievements with a telaprevir-based regimen.â&#x20AC;&#x2122;
Effect on concentration of INCIVEK or Concomitant Drug
Clinical Comment
Ketoconazole increases the plasma concentrations of telaprevir. Concomitant systemic use of itraconazole or posaconazole with telaprevir may increase plasma concentration of telaprevir. Plasma concentrations of itraconazole, ketoconazole, or posaconazole may be increased in the presence of telaprevir. When co-administration is required, IJHI EPTFT PG JUSBDPOB[PMF PS LFUPDPOB[PMF HSFBUFS UIBO NH EBZ BSF OPU recommended. Caution is warranted and clinical monitoring is recommended for itraconazole, posaconazole and voriconazole. QT interval prolongation and Torsade de Pointes have been reported with voriconazole and posaconazole. QT interval prolongation has been reported with ketoconazole. Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction with telaprevir. Voriconazole should not be administered to patients receiving telaprevir unless an assessment of the benefit/risk ratio justifies its use.
â&#x17E;&#x17E; â&#x17E;&#x17E; â&#x17E;&#x17E;
â&#x17E;&#x17E;
itraconazole posaconazole or voriconazole
â&#x17E;&#x17E;
Concentrations of telaprevir may be decreased, while rifabutin concentrations may be increased during co-administration. Telaprevir may be less effective due to decreased concentrations. The concomitant use of rifabutin and telaprevir is not recommended.
â&#x17E;&#x17E;
Concomitant use of alprazolam and telaprevir increases exposure to alprazolam. Clinical monitoring is warranted.
midazolam
â&#x17E;&#x17E;
Concomitant use of parenterally administered midazolam with telaprevir increased exposure to midazolam. Co-administration should be done in a setting which ensures clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with telaprevir is contraindicated.
zolpidem
â&#x17E;&#x17E;
BNMPEJQJOF
â&#x17E;&#x17E;
diltiazem felodipine nicardipine nifedipine nisoldipine verapamil
â&#x17E;&#x17E;
alprazolam
Exposure to zolpidem was decreased when co-administered with telaprevir. Clinical monitoring and dose titration of zolpidem is recommended to achieve the desired clinical response. Exposure to amlodipine was increased when co-administered with telaprevir. Caution 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.
zolpidem OPO CFO[PEJB[FQJOF TFEBUJWF CALCIUM CHANNEL BLOCKERS
amlodipine calcium channel blockers
CORTICOSTEROIDS 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.
telaprevir
â&#x17E;&#x17E; â&#x17E;&#x17E;
prednisone methylprednisolone
Systemic dexamethasone
â&#x17E;&#x17E;
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.
Inhaled/Nasal fluticasone budesonide
â&#x17E;&#x17E; â&#x17E;&#x17E;
Systemic prednisone methylprednisolone
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.
fluticasone budesonide
â&#x17E;&#x17E;
ENDOTHELIN RECEPTOR ANTAGONIST bosentan
bosentan
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) telaprevir atazanavir
Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased.
telaprevir darunavir
Concomitant administration of telaprevir and darunavir/ritonavir resulted in reduced steady-state exposures to telaprevir and darunavir. It is not recommended to co-administer darunavir/ritonavir and telaprevir.
telaprevir fosamprenavir
Concomitant administration of telaprevir and fosamprenavir/ritonavir resulted in reduced steady-state exposures to telaprevir and amprenavir. It is not recommended to co-administer fosamprenavir/ritonavir and telaprevir.
telaprevir lopinavir
Concomitant administration of telaprevir and lopinavir/ritonavir resulted in reduced steady-state telaprevir exposure, while the steady-state exposure to lopinavir was not affected. It is not recommended to co-administer lopinavir/ritonavir and telaprevir.
â&#x17E;&#x17E;
â&#x17E;&#x17E;
BUB[BOBWJS SJUPOBWJS
â&#x17E;&#x17E;
MPQJOBWJS SJUPOBWJS
â&#x17E;&#x17E; â&#x17E;&#x17E;
GPTBNQSFOBWJS SJUPOBWJS
â&#x17E;&#x17E; â&#x17E;&#x17E;
EBSVOBWJS SJUPOBWJS
HIV-ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS
â&#x17E;&#x17E;
UFOPGPWJS EJTPQSPYJM GVNBSBUF
telaprevir efavirenz telaprevir tenofovir
â&#x17E;&#x17E; â&#x17E;&#x17E;
FGBWJSFO[
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.
Concomitant administration of telaprevir and efavirenz resulted in reduced steadystate exposures to telaprevir and efavirenz. Concomitant administration of telaprevir and tenofovir disoproxil fumarate resulted in increased tenofovir exposure. Increased clinical and laboratory monitoring are warranted. Tenofovir disoproxil fumarate should be discontinued in patients who develop tenofovir-associated toxicities.
NFUIBEPOF
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. 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 and telaprevir in the treatment of pulmonary arterial hypertension is contraindicated. Co-administration of tadalafil and telaprevir in the treatment of pulmonary arterial hypertension is not recommended.
PDE5 INHIBITORS sildenafil tadalafil vardenafil
PDE5 inhibitors
5IFTF JOUFSBDUJPOT IBWF CFFO TUVEJFE 5IF EJSFDUJPO PG UIF BSSPX = increase, = decrease, â&#x17E;&#x17E;
telaprevir rifabutin
â&#x17E;&#x17E;
parenterally administered NJEB[PMBN
salmeterol
INHALED BETA AGONIST
â&#x17E;&#x17E;
â&#x17E;&#x17E;
Patients with renal or hepatic impairment should not be given colchicine with UFMBQSFWJS EVF UP UIF SJTL PG DPMDIJDJOF UPYJDJUZ " SFEVDUJPO JO DPMDIJDJOF EPTBHF PS an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function. Treatment of gout g flares: co-administration of colchicine in patients p on telaprevir: p NH UBCMFU GPS EPTF GPMMPXFE CZ NH IBMG UBCMFU IPVS MBUFS /PU UP CF repeated before 3 days. If used for prophylaxis p p y of gout g flares: co-administration of colchicine in patients p on telaprevir: p *G UIF PSJHJOBM SFHJNFO XBT NH UXJDF B EBZ UIF SFHJNFO TIPVME CF BEKVTUFE UP NH PODF B EBZ *G UIF PSJHJOBM SFHJNFO XBT NH PODF B EBZ UIF SFHJNFO TIPVME CF BEKVTUFE UP NH PODF FWFSZ PUIFS EBZ Treatment of familial Mediterranean fever (FMF): ( ) co-administration of colchicine in ppatients on telaprevir: p .BYJNVN EBJMZ EPTF PG NH NBZ CF HJWFO BT NH UXJDF B EBZ
BENZODIAZEPINES BMQSB[PMBN
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.
cyclosporine sirolimus tacrolimus
NARCOTIC ANALGESIC colchicine
ANTIMYCOBACTERIAL rifabutin
DZDMPTQPSJOF sirolimus UBDSPMJNVT
â&#x17E;&#x17E; â&#x17E;&#x17E; â&#x17E;&#x17E;
IMMUNOSUPPRESSANTS ketoconazole telaprevir
ANTI GOUT colchicine
Clinical Comment
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LFUPDPOB[PMF itraconazole posaconazole voriconazole
Effect on concentration of INCIVEK or Concomitant Drug
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ANTIFUNGALS
Concomitant Drug Class: Drug Name
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Concomitant Drug Class: Drug Name
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â&#x20AC;&#x201D;Stuart K. Roberts, MD
ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir) and ILLUMINATE (Illustrating the Effects of Combination Therapy with Telaprevir). The ADVANCE and ILLUMINATE studies included treatment-naive patients with HCV genotype 1 who received 12 weeks of telaprevir with 24 or 48 weeks of peg/IFNÎą-2a/ribavirin. The REALIZE study consisted of treatment-experienced patients who received 12 weeks of telaprevir with 48 weeks of peg/IFNÎą-2a/ribavirin.
= 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. 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 of 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 the prescribing information for ribavirin. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant (see also ribavirin prescribing information). Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans (see peginterferon alfa prescribing information). Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential 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: Telaprevir treatment alone in mice and rats did not result in harm to the fetus. The highest doses tested produced exposures equal to 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 clinical dose. Potential effects on sperm (e.g., decreased % motile sperm and increased non-motile sperm count) were observed in a rat fertility study at FYQPTVSFT GPME UIF IVNBO FYQPTVSFT BU UIF SFDPNNFOEFE DMJOJDBM EPTF "EEJUJPOBM FGGFDUT PO GFSUJMJUZ JODMVEF NJOPS JODSFBTFT JO QFSDFOU QSFJNQMBOUBUJPO loss, in percent of dams with nonviable embryos and percent of nonviable conceptuses per litter. These effects are likely associated with testicular toxicity in male but contributions of the female cannot be ruled out. There are, however, no adequate and well-controlled trials in pregnant women. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Extreme care must be taken to avoid pregnancy in 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 time, female patients of childbearing potential should use 2 effective non-hormonal methods of contraception. Examples may include barrier methods or IUDs. 3FGFS BMTP UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS SJCBWJSJO Two weeks after completion of INCIVEK treatment, hormonal contraceptives are again appropriate as one of the 2 required effective methods of birth control; IPXFWFS TQFDJGJD QSFTDSJCJOH JOGPSNBUJPO SFDPNNFOEBUJPOT TIPVME CF GPMMPXFE GPS UIF DPOUSBDFQUJWFT 3FGFS BMTP UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS SJCBWJSJO Nursing Mothers It is not known whether telaprevir is excreted in human breast milk. When administered to lactating rats, levels of telaprevir were higher in milk compared to UIPTF PCTFSWFE 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 telaprevir-treated and control dams. Because 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, caution should be exercised in the administration and monitoring of INCIVEK in geriatric patients reflecting the greater frequency of decreased hepatic function, and of 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 QIBSNBDPLJOFUJD 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 JNQBJSN U FOU $IJME 1VHI " TDPSF 3FGFS BMTP UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS QFHJOUFSGFSPO BMGB BOE SJCBWJSJO XIJDI NVTU CF DP BENJOJTUFSFE XJUI */$*7&, 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- QFSS 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 N- QFS NJO */$*7&, IBT OPU CFFO TUVEJFE JO TVCKFDUT XJUI FOE TUBHF SFOBM EJTFBTF &43% PS PO IFNPEJBMZTJT 3FGFS BMTP UP UIF QSFTDSJCJOH information for peginterferon alfa and ribavirin which must be co-administered with INCIVEK. Co-infection 5IF TBGFUZ BOE FGGJDBDZ PG */$*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 appetite, dysgeusia, and 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.
atorvastatin
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HMG-CoA REDUCTASE INHIBITORS atorvastatin
Plasma concentrations of atorvastatin are markedly increased when co-administered XJUI UFMBQSFWJS "WPJE DPODPNJUBOU BENJOJTUSBUJPO PG UFMBQSFWJSS BOE BUPSWBTUBUJO
HORMONAL CONTRACEPTIVES/ESTROGEN ethinyl estradiol norethindrone
â&#x17E;&#x17E;
FUIJOZM FTUSBEJPM norethindrone
Exposure to ethinyl estradiol was decreased when co-administered with telaprevir. 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.
Manufactured for Vertex Pharmaceuticals Incorporated $BNCSJEHF ." 6 4 1BUFOU /P ÂŞ 7FSUFY 1IBSNBDFVUJDBMT *ODPSQPSBUFE "MM SJHIUT SFTFSWFE */$*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 Vertex Pharmaceuticals Incorporated. The brands listed are the registered trademarks of their respective owners and are not trademarks of Vertex Pharmaceuticals Incorporated. 79
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Analysis showed that half of treatment-naive patients (446 of 885) had their ribavirin dose reduced at least once, and of these, 90% had a reduction to 600 mg or less per day. (Ribavirin is typically given in 1,000 or 1,200 mg per day doses, depending on a patientâ&#x20AC;&#x2122;s weight.) The researchers found that patients who received telaprevir achieved high SVR rates, regardless of ribavirin dosage. In the telaprevir-treated population, SVR was achieved in 74% of patients who received 600 mg of ribavirin or less per day, 75% of those who received 800 to 1,000 mg per day and 79% of those who did not receive a reduced dose. In the placebo group, SVR rates were much lower: 42%, 54% and 46%, respectively. Also, patients receiving placebo and peg/IFNribavirin were significantly less likely to reduce their ribavirin intake; only 18% of patients in the placebo group had a ribavirin dose reduction. The study also showed that treatmentexperienced patients were less likely to require ribavirin dose reduction than treatment-naive patients, but still had more dose modifications than patients in the placebo group. SVR rates were lower among treatment-experienced than in treatment-naive patients, and varied based on past experience. Prior partial responders and prior null responders, particularly, had reduced SVR rates ranging from 0% to 50%. Although the small sample size of previously treated patients limited interpretation of the data, the results suggest that there was minimal effect of ribavirin dose reduction on SVR among treatment-experienced patients, the investigators said. This study answers very two important questions for clinicians, said Paul Pockros, MD, director of the Liver Disease Center, Scripps Clinic, La Jolla, Calif., who was not involved in the research. â&#x20AC;&#x153;People always ask about ribavirin dose reductionâ&#x20AC;&#x201D;does it matter? The second question we ask is, â&#x20AC;&#x2DC;Should the dose be increased after the anemia is recovered?â&#x20AC;&#x2122; The dose reduction data suggest it doesnâ&#x20AC;&#x2122;t make any difference, and that ribavirin does not need to be increased.â&#x20AC;? The package insert for telaprevir calls for physicians to use the labeled ribavirin dose-modification guidelines to manage anemia. â&#x2013; Investigators involved with the study reported the following disclosures: advisory committees/review panels for Abbott Laboratories, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck & Co., Onyx Pharmaceuticals, Pharmasset, Roche/Genentech, Tibotec, Vertex Pharmaceuticals and Wyeth Pharmaceuticals.
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NAFLD continued from page 1
Digestive Disease Week (DDW) meeting (abstract 705). An analysis of a large, national database spanning from 1988 to 2008 showed that 10% of adolescents now meet the criteria for NAFLD. Lead investigator Miriam Vos, MD, assistant professor of pediatrics at Emory University and Children’s Healthcare of Atlanta, explained in a press conference prior to the DDW meeting that prior epidemiologic pediatric NAFLD studies
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
only looked at single time points, but failed to examine how disease prevalence has changed over time. To document changes in NAFLD prevalence over two decades, Dr. Vos and colleagues examined data from the National Health and Nutrition Examination Survey (NHANES) collected between 1988 and 2008, including information from 10,359 adolescents between the ages of 12 and 19 years. They defined suspected NAFLD as the presence of overweight or obesity (body mass index ≥85th percentile) along with alanine
transaminase (ALT) levels greater than 25.8 for males or 22.1 for females. Dr. Vos noted that some studies have defined NAFLD as ALT levels greater than 30, but that these lower thresholds are thought to be more accurate. The investigators found that rates of suspected pediatric NAFLD increased from 3.6% (±0.6%) in 1988 to 9.9% (±1.3%) in 2008 (P<0.0001). Although the percentage of obese adolescents also increased significantly, from 11.2% (±1.1%) in 1988 to 20.6% (±2.1%) in 2008, the corresponding increase in
The Liver Meeting The 63rd Annual Meeting of the American Association for the Study of Liver Diseases
‘We’re not sure why we found this disparity between the prevalence of obesity and the rate of NAFLD, but we suspect one reason might be that waist circumference among obese adolescents is increasing and NAFLD is closely associated with abdominal weight gain.’ —Miriam Vos, MD
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suspected NAFLD among obese adolescents was more pronounced, rising from 16.7% in 1988 to 36.9% in 2008 (P=0.006). P “We’re not sure why we found this disparity between the prevalence of obesity and the rate of NAFLD, but we suspect one reason might be that waist circumference among obese adolescents is increasing and NAFLD is closely associated with abdominal weight gain,” Dr. Vos said in a press conference. According to Zobair Younossi, MD, MPH, chair of the Department of Medicine at Inova Fairfax Hospital and vice president for research at Inova Health System, Falls Church, Va., the increasing prevalence of pediatric NAFLD now mirrors the adult population and the problem warrants an aggressive public health and clinical campaign. “A multidisciplinary approach of screening and intervention primarily targeting obesity must be considered at this point,” said Dr. Younossi, who was not involved in the study. “Since this is a young cohort, they have a long period of time for NAFLD to progress. Some of these children may progress to cirrhosis, with all its complications and associated morbidity, liver-related mortality and costs. If untreated, NAFLD in this population can become a major health problem for the American population in the future.” ■ Drs. Vos and Younossi reported no conflicts of interest.
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First Studies Reported of Boceprevir in Prior Null Responders, ‘Head-to-Head’ With Telaprevir in Patients With HCV BY GEORGE OCHOA Two studies presented at the European Association for the Study of the Liver (EASL)/International Liver Congress meeting in Barcelona, Spain, were the first to explore certain aspects of treatment with boceprevir. One study was the first to show the efficacy of boceprevir in the treatment of null responders with hepatitis C virus (HCV) infection. Another study addressed the absence of head-tohead clinical trials between boceprevir (Victrelis, Merck & Co.) and telaprevir (Incivek, Vertex Pharmaceuticals).
peginterferon and ribavirin was effective in prior partial responders and relapsers, which has been previously reported. “The RESPOND-2 [Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2] trial by Bacon and colleagues [N Engl J Medd 2011;364:1207-1217] already established effectiveness of boceprevir in prior
relapsers and partial responders, but not in prior null responders,” explained Donald M. Jensen, MD, professor of medicine and director, Center for Liver Disease, University of Chicago Medical Center. “This abstract by Bronowicki demonstrates that 40% of prior nulls [null responders] can respond to this treatment.” The results were based on an interim
analysis of PROVIDE, an ongoing, open-label study of patients who participated in the peginterferon and ribavirin control arms of the Phase II and III studies of boceprevir and who failed to achieve SVR. After treatment with the triple-drug regimen, SVR was achieved in 40% (19 of 47) of prior null see Boceprevir, page 30
Boceprevir in Null Responders In the first study, investigators found that boceprevir used in combination with peginterferon and ribavirin led to high rates of sustained virologic response (SVR) in patients with HCV who failed prior treatment with peginterferon and ribavirin alone. The study also showed that the combination of boceprevir with
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proven reduction in the risk of overt HE breakthrough2† proven reduction in the risk of HE-related hospitalizations2‡§
Prescribe. Protect. Repeat.
*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. 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 Web site: www.salix.com 1700 Perimeter Park Drive, Morrisville, NC 27560 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIF 12/16
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. 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):1012-1017. 2. Xifaxan [prescribing information]. Morrisville, NC: Salix Pharmaceuticals, Inc; 2010.
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H E PAT O L O G Y I N F O C U S
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
Boceprevir continued from page 29
responders, defined as a greater than 2-log10 decline in HCV RNA at treatment week 12 in the prior study. Among prior partial responders/relapsers, 68% (62 of 91) of patients achieved an SVR with the triple-drug combination. The total proportion of patients in the study who achieved SVR was 59% (81 of 138), noted lead study author, Jean-Pierre Bronowicki, MD, PhD, of the University
Henri Poincaré of Nancy, in Vandoeuvreles-Nancy, France. Overall, 7% of patients discontinued treatment because of adverse events: 48% had anemia, 34% dysgeusia and 22% neutropenia. The degree of interferon responsiveness after lead-in with peginterferon and ribavirin correlated with prior response and could help predict SVR for prior null
responders, the researchers concluded.
Indirect ‘Head-to-Head’ Comparison of Boceprevir, Telaprevir Another study, presented at the EASL meeting by Cooper et al, attempted to compare boceprevir and telaprevir in a head-to-head clinical trial. The researchers used an indirect comparison
metaanalysis and metaregression of the current evidence to evaluate the relative efficacy of the two drugs in combination with peginterferon-α and ribavirin. Phase II and III randomized placebo-controlled trials evaluating the efficacy of boceprevir or telaprevir in adult patients infected with HCV genotype 1 were considered for the analysis; four boceprevir trials and six telaprevir trials met the inclusion criteria. The researchers found no significant differences between boceprevir and telaprevir in SVR among treatment-naive or -experienced patients (relative risk [RR], 1.14; 95% confidence interval [CI], 0.93-1.37; P=0.20 and RR, 0.80; 95% CI, 0.18-3.45; P=0.30, respectively). Additionally, there were no significant differences between boceprevir and telaprevir in rates of relapse or discontinuation of therapy among naive and experienced patients. Also, boceprevir and telaprevir were shown to be comparable in efficacy for both standard-dose and response-guided therapy. Telaprevir was associated with higher rates of rash (RR, 0.70; 95% CI, 0.54-0.92; P=0.01) and pruritus (RR, 0.67; 95% CI, 0.530.85; P=0.001) compared with boceprevir, which was associated with increased rates of neutropenia among treatmentnaive response-guided patients (RR, 1.46; 95% CI, 1.09-1.95; P=0.05). P Commenting on the method of data analysis used in this study, Steven D. Pearson, MD, MSc, president of the Institute for Clinical and Economic Review, Boston, pointed out that “indirect comparisons can be ‘valid’ if the technique is well done. Many coverage decisions require indirect comparisons. They are more open to question than direct comparisons, but often direct comparisons are not available or even feasible.” However, Dr. Jensen said: “I hesitate to put too much reliance on a comparison between two agents that is not head-tohead and would be reluctant to say that these therapies are comparable based on
H E PAT O L O G Y I N F O C U S
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‘These represent important Helping patients manage AEs can have a positive effect on compliance, Dr. Nguyen stressed, and that in turn can be a cost-saver. “These are expensive drugs,” she noted. Considering both studies, Dr. Jensen said, “These represent important findings, but may not be that
findings, but may not be that surprising. They demonstrate what many have suspected: that telaprevir and boceprevir therapies provide generally comparable response rates, and that boceprevir is effective in prior interferon/ ribavirin null responders.’
surprising. They demonstrate what many have suspected: that telaprevir and boceprevir therapies provide generally comparable response rates, and that boceprevir is effective in prior interferon/ ribavirin null responders.” ■ Drs. Nguyen and Pearson reported no relevant financial conflicts of interest. Dr. Jensen reported that he is an advisory board member or consultant for Merck & Co. and Vertex Pharmaceuticals.
—Donald M. Jensen, MD this analysis alone. Nonetheless, it is my personal impression that these therapies are fairly comparable, so in that case, this study confirms my impression.” The study authors noted that dosing schedule and adverse event (AE) profiles are the key factors that allow for differentiation between the drugs—a point echoed by pharmacist Janet Nguyen, PharmD, BCPS, vice president of network strategy, A-Med Health Care, Huntington Beach, Calif. “Telaprevir has a much easier dosing schedule compared with boceprevir, with a three-month duration [compared with six to eight months for boceprevir] and one less blood draw,” she said. As for side effects, she noted that the study “called out the most significant [AEs]—rash for telaprevir and neutropenia for boceprevir.”
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following transplantation compared with 35.3% who had monthly all-cause health care costs were lower in treated not signed a contract. Rates of heavy drinking in particu- patients than in non-treated patients, and that all-cause lar were similar between the two groups, with 15.6% and health care costs were approximately 4-fold higher in 16.2% of those who committed to abstinence and those treated HCV patients with end-stage liver disease than who did not, respectively, in treated patients with reporting heavy alcohol non-cirrhotic disease. ‘Another finding—that the recurrent use of consumption. Mean cost on a peralcohol rarely results in significant post– However, the researchpatient monthly basis ers qualified the reliabilamong treated HCV liver transplant morbidity—is not novel, but ity of the findings, saying patients was $1,509 is equally provocative and gives pause that among 63 patients compared with $1,943 in both groups who for untreated patients for thought.’ reported being abstinent, (P<0.001). Stratified —Stuart C. Gordon, MD only 24 had blood alcoaccording to liver dishol measured and two of ease severity, the mean these had positive tests. monthly health care “The introduction of an ‘alcohol contract’ may have cost among treated non-cirrhotic patients was $918 value in improving public perception of transplanting compared with $1,375 among untreated non-cirrhotic alcoholic liver disease patients but is insufficient to alter patients (P<0.001). Mean monthly all-cause costs rates of recidivism,” the investigators concluded. among treated HCV patients with end-stage liver disDr. Gordon: Although there are many concerns ease totaled $3,634 compared with $5,077 for similar regarding the ethics of liver transplantation, alcohol untreated patients (P<0.001). recidivism looms among the largest. In the absence of The authors concluded that because early HCV treatreliable predictors of alcohol relapse, the six-month ment may prevent progression of liver disease to cirrhoabstinence rule provides the medical community with sis and liver failure, it can significantly reduce follow-up some sense that they are fulfilling an ethically fair obli- health care costs. gation to society. The present report from the United Dr. Gordon: Recent cost-effectiveness modeling Kingdom shatters any myth that the signing of an “alco- has suggested that one-time HCV screening followed by hol contract” by a potential transplant recipient—with treatment with currently available therapies in a birth the intention of creating a legal obligation—has in any cohort should prove to be the most cost-effective HCV way diminished a return to alcohol consumption. management strategy (Rein DB et al. Ann Intern Med That nearly half of the patients admitted recidivism 2012;156:263-270). The present analysis from a geodespite the contract—with the suggestion by positive graphically and demographically diverse U.S. managed blood alcohol levels among the “deniers” that the actual care database with a long period of follow-up proves that numbers were even higher—should serve as a sobering the vast majority of HCV patients in the United States reminder to those who either 1) embrace the value of are not receiving antiviral treatment. A previous analysuch contracts; or 2) are reassured that they have now sis of the same database showed that health care costs heeded society’s judgment call. increase in direct proportion to HCV liver disease severThe authors of this insightful study nevertheless con- ity (Gordon S et al. Hepatology 2012, in press). clude that these patients need still more “robust abstiThe surprising finding of the present study was that nence support.” Skeptics and cynics could take issue all-cause health care costs were significantly lower in with such a conclusion. Another finding—that the those patients who received antiviral therapy compared recurrent use of alcohol rarely results in significant post– with those who were not treated. liver transplant morbidity—is not novel, but is equally These data add to a growing body of literature showprovocative and gives pause for thought. ing that the early treatment of HCV during a window of opportunity before end-stage liver disease evolves may Impact of HCV in fact reduce overall medical costs. Treatment and Disease Severity on Health Ira Jacobson, MD Care Costs in Chronic HCV Patients: Analysis of a Large U.S. Private Health Insurance Claims Chief of the Division of Database (Gordon SC et al) Gastroenterology and Hepatology Although successful treatment of chronic HCV infecProfessor of Medicine tion lowers the risk for morbidity and mortality in this Weill Cornell Medical College population, there are no data examining the impact of New York, New York treatment on health care costs. To address this question, Attending Physician Dr. Gordon and his colleagues analyzed the database NewYork-Presbyterian Hospital of a large U.S. medical insurance provider, including New York, New York medical records of patients with chronic HCV infection, 4,116 of whom received antiviral treatment and 29,334 of whom did not, between January 2001 and August 2010. All patients had been followed for at least two ATOMIC: 97% RVR for PSI-7977 + PEG/ years following initial assessment. RBV x 12 Week Regimen in HCV GT1: The investigators noted that overall, 82% of patients An End to Response-Guided Therapy? with health insurance did not receive any antiviral (Kowdley et al) HCV treatment. They also found that mean subsequent
1115.
1.
1113.
ELECTRON: Once Daily PSI-7977 Plus RBV in HCV GT1/2/3 (Gane EJ et al)
In the ATOMIC study, 316 patients with HCV genotype 1, 11 with HCV genotype 4 and five with HCV genotype 6 were randomized to receive treatment with one of three drug regimens: The first two groups received 12 and 24 weeks, respectively, of PSI7977, a uridine nucleotide analog, along with pegylated interferon PEG-IFN/RBV. A third group of patients received the same regimen for 12 weeks and were subsequently re-randomized to receive either PSI-7977 alone or in combination with RBV. Preliminary findings presented at the meeting showed between 94% and 98% of patients had HCV RNA levels lower than 15 IU/mL at four weeks, and response rates edging toward 100% in all groups at the end of treatment. SVR rates of 92% to 94% at week 4 also were achieved in all groups. Furthermore, 90% of patients in the 12-week PSI-7977/PEG-IFN/RBV group achieved SVR at week 12. SVR week 12 data from the other arms were not available at the time of the presentation.
‘The ELECTRON study has helped to establish beyond doubt the capacity of IFN-free therapy to cure a high proportion of patients with HCV.’ —Ira Jacobson, MD
Four percent of patients discontinued treatment because of AEs, with most AEs occurring in the combination PEG-IFN/RBV treatment group. Notable AEs included grade 3 Hb abnormalities in 6% of patients and grade 3/4 neutropenia in 17% of subjects. Individuals re-randomized to receive PSI-7977 alone experienced “an almost immediate return to baseline values in Hb and absolute neutrophil counts, confirming the predominant effect of PEG in hematologic abnormalities,” the investigators reported. In the open-label ELECTRON study, investigators administered 24 weeks of PSI-7977 with RBV in four separate groups of treatment-naive, non-cirrhotic patients with HCV genotype 1/2/3: 11 subjects received PSI-7977/RBV with PEG-IFN for 12 weeks; 10 patients received PSI-7977/RBV with eight weeks of PEG-IFN; nine received PSI-7977 with four weeks of PEG-IFN; and 10 subjects received PSI-7977/RBV without PEG-IFN. The researchers found that all patients in all four groups experienced complete virologic response by four weeks. SVR was maintained in all patients at 12 weeks, regardless of PEG-IFN administration. Although the researchers did not have full follow-up data for patients up to 24 weeks at the time of presentation, SVR was maintained in all subjects who did complete the duration of treatment. Dr. Jacobson: The ATOMIC study brings IFN-based therapy for HCV genotype 1 infection to a new plateau with its demonstration of 90% SVR rate with only 12 weeks of triple therapy. It raises the bar see Best of EASL, page 34
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Best of EASL continued from page 32
for what an IFN-free regimen must achieve to be considered the clear treatment of choice (although that bar may have been met already with the studies cited above). The ELECTRON study has helped to establish beyond doubt the capacity of IFN-free therapy to cure a high proportion of patients with HCV, and may bode well for an extraordinarily simplified future regimen of one direct-acting antiviral (DAA) agent plus ribavirin for patients with HCV genotypes 2 and 3. The high SVR rates in HCV genotype 1 treatmentnaive patients must be duplicated, particularly since it has been reported that SVR rates in the same patient population are somewhat lower with this regimen. The much lower rates of SVR in HCV genotype 1 null responders reflect once again the theme of intrinsic IFN responsiveness as a predictor of success with nonIFN containing therapies, and it is notable that the low SVR rates in these patients were associated with high relapse rates rather than a notable impairment in initial viral decline. Whether a longer duration of therapy in such patients is needed or concomitant therapy with another DAA would be superior requires further evaluation. All in all, the ELECTRON study powerfully reinforces the “cornerstone” role that a well-tolerated potent nucleotide polymerase inhibitor is likely to play as future HCV therapies unfold.
breakthrough during treatment, and three experienced relapse following treatment. Among treatment-naive patients, IL28B genotype did not affect the likelihood of virologic response. Common AEs included fatigue (42%), nausea (22%) and headache (20%), with no significant differences among the three groups. One patient experienced hyperbilirubinemia. Dr. Jacobson: The very high SVR rates reported in this study, with a mere 12 weeks of therapy, were deeply gratifying and perhaps somewhat surprising in light of the fact that neither of the DAAs have a high barrier to resistance. The regimen’s success may testify to the utility of RBV in preventing resistance, or possibly, as some have speculated, to high intrahepatic concentrations of ritonavir-boosted ABT-450, permitting suppression of low-level resistant variants. The lower SVR rates in null responders, associated with substantial relapse rates, reflect an important emerging and unanticipated theme—the importance of host pathways, reflected by IFN responsiveness, in mediating viral eradication with IFN-free regimens. Whether this can be overcome with “optimized” antiviral regimens remains to be seen. This regimen has great promise and its components are being further evaluated with the addition of an NS5A inhibitor to the armamentarium.
1422.
Potent Viral Suppression with 12-Week InterferonAll-Oral Combination Free Regimen of ABTof Daclatasvir (NS5A Inhibitor) and GS-7977 450/R + ABT-333 + (NS5B Inhibitor), +/- Ribavirin, in TreatmentRibavirin Achieved SVR12 in More Than 90% Naïve Patients with Chronic HCV GT1, 2, or 3 of Treatment-Naive HCV Genotype-1-Infected (Sulkowski M et al) Subjects and 47% of Previous Non-Responders In this parallel, open-label study, researchers randomized (Poordad F et al) 44 treatment-naive patients with non-cirrhotic HCV In this multicenter trial, HCV genotype 1 patients genotype 1a/b and the same number of non-cirrhotic (mostly genotype 1a) were randomized to one of three HCV genotype 2/3 patients to one of three treatment groups: 1) 19 treatment-naive patients received 250 mg arms: 1) similar numbers of HCV genotype 1a/b and of ABT-450, an NS3 HCV PI, boosted with ritonavir 16 genotype 2/3 patients received 400 mg of the NS5B 100 mg daily, 400 mg of ABT-333, a non-nucleoside inhibitor GS-7977 daily for seven days, followed by 23 HCV polymerase inhibitor, and RBV 1,000 to 1,200 weeks of combination therapy with GS-7977 and daclamg; 2) 14 treatment-naive patients received the same tasvir 60 mg daily; 2) HCV genotype 1a/b and genotype drug regimen with a lower 2/3 subjects received the ritonavir-boosted ABTtwo drugs concurrently for 450 dose of 150 mg daily; 24 weeks; 3) HCV geno‘The very high SVR rates reported in this 3) 17 HCV patients who type 1a/b and genotype study, with a mere 12 weeks of therapy, 2/3 patients were adminwere prior non-responders received the same low istered a combination of were deeply gratifying and perhaps ABT-450 dose regimen as GS-7977, daclatasvir and somewhat surprising.’ the second group. TreatRBV for 24 weeks. ment duration in all arms HCV RNA levels —Ira Jacobson, MD was 12 weeks. Ten patients dropped below the lower in the high-dose ABTlimit of quantification at 450 group, five in the low-dose group and none of the four weeks in approximately 87% of genotype 1a/b and non-responders had the interleukin-28 B (IL28B) CC genotype 2/3 patients receiving sequential GS-7977 then genotype. There were no other significant differences GS-7977/daclatasvir treatment, and in 93% of genotype between groups. 1a/b patients and 78.6% of genotype 2/3 patients receivData analysis revealed all patients in the high-dose ing concurrent GS-7977/daclatasvir. In the GS-7977/ group achieved a rapid virologic response, defined as daclatasvir/RBV treatment group, 73.3% and 64.3% of HCV RNA less than 25 IU/mL at week 4 compared genotype 1a/b and genotype 2/3 patients, respectively, with 92.9% of low-dose treatment-naive patients and had undetectable HCV RNA levels at four weeks. 88.2% of low-dose treatment-experienced prior nonAn intent-to-treat analysis showed undetectable responders. Nearly 95% and 93% of patients in the HCV RNA levels at week 24 in 87% of genotype 1a/b high- and low-dose groups, respectively, achieved SVR and 93% of genotype 2/3 patients receiving sequential at four and 12 weeks, while SVR at weeks 4 and 12 GS-7977 plus GS-7977/daclatasvir and in 86% and 93% was achieved in 47% of low-dose ABT-450 prior non- of genotype 1 and genotype 2/3 subjects, respectively, responders. Six prior non-responders experienced viral in the concurrent treatment group. In the GS-7977/
1399.
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
daclatasvir/RBV group, 93% of genotype 1a/b and 86% of genotype 2/3 subjects experienced undetectable HCV RNA at 24 weeks. Strikingly, 100% of the 44 HCV genotype 1a/b patients in all three groups experienced SVR at week 4. Among HCV genotype 2/3 patients, 88% of sequential treatment recipients, 100% of concurrent treatment subjects and 86% of those in the GS-7977/daclatasvir/RBV group experienced SVR at week 4.
‘The early SVR results from this trial can only be described as stunning. A combination of two DAA agents offered “equal opportunity” viral suppression and universal SVR at week 4, with or without RBV, in both HCV genotype 1 subtypes.’ —Ira Jacobson, MD
Grade 3-4 laboratory abnormalities included elevated cholesterol (N=1), elevated glucose (N=2), low Hb (N=6), lymphopenia (N=1) and low phosphorus (N=2). The incidence of AEs was similar among all treatment groups. Dr. Jacobson: The early SVR results from this trial can only be described as stunning. A combination of two DAA agents offered “equal opportunity” viral suppression and universal SVR at week 4, with or without RBV, in both HCV genotype 1 subtypes. The early success of this combination is doubtless attributable to the inclusion in the regimen of two potent agents, one of which—GS-7977—offers a high barrier to resistance. The results of this regimen in a group of prior non-responders, even to PIs, as is currently under study, will be of enormous interest, as would assessment of a shorter duration regimen, which also is being studied. The combination of an NS5A inhibitor with a potent nucleotide polymerase inhibitor has transformative potential in the field of HCV therapy. ■ Dr. Afdhal has received research support from ScheringPlough/Merck & Co., and Vertex Pharmaceuticals; he has served as a consultant/advisor to Schering-Plough and Vertex Pharmaceuticals. Dr. Gordon reported no conflicts of interest. Dr. Jacobson has received grants/research support from Bristol-Myers Squibb, Gilead, Pharmasset and Schering-Plough; he has served as a consultant/advisor for Abbott Laboratories, Bristol-Myers Squibb, Gilead, Pharmasset and Schering-Plough; and he is a member of the speakers bureau for Bristol-Myers Squibb, Gilead and Schering-Plough.
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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
Single-dose Lubiprostone Enhances Efficacy, Reduces Volume of PEG-based Bowel Prep BY CAROLINE HELWICK SAN DIEGO—A single-dose of lubiprostone given prior to polyethylene glycol (PEG) solution for bowel preparation reduced the volume of PEG required and enhanced the quality of bowel preparation, according to findings from a randomized controlled trial reported at the 2012 Digestive Disease Week meeting. “The addition of lubiprostone resulted in a significant improvement in the total Boston Bowel Preparation Scale score. We saw improvement in scores with lubiprostone in all parts of the colon,” said study author Rupa Banerjee, MD, of the Asian Institute of Gastroenterology in Hyderabad, India. PEG solutions commonly are used for bowel preparation because they are safe and effective, but the large volume of solution required often is poorly tolerated, said Dr. Banerjee. Lubiprostone, a chloride channel activator that is FDA-approved to treat idiopathic chronic constipation, works through facilitated diffusion—or passive transport—and improves small intestinal and colonic transit. Dr. Banerjee and colleagues hypothesized that the addition of lubiprostone could improve the efficacy of standard PEG preparation and reduce the required dosage. The investigators designed a
prospective, double-blind, placebo-controlled randomized trial to test the efficacy of PEG-based bowel preparation with the addition of single-dose lubiprostone (24 mcg) or placebo. They also compared the efficacy of full- versus reduced-dose PEGbased bowel preparation with the addition of lubiprostone. In the first phase of the study, researchers randomized 442 patients to receive 2-L PEG plus lubiprostone or 2-L PEG plus placebo. After this part of the study was completed, researchers randomized an additional 150 patients to receive 1-L PEG plus lubiprostone or 1.5-L PEG plus lubiprostone; bowel preparation in this part of the study was compared with the group of patients who received 2-L PEG plus lubiprostone in the first part of the study. Dr. Banerjee noted that her center typically does not use split-dosing for bowel preparation. “We have a huge patient load, and we are famous for same-day procedures,” she said. “A split-dose, therefore, is difficult for us.” Patients were given 200 mL of PEG solution every 10 minutes one hour after consuming lubiprostone or placebo. None of the patients underwent an overnight fast or any special diet the day prior to colonoscopy. Four experienced endoscopists performed the colonoscopies. All procedures were done with patients under moderate propofol sedation. Complete
Elderly Colonoscopy continued from page 1
“We found a significant number of elderly persons—9.5%—had colorectal cancer on index colonoscopy,” said Theodor Asgeirsson, MD, a colorectal
‘If you think the person will live for another seven years or more, then screen. If not, then it’s not worth the resources.’ —Therese G. Kerwel, MD
colonoscopy was defined as reaching the cecum. Bowel preparation was rated on a scale of 0 to 9 according to the Boston Bowel Preparation Scale (BBPS). Mean BBPS score was 7.4 for patients who received lubiprostone and 6.4 for patients given placebo (P<0.0001). Bowel preparation was deemed excellent in 66.5% of patients in the lubiprostone group versus 38% in the placebo group; preparation was adequate in 42.5% and 24% of these patients, respectively, and a repeat procedure was required in 9.5% and 16.7%, respectively (P<0.01). “So then we asked, ‘Given the significant improvement in bowel prep quality with the addition of lubiprostone in phase one, could the PEG requirement be reduced?’ ” The second phase of the study determined that, indeed, reduced doses were adequate when lubiprostone was part of the regimen. With the addition of lubiprostone to the PEG preparation, no significant differences were observed in overall BBPS scores, even among patients who received the lowest doses of PEG (1 L). Mean BBPS score was 7.44 in the 2-L PEG group, 7.15 in the 1.5-L group and 7.23 in the 1-L group. When researchers analyzed the different regimens according to success of bowel preparation (excellent, adequate or poor), r no regimen was superior. Additionally, the
surgeon with Spectrum Health in Grand Rapids, Mich. “That was shocking to us.” Therese G. Kerwel, MD, also a surgeon, presented the study at the meeting. The researchers reviewed the records of 903 elderly individuals (aged 76-85 years) who underwent colonoscopy at Spectrum Health in 2009 and 2010. The colonoscopies were performed for screening purposes in 19% of patients, for surveillance in 42%, to evaluate symptoms in 35% and for other reasons in 4%. Fifty-three patients had never undergone a colonoscopy. Colonoscopy revealed colorectal cancer in 9.5% of previously unscreened elderly persons. An additional 56 individuals had not had a colonoscopy for 10 years or longer, and cancer was detected in 5% of this group. Most cancers (95%) were stage 2 and all were treated with curative intent. Complication rates were no higher than those observed in younger populations. “We found that in healthy elderly individuals there is a high likelihood of finding cancers that can be cured,” Dr. Asgeirsson said. The remaining 88% of the colonoscopies were performed within nine years of a prior exam, and 3% of these individuals were found to have cancer. No cancers were detected in the subgroup examined four to five years after a prior colonoscopy. This short interval between examinations suggests that some elderly patients were being too aggressively screened, Dr. Asgeirsson noted.
lubiprostone-PEG combination was well tolerated. Dr. Banerjee acknowledged several limitations of the study: Only outpatients were recruited; patients received instruction prior to colonoscopy, which may have enhanced compliance with bowel preparation; and the researchers did not evaluate lesion miss rates. Nevertheless, she said, the study firmly establishes the enhanced efficacy of singledose lubiprostone in combination with PEG for bowel preparation and shows that the addition of lubiprostone allows for lower volumes of PEG. This could have positive implications for patient compliance with bowel preparation regimens, she added. “Lack of dietary restrictions and reduced PEG dose requirements could improve patient acceptance of colonoscopy.” Sushovan Guha, MD, PhD, of the University of Texas MD Anderson Cancer Center, in Houston, said that he could see advantages to using this approach in his patients. “We use Dulcolax—a lot of it. Instead of that, we could use a single lubiprostone dose, and then we could give just 1 L of PEG instead of 4 L. That’s a huge difference for equal benefit.” ■ Drs. Banerjee and Guha reported no conflicts of interest.
Conclusion: Screening Colonoscopy Recommended for Healthy Elderly The high rate of colorectal cancer detected in this study population suggests that for healthy, fit patients with a life expectancy of at least seven more years, screening colonoscopy may be warranted independent of age, Dr. Kerwel said in her presentation. “The U.S. Preventive Services Task Force says that you don’t see benefit [from screening] until about seven years, so that’s the benchmark. If you think the person will live for another seven years or more, then screen. If not, then it’s not worth the resources,” she said. Dr. Asgeirsson noted that the yield is far lower in patients undergoing surveillance colonoscopies. “Maybe we should focus our resources on those who never have had a colonoscopy before,” he said. John Petrini, MD, a gastroenterologist at Sansum Clinic in Santa Barbara, Calif., said, “These findings could affect our thinking about who should be screened. The U.S. Preventive Services Task Force says to stop screening at age 75, largely because of the fear of increased complications, but this study showed the elderly are not at increased risk with a carefully done colonoscopy. “It can be a hard conversation to have with an 85-year-old, to say they are considered too old for screening. They don’t take it well.” ■ Drs. Kerwel and Petrini reported no conflicts of interest.
38
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
Is Urgent ERCP Necessary To Treat Ascending Cho olangitis? Small, Retrospective Study Suggests ERCP Can Wait BY TED BOSWORTH NATIONAL HARBOR, MD.—When patients show up to emergency care centers with ascending cholangitis, do institutions need to call in a specialist to perform an urgent endoscopic retrograde cholangiopancreatography (ERCP) after
hours or during weekends? This question was addressed by researchers who conducted a retrospective review of a center where these patients typically are managed conservatively. Based on a series of 60 patients, outcomes did not appear to be better in patients treated urgently than in those initially managed with medical therapy and supportive care.
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%)
“Based on our results, an ERCP procedure under forced, non-ideal circumstances may not be justified,” said Brandon Craft, MD, a gastroenterology fellow in the Department of Gastroenterology at the Medical University of South Carolina, Charleston. He acknowledged that confirmation of the findings would require a randomized
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.
‘Based on our results, an ERCP procedure under forced, non-ideal circumstances may not be justified.’ —Brandon Craft, MD trial, but noted that outcomes were similar between patients who underwent ERCP within 24 hours of presentation and those with a delay of more than five days. The only death in the series was a patient with advanced cancer who underwent ERCP within 24 hours (and subsequent withdrawal of care). Ascending cholangitis is potentially life-threatening, and because of this, many institutions have policies of performing urgent ERCP or at least conducting the procedure within 24 hours of presentation. However, Dr. Craft pointed out that patients typically stabilize and rapidly defervesce upon treatment with antibiotics, providing an opportunity to perform ERCP at a later time, when experienced staff and optimal support are available. Most cases at Dr. Craft’s institution are treated safely this way and have been for many years. In this study of 60 patients, all were managed with IV fluid resuscitation and antibiotics, although a variety of specific regimens were used. Patients were a mean age of 61 years; 43% had stones and 28% had blocked stents. Almost 70% of patients in the series presented after usual clinical hours or during weekends. More than half of the patients were transferred from a different institution; among these patients, the average time from onset of symptoms to the time of transfer was 1.4 days. Upon treatment with antibiotics, approximately 80% of patients defervesced. Slightly more than 10% were managed in an intensive care unit. Researchers stratified patients into four groups based on the number of days
39
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
‘Patients in non-ERCP centers may not need to undergo emergency percutaneous transhepatic cholangiography or surgery for decompression if they are responding to resuscitation and antibiotics. Rather, nonendoscopic management can be considered until a transfer
ERCP capability, where physicians may need to decide between an interinstitutional transfer versus urgent percutaneous or surgical drainage, if urgent ERCP is not feasible. “Patients in non-ERCP centers may not need to undergo emergency percutaneous transhepatic cholangiography or surgery for decompression if they are responding to resuscitation and antibiotics. Rather, non-endoscopic management can be considered until a transfer is practical if the patient is clinically responding and stable,” Dr. Craft said.
It is not clear whether conservative management is more cost-effective—e.g., if extra costs associated with after-hours care are outweighed by any potential savings from shorter lengths of stay—but Dr. Craft said that a review of a larger cohort is now being conducted. Asked for comment, M. Mazen Jamal, MD, chief of endoscopy, Long Beach Veterans Affairs Health Center, Long Beach, Calif., cautioned that it is premature to declare that urgent ERCP need not to be conducted in this setting. “The weaknesses of this study are that
it is retrospective and nonrandomized,” Dr. Jamal said. “Additionally, the sample size is small and may not adequately represent the U.S. population.” He did not discount the possibility that ERCP can be performed on a nonurgent basis, but simply believed that a multicenter randomized trial is needed to confirm the findings of this study. These data were presented at the 2011 meeting of the American College of Gastroenterology. ■ Drs. Craft and Jamal reported no conflicts of interest.
is practical if the patient is clinically responding and stable.’ —Brandon Craft, MD
Your Practice. Your Needs. Your Partner. Endoscopic Learning Library — 5 New Titles The ASGE Endoscopic Learning Library offers an expansive collection of the latest endoscopy-related topics. Each DVD offers CME and features full-color, or, live-action educational material on the most current topics available. e. The library features five new DVDs for 2012 including:
from symptom onset to ERCP: 24 hours, 24 to 48 hours, 48 to 120 hours or more than five days. The primary end point was renal or cardiorespiratory failure, or death. Although the study was retrospective and nonrandomized, the distribution of potential confounding factors (e.g., age, etiology, type of presentation, outside transfers) in the subgroups was similar. There were no significant differences among groups in the primary end point. There was one post-sphincterotomy bleed and one case of pneumonia. No cases of organ failure developed while patients were waiting to undergo ERCP. There were two cases of organ failure that occurred after ERCP, both of which occurred in groups with a relatively short time to ERCP. Hospital length of stay was longer in patients who had a more than five-day delay to ERCP, but was similar among the other groups. Most of the patients in the longer hospital stay group were patients with multiple comorbidities who were transferred from other institutions. Dr. Craft said that the results of the study do not preclude the value of urgent ERCP in patients who do not defervesce on antibiotics or who otherwise are not doing well, but he suggested that the data do support the safety of a conservative approach in most patients who respond to aggressive medical management. He suggested that the findings support avoiding routine ERCP after hours for cholangitis when experienced staff, such as endoscopy nurses and imaging technicians, may not be available. The findings also may be relevant for centers without
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40
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
Laparoscopic Cholecystectomy/ERCP One-Step Combo May Result in Better Care, Lower Costs BY MONICA J. SMITH SAN DIEGO—Combining laparoscopic cholecystectomy with endoscopic retrograde cholangiopancreatography (ERCP) may result in better patient care and substantially reduced cost than the traditional two-step procedure, according to research presented at the 2012 Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) annual meeting. “We set out to combine laparoscopic cholecystectomy with ERCP in hopes of reducing patient days in the hospital, hospital costs, the amount of anesthesia that patients receive and the need for ERCPs in general; if we do a cholangiogram and it’s negative, there’s no need to do an ERCP,” said Matthew Johnson, MD, acute care surgery fellow at the University of Nevada School of Medicine, University Medical Center, Las Vegas.
The researchers noticed a downward trend in hospital stay and preoperative time (defined as time to laparoscopic cholecystectomy) in the one-step group compared with the two-step group, 3.8 versus 5.3 days, and 2.3 versus 3.1 days, respectively. Where the numbers really got interesting, and statistically significant, was in cost savings. Total hospital charges for the one-step procedure were $58,145, compared with $78,895 for the standard two-step procedure. Neither group experienced complications, and operative times were comparable. Now the researchers are working on a prospective randomized study with 100 patients in each arm in hopes of achieving significance in areas that were underpowered in their initial small study. “This could be a practice changer,” said Brian P. Jacob, MD, associate clinical professor of surgery, Mount Sinai Medical Center, New York City, who moderated the session at which this research was presented.
‘Most ERCPs are done by highly skilled
“For instance, in New York City, at our hospital, surgeons don’t do much of their own advanced endoscopy,” Dr. Jacob said. “But that represents a small percentage of most practices. It would make sense in cases with a positive cholangiogram to then perform an intraoperative ERCP at that same time, as long as professionals and hospitals could still get reimbursed for both procedures.” The truth is ERCP is difficult, with an increased risk for pancreatitis and injury to the duodenum, and it typically hasn’t been a part of surgeon training. “Experience is a huge part of ERCP being successful,” Dr. Jacob said, noting it would take him possibly hundreds of ERCPs before his experience with the latter caught up to his experience with laparoscopic cholecystectomy. “If more surgeons could obtain ERCP experience starting out in fellowship, it could save patients with
‘I truly feel that this is more beneficial to patients …
gastroenterologists; most cholecystectomies
in terms of having one team to care for the
are done by surgeons; and to get the
patients rather than having it spread out
two schedules to blend is often very
to three separate teams: medicine,
challenging.’
gastroenterology and surgery.’ —Brian P. Jacob, MD
Nathan Ozobia, MD, FACS, one of the authors of the paper, has been performing one-step procedures for selected cases of obstructing biliary disease since 1997, a laparoscopic cholecystectomy with intraoperative cholangiogram (IOC) to confirm the presence or absence of stones followed by an intraoperative ERCP if necessary. To examine the feasibility and potential cost savings of this approach, the researchers conducted a retrospective chart review of Dr. Ozobia’s experience from 2008 to 2010 with 10 patients who received the one-step procedure and 10 who underwent the traditional two-step procedure. Surgical residents, under close supervision of the attending surgical endoscopist, performed the procedures, including ERCP. In the one-step procedures, an IOC was obtained at the same time of the cholecystectomy. If the IOC showed positive for common bile duct stones, or if a cholangiogram was not possible due to technical challenges, the physicians performed an intraoperative ERCP. Notably, patients were maintained exclusively in a supine position during the ERCP. Depending on findings of the latter, they went on to conduct a sphincterotomy, balloon exploration of the common bile duct with stone extraction, and/or bile-duct stenting. In the two-step procedure, a gastroenterologist conducted an ERCP prior to the cholecystectomy, with procedures carried out by the gastroenterology team if warranted. The laparoscopic cholecystecomy would be performed 24 to 48 hours later, usually without IOC.
—Matthew Johnson, MD
“This is one of those things that we should be able to bring home and just start doing; but it raises the question, why aren’t we doing it today?” Dr. Jacob said. “Very often, the reason is simply that most ERCPs are done by highly skilled gastroenterologists; most cholecystectomies are done by surgeons; and to get the two schedules to blend is often very challenging. If more surgeons learned how to do ERCP, there would be no reason not to do it at the same time.” Across the country, many surgeons do in fact employ endoscopy, but this varies by state, is hospital-specific within each state, and skill at endoscopy does not necessarily include skill at ERCP.
positive intraoperative cholangiograms from needing a second procedure, and I do think it’s probably more straightforward than the laparoscopic common bile duct exploration,” Dr. Jacob said. “But we need more data to suggest that that’s true.” Dr. Johnson, who considers himself lucky to have a mentor who was trained in ERCP, is optimistic that their ongoing research will corroborate and strengthen their current findings. “If our numbers continue to be very statistically significant, we could hopefully change the standard of care in relation to these diseases, and perhaps have a [gastroenterology] collaboration in the training of surgeons if there is a need in fact,” he said. “I truly feel that this is more beneficial to patients, and not just looking at the numbers, but in terms of having one team to care for the patients rather than having it spread out to three separate teams: medicine, gastroenterology and surgery.” Due to increased resident interest, Drs. Johnson and Ozobia are developing a training module for the University of Nevada School of Medicine that will incorporate ERCP in hopes of instituting this training early on for surgical residents. “Learning ERCP has been one of the most difficult tasks in my surgical training, but it is an invaluable tool in the surgeon’s armamentarium,” Dr. Johnson said. “This is especially true in the management of complicated biliary disease, which we encounter so frequently.” ■
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OPINION
42
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
Money for Drugs
Part 2 of a 3-Part Series
Should 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. Part 1 of this series appeared in Gastroenterology & Endoscopy News May 2012;63:44,49,50.]
NO
YES
No, Physicians Should Remain Independent of Pharma Has Medicine Lost Its Moral Compass? Art Gale, MD Internal Medicine St. Louis, Missouri Two former editors of The New England Journal of Medicine (NEJM), Marcia Angell, MD, and Jerome Kassirer, MD, wrote separate books, both published in 2005, on how financial conflicts of interest involving physicians and the pharmaceutical industry have undermined the validity of clinical research and compromised the integrity of the medical profession. Dr. Angell’s book is titled “The Truth about Drug Companies” (Random House Trade Paperbacks; 2005) and Dr. Kassirer’s book is “On the Take” (Oxford University Press, USA; 2005). Each work takes a slightly different approach. Dr. Angell focuses mainly on drug companies, whereas Dr. Kassirer’s book focuses mainly on physicians. Both authors document the wellknown practices drug companies use to entice physicians to prescribe their products. These include gifts, dinners at expensive restauraants and payments to be a “con nsultant” in name only. Dr. Angell also discusses at length the role of contract research organizations that establish networks of practicing physicians who perform clinical studies. There are approximately 1,000 such organiizations. They receive reevenues of about $7 billiion annually from their drugg company clients. In 2001, these organizations offered bounties to physicians that averaged about $7,000 per patient
enrolled. In one trial, physicians were offered $12,000 per patient and another $30,000 on enrollment of a sixth patient. Many of the drugs tested are already approved, so-called postmarketing or Phase IV studies. With decreasing reimbursement from managed care and increasing professional liability premiums, one can understand why so many doctors enroll their patients in these trials. A physician can make much more money from clinical trials than from seeing patients. And the work is a lot easier. Many critics view these studies as just excuses to pay doctors to put patients on a company’s already approved drug. The authors reserve their harshest criticism for their colleagues in academia. As former editors of one of the world’s premier medical journals, Drs. Angell and Kassirer have reviewed hundreds of articles submitted for publication and are eminently qualified to analyze clinical investigators and the conflicts of interest that affect their research. see No, page 44
Yes, Physicians Must Interact With Pharma Cooperation Is Crucial For Lifesaving Medications Marjorie Powell, JD Senior Assistant General Counsel Pharmaceutical Research and Manufaturers of America Physicians play a vitally important role in conducting clinical trials of potential new medicines and helping to explain new treatments and how they work to other health care providers. Collaborations between biopharmaceutical research companies and physicians at respected research institutions have been critical to the development of clinical trials of new medicines for years. The United States leads the world in the development of new medicines and most of the drugs that U.S. companies have created are still on the market today, saving and enhancing the lives of millions of patients and helping to control the costs of surgery and hospitalization. Clinical trials are crucial to determining the safety and effectiveness of new medicines, and are an essential part of the increasingly expensive 10- to 15-year drug development
and approval process. Biopharmaceutical companies often turn to physicians at respected academic medical centers, including the University of Missouri School of Medicine, the University of Kansas Medical Center and the Washington University School of Medicine in St. Louis, to conduct their clinical research. The clinical testing database of the NIH shows that in the arena of new cancer medicine development alone, these three respected institutions are conducting nearly 70 trials of potential new anticancer drugs in collaboration with biopharmaceutical companies. University medical centers attract some of the nation’s best physician clinicians and researchers. This finite pool of talented physicians is precisely the dynamic, experienced expertise companies want, and need, to conduct their clinical trials. Importantly, extensive safeguards exist to protect the interests of patients, help avoid biased clinical trial results and maintain the highest standards of o medical research ethics. FDA regulations are in place and detailed guidelines have been provided by the NIH H and the medical schools th hemselves to help assure th hat clinical research is cond ducted in a way that proteects all participating pattients. At the Univerrsity of Missouri Scchool of Medicine, forr example, all clinical tests of new medicines are reviewed and d approved by an insttitutional review boarrd and all faculty mem mbers are required to subm mit conflict of interest reports that disclose all outtside activities and relation nships, including see Yes, page 44
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.
OPINION
44
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
NO
YES
continued from page 42
continued from page 42
Dr. Angell writes, “Until the 1980s, researchers were largely independent of the companies that sponsored their work. Now, however, companies are involved in every detail of the research ... even whether to publish the results.” She thoroughly documents the financial relationship between academic medical centers, especially her own (Harvard) and the drug companies.
Two-thirds of academic medical centers hold equity in companies that sponsor some of their research. Harvard is hardly unique. Two-thirds of academic medical centers hold equity
in companies that sponsor some of their research. The academic medical centers reap huge profits from these arrangements. They also receive major gifts and endowments from the drug companies. But there is a price to pay. In Dr. Angell’s view, researchers become little more than “hired hands” of the pharmaceutical industry. She concludes “all see No, page 45
involvement in clinical trials of new medicines being developed by biopharmaceutical companies. The Pharmaceutical Research and Manufacturers of America (PhRMA), meanwhile, provides its “Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results” to help ensure that clinical research sponsored by biopharmaceutical companies is carefully conducted and meaningful research results are published for health care professionals and patients. Revisions to the Principles, put in place nearly two years ago, call for increased transparency about clinical tests for physicians and their patients and improved disclosure to better manage potential conflicts of interest in medical research.
EFFFICACY YOU EXPECT1
WITH WIT TH LO OWER R DOSE1
• LLowest volume phosphate-free lavage1,2 •N No oral sodium phosphate Some critics, who ignore the many effective efforts to protect the integrity of clinical trial data, insist that only tests conducted by the NIH are truly unbiased.
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 Laborattories, ories Inc.; Inc ; MoviPrep® ( PEG PEG-3350, 3350 Sodium Sulfate Sulfate, Sodium m Chloride, Chloride Potassium Chloride, Chloride Soodium Ascorrbate and Ascorbic Acid for Oral Solution), 2006; Morrisville, NC: 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.halflytely.com fl ©2011 Braintree Laboratories, Inc.
HL-12437T
January, 2011
Some critics, who ignore the many effective efforts to protect the integrity of clinical trial data, insist that only tests conducted by the NIH are truly unbiased. They overlook a key fact: NIH officials have repeatedly acknowledged that their institutes are not equipped to conduct the thousands of clinical tests needed for the development of new medicines every year. The NIH and its grantees conduct vitally important basic research that can be used by biopharmaceutical companies to help develop new medicines. But actual drug development, including preclinical and clinical testing, is the expensive and time-consuming responsibility of our nation’s innovative drug companies, which must spend tens of billions of dollars annually to get the job done. In 2010, America’s biopharmaceutical research companies spent a record $67.4 billion on research and development. And various estimates show that clinical trials account for 45% to 75% of total pharmaceutical development costs. Our drug development and see Yes, page 45
OPINION
GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ AUGUST 2012
NO
45
YES
continued from page 44
continued from page 44
of this makes a mockery of the traditional role of researchers as independent impartial scientists.â&#x20AC;? Both authors cite a particularly egregious example of authorsâ&#x20AC;&#x2122; financial ties to drug companies. These ties were so extensive that there was insufficient room to publish them in print. Instead, they had to be published on NEJMâ&#x20AC;&#x2122;ss Web site, where they consumed three single-spaced typewritten pages! Conflicts of interest extend even to the venerable National Institutes of Health (NIH). In 1995, the director of the NIH, Harold Varmus, MD, â&#x20AC;&#x153;quietly rescinded the policy that barred NIH directors from accepting consulting fees and stock options from companies.â&#x20AC;? As a result, directors of various institutes have earned hundreds of thousands of dollars in â&#x20AC;&#x153;consultingâ&#x20AC;? fees. For example, the deputy director of the NIH Laboratory of Immunology, whose salary was $179,000 in 2003, earned $1.4 million in consulting fees over 11 years and received stock options valued at $865,000. Other senior scientists with ties to industry included the director of the National Institute of Arthritis, a director of the National Institute of Diabetes and Digestive and Kidney Diseases and the former director of the National Human Genome Research Institute. When these revelations were published, a former acting director of the NIH opined that none of these revelations compromised the public interest because NIH scientists are â&#x20AC;&#x153;highly ethical people with enormous integrity.â&#x20AC;? Dr. Kassirer quotes the current director of NIH, Elias Zerhouni, MD, who found no evidence that â&#x20AC;&#x153;medical decisions had been influenced by company payments to agency officials.â&#x20AC;? After Congress promised a full investigation, Dr. Zerhouni changed his mind and said that NIH top scientists were no longer accepting consulting fees or stock options. The conflict of interest in clinical research is so pervasive that, as editor of the NEJM, M Dr. Kassirer had difficulty finding independent authors to write review articles. In the late 1990s, he stated, â&#x20AC;&#x153;We occasionally had to reject five or six prominent authors before we found one who had no conflicts.â&#x20AC;? His successor at NEJM M solved this problem by changing the policy because he found it too difficult to find authors who were free of such conflicts. What do all the conflicts of interest have to do with the practice of medicine? The answer is: a lot. Probably their most important effect is through the development of clinical guidelinesâ&#x20AC;&#x201D;guidelines
approval process today, one that is carefully monitored by the FDA, is working well. And perhaps the best evidence of the systemâ&#x20AC;&#x2122;s success is the progress that has been made in the fight against disease that can be, in large part, attributed to new medicines. For example, the development of new heart disease and stroke medicines has helped to reduce deaths from these two major
see No, page 46
killers by nearly 30%. New anticancer drugs, meanwhile, have contributed to an increase in cancer survivors from 3 million in 1971 to 11.7 million in 2007. Physicians learn about new medicines from a range of sources, including firsthand experience, medical journals, continuing medical education programs and discussions with biopharmaceutical company representatives and fellow
DECEMBER 13â&#x20AC;&#x201C; 15, 2012 HOLLYWOOD, FLORIDA
physicians at company-sponsored meetings. PhRMA agrees with the American Medical Association, which in Congressional testimony said, â&#x20AC;&#x153;There is a clear need for interactions between physicians and the pharmaceutical industry to ensure the free flow of valid scientific information. When the information is accurate and complete, physicians have see Yes, page 47
â&#x20AC;Ścurrent best practices pra actice es related related d to o the use of biologic biolo ogic therapies therapies in n IBD IB D advanced man nagement sstrategies trateg g i es â&#x20AC;Śadvanced management to mitigate side ef effects ffects w approaches approache approach hes and and techniques techn hniq iques es to to â&#x20AC;Śnew optimize ze care of your yo our patients patients â&#x20AC;Śadvances breakthroughs nces and br reakthroughs being made ade in the ďŹ eld ďŹ elld â&#x20AC;&#x153;This confereence is absolut absolutely telyy iinvaluable n al nv alua lua uabl blle to m b myy pr practice!!!â&#x20AC;? racti acti ac tice tice c !!!!!â&#x20AC;? !â&#x20AC;? â&#x20AC;&#x153;High qualityy with high interaction: this is what sets this meeting apart from other meetings â&#x20AC;?
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OPINION
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
NO continued from page 45
that practicing physicians are supposed to follow in treating patients. The government and industry now are promoting “evidence-based medicine.” But has anyone asked where the “evidence” comes from? It often comes from the same conflicted studies by the same conflicted clinical investigators just described. How can physicians believe anything that they are told by so-called experts when they learn that clinical guidelines are based on flawed research that may not be independent and objective? Dr. Kassirer cites two physicians, one the dean of Cornell Medical School in New York City and the other chief of cardiovascular medicine at Brigham and Women’s Hospital in Boston, as examples of experts who are promoting stricter guidelines for blood lipid levels. Both have financial ties to Pfizer. Dr. Kassirer asked one of the physicians, Peter Libby, MD, of Brigham Hospital, why he lent his distinguished name to brochures and Web sites that promote lipid-lowering drugs. Dr. Libby replied that it is a way
to spread an educational message that he believes in. He believes that by disclosing all of his financial conflicts of interests he can maintain his “independence, objectivity, and reputation.” According to Dr. Kassirer, Dr. Libby “asserts that he exploits a corrupt system in a way that benefits patients.” Apparently, Dr. Libby and other “distinguished” researchers hold to the discredited tenet that the end justifies the means. On a more personal level, when drug reps come into our offices, they present studies that show why their drug is the best. Most of these studies are sponsored by drug companies and are conducted by, to quote Dr. Angell again, “hired hands,” and therefore are suspect. When I asked a drug rep recently whether his company sponsored a study he was citing, he replied, “Of course, what did you expect?” Most practicing physicians are well aware that they cannot always take the word of the drug reps at face value. So why make a big fuss about it? The facts are that the pharmaceutical industry
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spends far more on marketing than on research. Their marketing is effective or they wouldn’t spend so much money on trying to influence physicians. The ultimate cost of all these suspect drug studies is borne by our patients—often our Medicare patients, who can least afford the drugs that are being promoted. Drs. Angell and Kassirer do not deny that many products of the pharmaceutical industry have improved the lives of patients. Nor do they deny the importance of the researchers, often physicians, in developing these products. But Dr. Kassirer believes that pharmaceutical companies, in their lust for profits, have crossed the line between “advancing the cause of science and the betterment of patient care on the one hand and the pecuniary interests of physicians on the other. Too many physicians have become mere tools of industry’s promotional and marketing efforts. Others have engaged in pseudoscientific studies and published biased articles that foster industry’s goals over patient goals.” The final sentence in Dr. Angell’s
YES
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book sums it up: “Nowadays, even the most distinguished and apparently unbiased academics may be on the pharmaceutical industry’s payroll. If they are, you need to be especially skeptical about their pronouncements.” As we enter the third millennium, is this the kind of reputation we want our profession to have? Do we want future generations to look back and say we were, in Dr. Kassirer’s words, “on the take”? If we have lost our moral compass, we need to regain it. In their concluding chapters, Drs. Angell and Kassirer make specific recommendations on ways that the pharmaceutical industry and the medical profession can reclaim the high ground. But they have a healthy skepticism that this can be accomplished. Their books are more directed to the public than to doctors or drug companies. They believe that the public needs to learn the facts. The message is clear: If we as a profession do not police ourselves, the public eventually will. ■ Dr. Gale reported no conflicts of interest.
Much of the agitprop generated in the media and fourth estate originates from the Center on Medicine as a Profession (CMAP). “CMAP was established in October 2003 at the Columbia College of Physicians & Surgeons through a joint agreement by the Institute on Medicine as a Profession (IMAP) and Columbia University. In February 2003, George Soros, Chairman of the Open Society Institute, generously funded the establishment of IMAP with a gift of $7.5 million. CMAP carries out IMAP’s programmatic agenda.”1 This connection with Soros, a financier who is spending many billions of dollars attempting to reshape the world into his view of a leftist utopia, is rarely to never disclosed by Soros-compensated physicians doing his bidding, nor the journalists that use CMAP for source material and physician quotes. This is disingenuous, hypocritical and completely undermines CMAP credibility. ■
Reference 1. www.cmap.columbia.edu/index.shtml
OPINION
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
47
YES continued from page 45
the necessary tools to make the right prescribing decisions.” When physicians meet with biopharmaceutical company representatives or attend events at which fellow physicians explain medicines and how they work, they are given the latest FDA-regulated information about the benefits, risks and appropriate uses of drugs. At physician speaker forums, health care providers can discuss this important information with a peer who has firsthand knowledge and expertise in the therapeutic area being discussed. That interaction helps to improve knowledge and patient care. It is, of course, vitally important to guarantee that sound scientific data are presented and that materials contain legitimate information. Strict federal regulations and self-imposed stringent industry standards are already in place to ensure the accuracy of discussions and documents offered during industry–physician interactions. The FDA requires that materials be “truthful, accurate and consistent with product labeling” approved by the agency. Companies are held accountable for the presentations of their speakers. Biopharmaceutical research companies and PhRMA have launched a number of wide-ranging efforts to help guarantee compliance with federal rules and industry standards. For example, the PhRMA Code on Interactions with Healthcare Professionals says company decisions to hire physicians as speakers should be based on the doctors’ medical knowledge, expertise in a particular therapeutic area, communication skills, faculty and medical society affiliations, participation in clinical trials and reputation. For their part, the many biopharmaceutical companies adhering to the PhRMA Code conduct periodic reviews of speakers to determine if they are complying with FDA regulations and their own ethical compliance policies. The speakers may be fired if they violate federal rules or company policies. Biopharmaceutical research companies are also committed to transparency in their relationships with health care professionals. PhRMA and its members supported recent Congressional transparency efforts, including enactment of the Physician Payment Sunshine Act. Several companies have voluntarily released information about payments to doctors before implementation of the Sunshine Act. When the law is fully implemented in 2014, drug companies will be required to provide a thorough listing of payments or other transfers of value to physicians and teaching hospitals to the U.S.
Department of Health and Human Services, which will post the information on a federal Web site. Additionally, the PhRMA Code, which was strengthened in July 2008, requires that health care providers serving on committees that establish clinical guidelines or formularies must disclose to the committees their speaking and consulting arrangements with biopharmaceutical companies.
In the end, the contentions of our critics distort the value of company–physician interactions and worse, threaten to jeopardize patient care. Allegations that the promotional efforts of biopharmaceutical companies unduly influence physician prescribing and help to drive up health care costs are contradicted by a simple fact: 78% of the prescriptions written today are for generic drugs, not
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brand-name medicines. The educational programs of biopharmaceutical firms help to make physicians aware of appropriate, often newly FDA-approved, medicines and their proper uses. Their arsenal of weapons to treat and prevent disease is growing, and that means better patient care. ■ Judge Powell reported no conflicts of interest.
48
F D A U P D AT E & P R O D U C T N E W S
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
FDA Clears Cook Medical’s Evolution Colonic Controlled-Release Stent
Compatibility of Olympus Equipment With the AMSCO V-PRO Sterilizers
On July 9, Cook Medical announced that the FDA had granted 510(k) clearance for its Evolution Colonic Controlled-Release Stent. The new stent helps reduce the
STERIS Corporation and Olympus America, Inc., recently completed validation studies to confirm the compatibility of Olympus equipment with the AMSCO V-PRO Low Temperature Sterilization Systems. This compatibility gives health care providers another safe reprocessing alternative for their delicate endoscopic devices. The V-PRO maX system, a lowtemperature vaporized hydrogen peroxide sterilization processing program, has three cycles: a 35-minute flexible cycle, a 55-minute lumen cycle and a 28-minute non-lumen cycle. The V-PRO 1 Plus Sterilizer has two cycles: a lumen cycle and a nonlumen cycle. And the V-PRO 1 Sterilizer has one cycle, which is identical to the lumen cycle in other V-PRO sterilizers. The flexible cycle enables sterilization of single- and dualchannel surgical flexible endoscopes with or without load. The non-lumen cycle sterilizes devices such as telescopes, bipolar forceps, cameras, light cables, batteries and nonlumen endoscopes. The lumen cycle sterilizes stainless steel instruments, such as resectoscopes, trocars and cannulas. Olympus flexible endoscopes that are compatible with the V-PRO maX (non-lumen or flexible cycles) and V-PRO 1 Plus (non-lumen cycle) systems are identified by a white line on the control section; Olympus flexible endoscopes that do not contain this identifying white line are not compatible with the V-PRO systems. For more information, review the official document “Compatibility of Olympus Equipment with the Amsco V-PRO Sterilizers” or visit www.olympusamerica.com/msg_section/cds/ cds_position.asp. —Based on press releases from Olympus and STERIS
after the first procedure. There were no adverse events associated with device malfunction. The new stent adds to the existing line of Evolution stents, which includes fully and partially covered and uncovered esophageal stents, as well as the duodenal stent, which received FDA approval in March 2011. The delivery system across all Evolution stents provides physicians with a trigger action that deploys or recaptures a proportional length of the stent for precise placement. The Cook Medical’s Evolution Colonic Controlled-Release Stent Evolution colonic stent adds a visible endoscopic marker to uncomfortable symptoms associated define the proximal end of the stent. with colonic obstruction from malignant “The new Evolution colonic stent reitneoplasms and helps relieve large-bowel erates Cook Medical’s commitment to obstructions prior to colectomy proce- pioneering a full line of efficient, effective dures. The product is designed to con- products to improve the quality of life in form to the curves of the anatomy by patients who suffer discomfort or pain,” providing enhanced expansion and wall said Barry Slowey, global business unit apposition as well as a unique deliv- leader for Cook Medical’s endoscopy ery system that employs Kink-resistant division. “Now clinicians have the abilFlexor technology for stability. ity to precisely deploy and recapture To test the effectiveness of the Evolu- colonic stents. That can make it easier tion Colonic Stent System, researchers to place the stent the first time around, conducted a multicenter, international potentially reducing the need for repeat registry study of 80 patients, which procedures, while increasing efficiency.” showed the stent successfully relieved The Evolution colonic stent is currently symptoms of colonic obstruction and available to selected physicians across was an effective bridge to surgery the United States, and will be widely (Repici A et al. Dig Liver Dis 2012;44:9). available soon. For more information, At least 85% of patients reported mild visit www.cookmedical.com. to no symptoms of abdominal pain, —Based on a press release problems defecating or constipation from Cook Medical
Most Patients Fail To Understand Key Drug Info BY BRIAN DUNLEAVY A significant number of patients may not be able to comprehend important details in medication information distributed with antidepressants, including the package insert (PI) and medication guide, even when given as much as 45 minutes to read and absorb the information, a recent study has revealed. In the United States, the FDA requires that all antidepressants be dispensed with a medication guide, in addition to the PI; some pharmacies also include consumer medication information literature with each prescription. The purpose of this paperwork is to ensure that patients are thoroughly informed about the potential side effects and drug interactions associated with these medications.
However, based on the findings of a small study, the literature may not be very effective, particularly if patients are not highly educated. The study, the results of which were presented at the American Academy of Pain Medicine (AAPM) annual meeting (abstract 221), enrolled 52 adult participants (33 men and 19 women) from the Pittsburgh area, who had at most a high school diploma; some of the participants had not completed high school. They were given copies of the actual medication guide, PI and consumer medication information dispensed with an antidepressant currently on the market (with the participants blinded to the name of the drug), and were allowed a maximum of 45 minutes to read the materials. The study authors then questioned the participants to assess their understanding of the safety and use information and presented
“fictional scenarios” involving some of the symptoms included in the materials. According to the findings, fewer than 20% of the participants were able to identify the symptoms of a potentially lifethreatening condition associated with the study drug and described in detail in the literature provided. On questioning, only 61.5% of the participants recalled that there was a risk for suicide associated with the drug (a fact addressed only in the medication guide). “During our surveys on medication guides as part of postmarketing studies for [our clients], we realized there was low patient understanding of [the text], [which] led to the research,” noted Sidney H. Schnoll, MD, PhD, vice president, pharmaceutical risk management services, Pinney Associates, in Pittsburgh. Dr. Schnoll co-authored the study with his
colleagues at the risk management and strategic marketing firm. “[The findings show] that specialists and PCPs need to take the time to explain the benefits and risks of the medications [they prescribe] and go over the pros and cons of all medications with patients,” he added. According to Ebby Varghese, MD, who was not part of the research, the study, even with its small sample size, demonstrates that PIs are often “difficult see Drug Info, page 50
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Norton Greenberger; Richard Blumberg; Robert Burakoff September 20, 2011 Striking the perfect balance between comprehensiveness and ease of use, this book is essential for gastroenterologists, general internists, family physicians and surgeons. The second edition has been updated to reflect the latest advances in diagnostic and therapeutic endoscopy.
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John Dibaise April 20, 2012 This book is a unique question and single-answer review for gastroenterology in-service and board exams. The book features about 3,500 questions with only the correct answer provided, reinforcing the answer students need to remember on exam day.
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F D A U P D AT E & P R O D U C T N E W S
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
FDA Approves Lorcaserin for Obese and Some Overweight Adults In June, the FDA approved lorcaserin hydrochloride (Belviq; Eisai Inc.) as an adjunct to a reduced-calorie diet and exercise for long-term weight management. According to an agency press release, lorcaserin is approved for adults with a body mass index (BMI) of 30 kg/m2 or greater (obese), or adults with a BMI of 27 kg/m2 or greater (overweight) who also have one or more weight-related conditions, such as hypertension, type 2
diabetes or dyslipidemia. “Obesity threatens the overall wellbeing of patients and is a major public health concern,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement. “The approval of this drug, used responsibly in combination with a healthy diet and lifestyle, provides a treatment option for Americans who are obese or are overweight and have at least one
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weight-related comorbid condition.” Lorcaserin is a serotonin receptor agonist that works by selectively activating the serotonin 2C receptor in the brain, which is thought to suppress food intake and promote weight loss, according to the FDA and Eisai Co. Ltd, parent company of Eisai Inc., which will distribute the drug in the United States. Lorcaserin’s safety and efficacy were evaluated in three randomized
BELVIQ (lorcaserin hydrochloride) tablets
controlled trials that included nearly 8,000 obese and overweight patients, with and without type 2 diabetes. Treated for 52 to 104 weeks, all participants received lifestyle modification comprising a reducedcalorie diet, exercise and behavioral counseling. Approximately 47% of patients who did not have type 2 diabetes and who received lorcaserin lost at least 5% of their body weight compared with 23% of the placebo group. Of patients who had type 2 diabetes and who were treated with lorcaserin, 38% lost at least 5% of their body weight compared with 16% of the placebo group. Serious side effects of lorcaserin included serotonin syndrome and disturbances in attention or memory. The most common adverse events in nondiabetic patients included headache, dizziness and fatigue, and in diabetic patients hypoglycemia, headache and back pain. —Based on press releases from the FDA and Eisai Co. Ltd.
Drug Info continued from page 48
to read” because they “are not written in layman’s terms.” He believes the issue merits further investigation with larger studies. “The findings do point to a larger problem regarding patients’ understanding, not just of prescription drugs, but any medication—over-the-counter and prescription,” noted Dr. Varghese, medical director of the Interventional Pain Medicine Clinic, fellowship director of interventional pain medicine, assistant professor of clinical physical medicine and rehabilitation at University of Missouri-Columbia. “PIs, in general, are written in a way that assumes the individual taking that medication has some background in medical terminology or medical science. Quite the contrary, oftentimes people have little insight into their own medical problems; how can they be expected to decipher the risks identified in a complicated PI?” ■ Dr. Varghese has received honoraria from Medtronic and has been a speaker for Allergan and Pfizer.
F D A U P D AT E & P R O D U C T N E W S
GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2012
51
Sterrad Cyclesure 24 Biological Indicator Recalled By Manufacturer Due to Revised Shelf Life On July 3, the FDA delivered a communication, which was updated on July 6, informing facilities that Advanced Sterilization Products (ASP), a division of Ethicon, Inc., had issued a voluntary recall of specific lots of Sterrad Cyclesure 24 Biological Indicators due to revised expiration time. An FDA review of data from ASP showed that the Sterrad Cyclesure 24 Biological Indicators do not effectively monitor the sterilization process for its indicated 15-month shelf life and the product can be used safely for a six-month period. The Sterrad Cyclesure 24 Biological Indicator is employed, along with other methods, to monitor the effectiveness of the sterilization process in Sterrad sterilizers. Sterrad sterilizers are for devices sterilized at low temperatures, such as multiple single-channel flexible endoscopes, cameras, some rigid scopes, light cords, batteries and power drills. ASP’s Sterrad Cyclesure 24 Biological Indicator is the only biological indicator that can be used with the Sterrad sterilizer; biological indicators from other manufacturers have not received FDA clearance for use in Sterrad sterilizers. Last year, ASP made a change in the materials used to manufacture Sterrad Cyclesure 24 Biological Indicators; these new lots were distributed at the beginning of December 2011. Product lots manufactured prior to this material change are not subject to the recall. Hospitals and health care facilities should check their inventory for affected lots. To determine which Sterrad Cyclesure 24 Biological Indicators are subject to this recall, refer to the list of affected lots found in ASP’s Recall Alert (www.aspjj.com/us/news/ cyclesureletter). And to know whether the affected lots are past their expiration date, calculate a new expiration date as follows: [Printed Expiration date (minus) nine months = new expiration date]. The nonexpired product cases should be relabeled with the correct expiration date. Affected products should be returned to ASP immediately as outlined in ASP’s product return instructions. Using certain Sterrad Cyclesure 24 Biological Indicators for longer than six months may prevent verification of proper sterilization. Health care professionals and patients are encouraged to report
adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program at www.fda.gov/MedWatch/ report.htm. Include the following information in reports, if possible: • Adverse event details (date adverse event occurred, nature of the event) • Expiration date and/or lot
number listed on the Sterrad Cyclesure 24 Biological Indicators Download the form or call 1-800-332-1088 to request one, then complete and return to the address on the preaddressed form or fax to 1-800-FDA-0178. For more information, read the FDA Safety Communication at www.fda.
gov/MedicalDevices/Safety/AlertsandNotices/ucm310549.htm. —Based on press releases from ASP and the FDA
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 Advise patients to read the Medication Guide included in the full prescribing information. Advise patients who require a diet low in phenylalanine that MoviPrep contains phenylalanine. Ask patients to inform you if they have trouble swallowing or are prone to regurgitation or aspiration. 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. Inform patients that oral medications may not be absorbed properly if they are taken within one hour of starting each dose of MoviPrep. Tell patients not to take other laxatives while they are taking MoviPrep. 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. 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 © 2011 Salix Pharmaceuticals Inc. July 11
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 18, 2011. 2. MoviPrep [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2011. 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. © 2011 Salix Pharmaceuticals, Inc. All rights reserved. MOV11/41-2
www.MoviPrep.com