The April 2012 Digital Edition of Gastroenterology and Endoscopy News

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The Independent Monthly Newspaper for Gastroenterologists

Volume 63, Number 4 • April 2012

gastroendonews.com Gastros Feel the Pain Of Sedative Shortage

By Adam Marcus and George Ochoa In late January, the call went out at Rochester Medical Center in upstate New York. Clinicians were advised to dramatically cut back on their use of two mainstay IV sedatives—diazepam and lorazepam—supplies of which were becoming increasingly tight.

“We currently have very low supplies of both IV

see Drug Shortage, page 29

ASCO GI 2012

‘Optical Biomarkers’ For BE Surveillance

By Caroline Helwick San Francisco—Three “optical biomarkers” have been identified that could improve the early detection of esophageal cancer in patients with Barrett’s esophagus (BE).

“The problem with traditional monitoring is that

see BE Biomarkers, page 36

Colonoscopy a Lifesaver!

Best Data Yet Link Colonoscopy With Long-term Prevention of CRC Mortality

By Monica J. Smith February 22 was a banner day for advocates of screening colonoscopy and for any patient who has ever wondered if the procedure was worth it. The words varied from headline to headline, but the gist was the same: Colonoscopy saves lives!

“To see such positive news about colon cancer screening and prevention on the front page of The New York Times, and almost every paper I picked up, was very gratifying,” said David Greenwald, MD, gastroenterology fellowship training director and associate division director at Montefiore Medical Center, New York City.

The latest findings of the long-running National

Polyp Study (NPS), published in the Feb. 23 issue of The New England Journal of see Lifesaver, page 26

IBS Awareness Month

IBS Remains Mysterious Disorder, With Few Effective Remedies

I N S I D E

The Liver MeeTing 2011 (AASLD) Experts’ Picks: Best of The Liver Meeting 2011—Part 2 �������� page 6

By Monica J. Smith Despite its prevalence and capacity to disable those who suffer from it, irritable bowel syndrome (IBS) is not well understood and has a dearth of effective pharmacologic therapies. As a public health issue, IBS ranks second only to obesity; 15% to 20% of the population suffers from it, and it accounts for 30% of health-related costs in gastroenterology.

Once considered to be a physical manifestation of psychological and emotional problems,

Updated AASLD HCV guideline aims to simplify use of DAAs ����������������������������������� page 8 High cost of telaprevir overshadows clinical benefits in patient subset ����������������������������� page 10

see IBS, page 14

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2011 GastroenteroloGy 2012 GastroenteroloGy & & endoscopy endoscopy news news •• aprIl april 2012

Experts’ Picks:

Best of The Liver Meeting 2011—Part 2 Compiled and written by David Wild Gastroenterology & Endoscopy News asked the experts: What were your favorite abstracts presented at The Liver Meeting 2011? Following is a collection of selected abstracts and comments on the meeting as provided

to us by experts in the field. The complete abstracts can be found in the supplement to the October 2011 issue of Hepatology.

Maya Gambarin-Gelwan, MD Associate Professor of Clinical Medicine Division of Gastroenterology and Hepatology Center for the Study of Hepatitis C Weill Cornell Medical College New York, New York

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nfluence of age, gender, and race on normal alanine aminotransferase values based on the general US population free of liver disease including steatosis (Dunn W et al) Precise definitions of what the upper limit of normal for alanine aminotransferase (ALT) levels for the general U.S. population is a contentious issue, given the increasing prevalence of fatty liver disease. In this study, researchers in Kansas City and San Diego examined data from 12,915 patients in the National Health and Nutrition Examination Survey (NHANES)-III between 1988 and 1994 who had undergone evaluation for hepatic steatosis. The investigators reviewed ultrasonography images looking for hepatic steatosis based on parenchymal brightness, liver-to-kidney contrast, deep beam attenuation, bright vessel walls and gallbladder wall definition. They excluded subjects receiving hepatotoxic medications as well as those with iron overload, viral hepatitis and excessive alcohol consumption.

The investigators identified 6,046 patients who they considered to be free of liver disease, including steatosis. Median ALT values among those subjects were 15 among men (intraquartile range [IQR], 11-21) and 11 among women (IQR, 8-14). The 95th percentile ALT value was 34 (95% confidence interval [CI], 32-36) in men and 23 (95% CI, 22-26) in women.

When they parsed the data by race and age, the researchers found that among whites and blacks, 95th percentile ALT levels were 36 and 23 for men and women, respectively, under 40 years of age; 31 and 23 for men and women, respectively, between 40 and 59 years of age; and 24 and 23 for men and women, respectively, 60 years of age or older. The 95th percentile ALT levels among Mexican Americans were 43 and 29 for men and women, respectively, aged 40 or younger; 40 and 29 for men and women, respectively, aged 40 years through 59 years; and 27 and 29 for men and women, respectively, 60 years of age or older.

The researchers concluded that differences in ALT levels may not be attributable to unrecognized hepatic steatosis; rather, there may be biological differences in ALT by gender and race or ethnicity “that are magnified in young adults and dissipate with older age.”

Dr. Gambarin-Gelwan: There has been much debate over the past several years regarding what should be considered a normal ALT value, with reference ALT values of 19 for women and 30 for men suggested from a healthy Italian cohort. However, it is difficult to get a true understanding of what normal ALT values are in healthy patients given the presence of undetected fatty liver in the general population.

This study found an interesting, although previously known, difference in normal ALT values by ethnicity and age, which might not be attributable to hepatic steatosis. However, the researchers did not exclude diabetics, hypertensives and others at risk for fatty liver. Given the study’s design, there is a possibility that here again there were cases of undetectable fatty liver because ultrasound can miss fatty liver in those with less than 30% hepatic steatosis. Missed cases could have been responsible for the higher ALT values found in some individuals. Therefore, further research needs to be conducted before we can conclude these differences are truly age-, race- or ethnicity-related only. The study does, however, stress that ALT of 55 or 60 is not normal, despite the so-called normal reference values reported by commercial labs.

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amivudine Use in the 2nd or 3rd Trimester of Pregnancy has Similar Efficacy in Preventing Vertical Transmission (VT) of Chronic Hepatitis B (CHB) in Highly Viremic Mothers (Pan C et al) A joint Chinese and American team examined data from 164 mothers with chronic hepatitis B virus (HBV) infection who were positive for hepatitis B e antigen (HBeAg) and had HBV DNA levels greater than 6 log10 copies/mL. All were treated with lamivudine. Of these, 119 started treatment during the second trimester and 45 initiated treatment in the third trimester. Investigators compared viral loads and vertical transmission rates among infants born to these mothers with those of infants born to a control group of 92 untreated mothers, also HBeAg-positive with HBV DNA greater than 6 log10 copies/mL. All infants received 200 IU hepatitis B immunoglobulin within 12 hours of birth as well as vaccination for HBV. Mean maternal HBV DNA levels prior to delivery were 3.69 log10 copies/mL and 3.88 log10 copies/mL among mothers started on lamivudine during the second and third trimester, respectively, and 7.83 log10 copies/ mL among untreated mothers. Infants who tested positive for hepatitis B serum antigen (HBsAg) included 11.8% of newborns in the second trimester treatment group, 24.4% in the third trimester treatment group and 30.43% in the untreated group. Between seven and 12

months after birth, none of the infants born to lamivudine-treated mothers were found to have HBsAg or detectable HBV DNA levels compared with 8.7% of infants in the control group.

The investigators concluded there were no significant differences in viral vertical transmission rates between the second and third trimester lamivudine groups.

Dr. Gambarin-Gelwan: Although it is the current

recommendation to administer antivirals such as lamivudine to mothers with high-level HBV viremia during the third trimester to further decrease the perinatal transmission rate of hepatitis B, it is not clear whether earlier initiation of treatment might further reduce the risk for transmission. The current retrospective study suggests that lamivudine may be deferred until the third trimester for high-risk mothers.

Although the study provides important insight into the utility of adding antivirals during the second trimester, the criterion the investigators used to define a high viral load—HBV DNA level greater than 6 log10 copies/mL—is lower than what is commonly accepted and used in most other studies and current recommendations, namely HBV DNA greater than 8 log10 copies/ mL. Therefore, whether these results can be extrapolated to groups of patients with higher viral loads is a question that needs to be addressed by prospective, randomized controlled trials with mothers with high-level viremia as defined by the current recommendations.

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ntecavir is effective in preventing hepatitis B reactivation in cancer patients receiving chemotherapy (Mendelsohn r et al) Researchers at the Memorial Sloan-Kettering Cancer Center in New York City conducted this prospective study to evaluate the efficacy of entecavir in preventing HBV reactivation in cancer patients undergoing chemotherapy. To this end, they administered entecavir 0.5 mg orally concomitantly with chemotherapy initiation and continued until six months after chemotherapy was complete in 33 cancer patients who had tested positive for hepatitis B serum antigen and had normal serum alanine aminotransferase (ALT). Twelve of the patients had hepatitis B virus (HBV) DNA polymerase chain

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reaction levels greater than 1,000 IU/mL prior to initiation of therapy. Approximately half of the patients were of Asian origin, 70% had solid tumors and 24% had lymphomas.

During the study, six patients experienced significant increases in ALT; HBV DNA levels were undetectable in five of these patients. These cases of hepatitis were caused by medication side effects, liver metastases or biliary obstruction, the researchers said.

One patient who discontinued entecavir treatment experienced an increase in HBV DNA levels. Antiviral treatment was subsequently reinitiated, and HBV DNA levels returned to normal.

(P=0.0007). Three patients each in the enoxaparin group and the placebo group experienced PVT between two and six months after the one-year treatment period.

Multivariate analyses showed that severity of portal hypertension was the only factor associated with a risk for developing PVT (odds ratio [OR], 9.16; 95% CI, 1.1592-52.780; P=0.013). High bilirubin levels and enoxaparin treatment were significantly associated with the incidence of decompensation, with the latter reducing the risk, the researchers found (OR, 1.667; 95% CI, 1.026-2.710; P=0.039 for bilirubin; OR, 0.106; 95% CI, 0.024-0.469; P=0.003 for enoxaparin).

Dr. Gambarin-Gelwan: The important message from

advanced cirrhosis, occurring in about 8% to 25% of patients with liver cirrhosis. In the current study, investigators found enoxaparin is safe and effective in preventing PVT, and also is associated with a decreased likelihood for hepatic decompensation. These data need to be confirmed in larger clinical trials.

The use of anticoagulation in cirrhotic patients is greatly limited by coagulopathy and increased susceptibility to bleeding in patients with liver disease.

Additionally, the clinical impact of PVT on the natural history of cirrhosis and post-liver transplantation outcome is controversial. A study by our institution that was presented at the 2010 AASLD meeting (Hanouneh et al, abstract 1166) showed no effect of PVT on clinical deterioration, decompensation or death in patients with liver cirrhosis.

this study is that antiviral prophylaxis with entecavir is effective in preventing HBV reactivation or flare during chemotherapy, as has been previously shown for lamivudine. It also is important to remind our oncology colleagues that everyone receiving chemotherapy needs to be screened for HBV, independent of ethnic background and other HBV-associated risk factors, and prophylaxis to prevent viral reactivation needs to be offered to appropriate individuals. Preventing reactivation of HBV, with its high morbidity and associated mortality, is especially critical in these patients because there usually is no option for liver transplantation as a salvage treatment in those who develop liver failure due to their HBV reactivation in the setting of active malignancy.

ibrahim A. hanouneh, Md Gastroenterology Fellow Department of Gastroenterology and Hepatology The Cleveland Clinic Cleveland, Ohio

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noxaparin prevents portal vein thrombosis (PVT) and decompensation in advanced cirrhotic patients: final report of a prospective randomized controlled study (Villa E et al) Italian researchers set out to investigate the effectiveness of an anticoagulant, enoxaparin, in preventing portal vein thrombosis (PVT) and decompensation in patients with advanced cirrhosis. They prospectively randomized 34 patients with advanced cirrhosis to receive 4,000 IU of enoxaparin daily or placebo, both for 12 months. They performed ultrasound every three months and computed tomography every six months for a two-year period to determine the presence of PVT. The investigators found that of the patients receiving enoxaparin, none experienced PVT during the treatment period, whereas three patients in the placebo group developed complete PVT (defined as symptomatic involvement of more than 50% of portal vein diameter) and three others experienced partial PVT (P=0.023 for all cases of PVT in the placebo group vs. the enoxaparin group). One of the placebo patients with complete PVT consequently died from septic shock; the other patients recovered after administration of acute anticoagulant therapy. Additionally, 11.7% of enoxaparin recipients compared with 52.7% of placebo patients experienced decompensation during the treatment period

Dr. Hanouneh: PVT is a frequent complication of

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elationship between IL28b Genotype and Histological Progression in Patients with Chronic Hepatitis C (noureddin M et al) Although interleukin-28B (IL28B) genotypes are known to correlate with spontaneous clearance of hepatitis C virus (HCV) and also with response to therapy for chronic HCV infection, studies have yielded conflicting results on whether this genotype affects disease progression. To help determine this, researchers examined data from 483 patients with chronic HCV infection who were untreated and had two liver biopsies taken a median of four years apart.

Mean age of patients was 49 years, 68% were male and 74% were white. Nineteen percent had IL28B genotype CC, 56% had the CT genotype and 25% had the TT genotype. Patients with the CC genotype had significantly higher portal inflammation at first biopsy than patients with the CT or TT genotypes (mean grade, 2.3 vs. 2.1, respectively), as well as higher mean alanine aminotransferase values (143 for CC genotypes vs. 100 IU/L for CT/TT genotypes; P<0.05 for both).

A statistically similar 16% of CC patients and 23% of CT/TT patients experienced progression of fibrosis between the first and the second biopsies, the researchers found. Furthermore, mean changes in liver histology also were similar between the CC and CT/TT groups, the researchers found.

Multivariate analyses showed higher baseline alkaline phosphatase levels and low platelet counts were the only significant predictors of fibrosis progression.

Dr. Hanouneh: In 2009, genome-wide association

studies found a single-nucleotide polymorphism, rs12979860, located near the gene for IL28B was strongly associated with the likelihood for achieving sustained virologic response with combination pegylated interferon and ribavirin therapy. However, whether IL28B genotype affects disease progression

77

has been unclear. In the current study, the researchers demonstrated in a paired liver biopsy analysis that IL28B genotype is not associated with progressive inflammation or fibrosis on liver biopsy.

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raft and patient survival after liver transplantation for alcoholic hepatitis Comparison to alcoholic cirrhosis: Exploratory analysis based on UnoS data (Singal A et al) Investigators in Texas and California set out to compare graft and patient survival rates among individuals undergoing liver transplantation for alcoholic cirrhosis (AC) and alcoholic hepatitis (AH). To this end, they analyzed data from the United Network for Organ Sharing (UNOS), which was collected between 2005 and 2010. They identified 55 patients who underwent liver transplantation for AH and matched each patient to three liver transplant recipients for AC according to age, gender, ethnicity, model for end-stage disease (MELD) scores at the time of transplantation, donor risk index and year of transplantation.

The investigators found that AH patients were less likely than AC patients to have had transjugular intrahepatic portosystemic shunt implants and also were less likely to have incidental hepatocellular carcinoma at the time of transplantation, but were significantly more likely to have hepatitis C virus infection at the time of transplantation (P<0.028 for all).

Among the AH patients, 87% had graft survival at one year after transplant compared with 84% of AC patients (P=not significant). Three years after transplantation, graft survival rates were 82% and 77% for AH and AC patients, respectively; five years after transplantation, graft survival rates were 75% and 73% for the two groups, respectively (P=not significant). Survival rates also were similar between the two groups: Survival at one year after transplantation was 93% and 88% for the AH and AC groups, respectively; 87% and 81% at three years, respectively; and 80% and 78% at five years following, respectively.

Analyses showed that waiting time and ventilation prior to transplantation were significant predictors of graft loss. Alcohol use was not related to any of the instances of graft loss or patient mortality, the researchers reported.

Dr. Hanouneh: The six-month survival rate of

patients with severe AH is approximately 30%. Liver transplantation is a lifesaving procedure in these patients. In the United States, most liver transplantation programs are reluctant to perform transplantations in patients with acute AH, unless the patient has abstained from alcohol use for six months. This position is based on the view that these patients are responsible for their illness and are likely to resume alcohol use after transplantation.

However, the current study showed that patients with AH have similar post-transplantation survival outcomes compared with those with AC. A recent prospective European study by Mathurin et al, published in The New England Journal of Medicine (2011;36519:1790-1800) confirmed these findings. In that study, only three of 26 patients resumed drinking alcohol after liver transplantation. n Dr. Gambarin-Gelwan is an advisory board member for Bristol-Myers Squibb. Dr. Hanouneh has no conflicts of interest.

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2011 GastroenteroloGy & endoscopy news • aprIl 2012

updated AAsld hcV guideline Aims to simplify use of dAAs More Data Needed To Fill Gaps in Understanding

By Christina Frangou The American Association for the Study of Liver Diseases (AASLD) recently published an updated practice guideline on the treatment of chronic infection with hepatitis C virus (HCV) genotype 1 (Ghany MG et al. Hepatology 2011;54:1433-1444).

The guideline, authored by members of the AASLD practice guideline committee, was issued in response to the development of new direct-acting antivirals (DAAs) and the identification of several single nucleotide polymorphisms associated with spontaneous and treatmentinduced clearance of HCV infection.

The report makes 18 recommendations for clinicians who are considering using the new DAAs to treat patients with HCV. The two currently approved DAAs have complex prescribing rules, including outlines for response-guided therapy and unusual stopping rules, and many clinicians question how and when the agents are best used.

“We have entered into a very different treatment paradigm. I’d suggest that everyone read the guideline from the AASLD. It’s a very good overview of where we are today,” said David R. Nelson, MD, a study author and professor of medicine, Division of Gastroenterology, Hepatology and Nutrition at the University of Florida College of Medicine, in Jacksonville, during a presentation at The Liver Meeting last year.

The authors outline the current state of evidence regarding treatment with boceprevir and telaprevir, and provide some guidance on much-debated issues such as treatment of patients with cirrhosis and the role of interleukin-28B (IL28B) testing.

The guidelines are “very important and very helpful,” said Michal R. Charlton, MD, professor of medicine and head of the hepatobiliary section at Mayo Clinic, in Rochester, Minn. “The guidelines provide a lens through which clinicians can look to see the optimal approach to managing patients with HCV infection.”

Inside the Recommendations According to the authors of the report, the DAAs, in combination with peginterferon alfa and ribavirin, are now the “optimal therapy” for treating HCV genotype 1 chronic infection. Both therapies must be given with peginterferon and ribavirin, which limits selection of resistant variants and improves antiviral response. Furthermore, boceprevir and telaprevir should

not be used to treat patients infected with HCV genotype 2 or 3.

The authors reiterated the FDA recommendation that treatment-naive patients with cirrhosis treated with either boceprevir or telaprevir in combination with interferon and ribavirin should receive therapy for 48 weeks instead of on a response-guided basis. However, the authors added that this recommendation is “based on limited data and requires further study.”

The report also specifies that the stopping rules differ for telaprevir and boceprevir in treatment-naive patients.

Treatment with telaprevir, peginterferon

to starting DAA therapy. Studies have shown that patients’ response to triple therapy regimens in both boceprevir and telaprevir trials was strongly influenced by the outcome of their earlier treatment with peginterferon and ribavirin.

The decision to re-treat patients should depend on their previous response to peginterferon and ribavirin and on reasons why they may have failed, such as inadequate drug dosing or side-effect management, the report said. The authors call on physicians to review old treatment records to document previous treatment response.

This updated document is the first

‘We have entered into a very different treatment paradigm. I’d suggest that everyone read the guideline from the AAsld. it’s a very good overview of where we are today.’

—David R. Nelson, MD

‘The guidelines provide a lens through which clinicians can look to see the optimal approach to managing patients with hcV infection.’

—Michal R. Charlton, MD alfa and ribavirin should be stopped if the HCV RNA level is greater than 1,000 IU/mL at treatment weeks 4 or 12 and/ or detectable at treatment week 24. Treatment with boceprevir, peginterferon and ribavirin should be stopped if the HCV RNA level is greater than 100 IU/mL at treatment week 12 or detectable at treatment week 24. For both therapies, the evidence for the discontinuation rules is considered Class 2a, meaning the weight of evidence is in favor of the usefulness of this rule, but there is limited evidence.

Patients who previously received and failed therapy with interferon and ribavirin remain a conundrum with regard

to clarify treatment for patients who fail DAA therapy. The authors say that patients who do not have a virologic response, who experience virologic breakthrough or who relapse on one protease inhibitor (PI) should not be retreated with the other PI. Although the evidence is limited, the AASLD did make some recommendations for managing treatment-experienced patients. The AASLD suggests retreatment with boceprevir or telaprevir, together with peginterferon alfa and weight-based ribavirin, “be considered” for patients who had a virologic relapse or who were partial responders after a

previous course of treatment with standard interferon alfa or peginterferon alfa and/or ribavirin.

“Relapsers and partial responder patients can expect relatively high sustained virologic response rates to retreatment with a PI-containing triple regimen and should be considered candidates for retreatment,” the authors wrote.

For previously null responders, telaprevir may be considered but boceprevir cannot be recommended, the committee found. This finding differs from the FDA label, which indicates that boceprevir can be used in null responders. Null responders were excluded from Phase III trials of boceprevir (Poordad F et al. N Engl J Med 2011;364:1195-1206).

“Given the lack of definitive information for Phase III data, caution is advised in the use of [boceprevir] in null responders until further supportive evidence becomes available,” according to the AASLD. Additionally, the decision to re-treat a null responder with telaprevir should be individualized, particularly in patients with cirrhosis, because less than one-third of null responder patients in the telaprevir trial achieved a sustained virologic response (SVR). Moreover, the authors caution that a majority of null responders developed resistance to DAAs. “Any potential benefit from treating nonresponders must be weighed against the risk for development of antiviral resistance and for serious side effects, and the high cost of therapy,” the report said.

The AASLD acknowledged uncertainty about the benefit of the lead-in strategy required for treatment with boceprevir. Theoretically, the lead-in may improve efficacy by lowering HCV RNA levels, thus reducing the rate of viral breakthrough when the PI is introduced.

The authors noted, however, that poor responders during the lead-in period can still achieve SVR. “Thus, a poor response during the lead-in phase should not be used to deny patients access to PI therapy,” the authors said. Patients who develop anemia on PI therapy should be managed by reducing the ribavirin dose, they added.

The report also specified that IL28B genotype is a significant treatment predictor of response to therapy, but data are insufficient to determine whether IL28B testing can be used to recommend either interferon and ribavirin alone or a triple therapy with a PI. “Consideration should be given to ordering the test when it is likely to see HCV Guideline, page 10

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7HEN USED ")$ BASED ON ABSOLUTE CHANGE IN HOUR AVERAGE PAIN INTENSITY FROM BASELINE TO BETWEEN DAYS AND AS MEASURED BY A MM VISUAL ANALOG SCALE 6!3 -EAN 6!3 SCORE AT BASELINE WAS MM FOR 2%#4)6 AND MM FOR PLACEBO MEAN 6!3 SCORE BETWEEN DAYS AND WAS MM FOR 2%#4)6 AND MM FOR PLACEBO $IFFERENCE IN MEAN CHANGE IN PAIN SCORE BETWEEN THE GROUPS WAS MM P #) MM MM "ASED ON A HYBRID ANALYSIS OF BASELINE OBSERVATION CARRIED FORWARD LAST OBSERVATION CARRIED FORWARD 2

Indication and Usage s 2%#4)6 NITROGLYCERIN /INTMENT IS INDICATED FOR THE TREATMENT OF MODERATE TO SEVERE PAIN ASSOCIATED WITH CHRONIC ANAL lSSURE Important Safety Information s 2%#4)6 IS CONTRAINDICATED IN PATIENTS TAKING PHOSPHODIESTERASE TYPE 0$% INHIBITORS EG SILDENAlL VARDENAlL AND TADALAlL

WHICH CAN POTENTIATE THE HYPOTENSIVE EFFECT OF ORGANIC NITRATES AND IN PATIENTS WITH SEVERE ANEMIA INCREASED INTRACRANIAL PRESSURE

OR KNOWN HYPERSENSITIVITY TO NITROGLYCERIN OTHER NITRATES AND NITRITES OR ANY COMPONENTS OF THE OINTMENT s 0ATIENTS WITH CARDIOVASCULAR DISORDERS SHOULD BE CLOSELY MONITORED WHILE USING 2%#4)6 ┬И 6ENOUS AND ARTERIAL DILATION AS A CONSEQUENCE OF NITROGLYCERIN TREATMENT CAN RESULT IN HYPOTENSION s %XERCISE CAUTION IN PATIENTS WITH ANY OF THE FOLLOWING CONDITIONS BLOOD VOLUME DEPLETION EXISTING HYPOTENSION CARDIOMYOPATHIES

CONGESTIVE HEART FAILURE ACUTE MYOCARDIAL INFARCTION OR POOR CARDIAC FUNCTION FOR OTHER REASONS s 4HE ADVERSE REACTIONS OF 2%#4)6 ARE LIKELY TO BE MORE PRONOUNCED IN THE ELDERLY s .ITROGLYCERIN PRODUCES DOSE RELATED HEADACHES WHICH MAY BE SEVERE s 4HE FOLLOWING DRUG INTERACTIONS MAY OCCUR IN PATIENTS TAKING 2%#4)6 ┬И 0$% INHIBITORS POTENTIATION OF HYPOTENSIVE EFFECTS OF ORGANIC NITRATES CONCOMITANT USE IS CONTRAINDICATED ┬И !NTIHYPERTENSIVES POSSIBLE ADDITIVE HYPOTENSIVE EFFECTS ┬И !SPIRIN INCREASED NITROGLYCERIN LEVELS ┬И 4ISSUE TYPE PLASMINOGEN ACTIVATOR T 0! DECREASED THROMBOLYTIC EFFECT ┬И (EPARIN ANTICOAGULANT EFFECT OF HEPARIN MAY BE REDUCED -ONITOR ACTIVATED PARTIAL THROMBOPLASTIN TIME !044 ┬И %RGOTAMINE INCREASED BIOAVAILABILITY OF ERGOTAMINE ┬И !LCOHOL ADDITIVE VASODILATORY EFFECTS TO NITROGLYCERIN #ONSUMPTION OF ALCOHOL SHOULD BE AVOIDED _ ARE HEADACHE AND DIZZINESS s 4HE MOST COMMON ADVERSE REACTIONS > s 2%#4)6 OINTMENT IS FOR INTRA ANAL USE AND NOT FOR ORAL OPHTHALMIC OR INTRAVAGINAL USE Please see brief summary of US Prescribing Information for RECTIV on the following page.

References: 1. 2%#4)6 53 0RESCRIBING )NFORMATION *UNE 2. $ATA ON lLE !PTALIS 0HARMA 53 )NC

Aptalis Pharma US, Inc. 22 Inverness Center Parkway Birmingham, Alabama 35242 USA Tel (800) 472-2634 Fax (205) 991-8426 www.aptalispharma.com

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┬й2012 Aptalis Pharma US, Inc.

RECTIV is a trademark used under license by Aptalis Pharma US, Inc.

10

AASLD

2011 GastroenteroloGy & endoscopy news • aprIl 2012

high cost of telaprevir overshadows Clinical Benefits in Patient Subset Results Based on Cost-Effectiveness Model

By Christina Frangou san FranCisCo—For patients with hepatitis C virus (HCV) genotype 1 infection and the favorable CC interleukin28B (IL28B) polymorphism, the clinical

benefits of telaprevir do not outweigh the costs, according to the results of a costeffectiveness model reported at The Liver Meeting 2011 (abstract 118).

“Under current cost and efficacy conditions, a telaprevir-based regimen is not cost-effective as a front-line treatment

RECTIV (nitroglycerin) Ointment 0.4%, for intra-anal use Rx Only Initial U.S. Approval: 1955 Brief summary of Prescribing Information. Please consult package insert for full Prescribing Information.

INDICATIONS AND USAGE: RECTIV™ (nitroglycerin) Ointment 0.4% is indicated for the treatment of moderate to severe pain associated with chronic anal fissure.

CONTRAINDICATIONS: PDE5 inhibitor use - Administration of RECTIV is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), such as sildenafil, vardenafil, and tadalafil, as these are shown to potentiate the hypotensive effects of organic nitrates [see DRUG INTERACTIONS]. Severe anemia - RECTIV is contraindicated in patients with severe anemia. Increased intracranial pressure - RECTIV is contraindicated in patients with increased intracranial pressure. Hypersensitivity - RECTIV is contraindicated in patients who have shown hypersensitivity to it or to other nitrates or nitrites.

Skin reactions consistent with hypersensitivity have been observed with organic nitrates.

WARNINGS AND PRECAUTIONS: Cardiovascular disorders - Venous and arterial dilatation as a consequence of nitroglycerin treatment including RECTIV, can decrease venous blood returning to the heart and reduce arterial vascular resistance and systolic pressure. Exercise caution when treating patients with any of the following conditions: blood volume depletion, existing hypotension, cardiomyopathies, congestive heart failure, acute myocardial infarction, or poor cardiac function for other reasons. If patients with any of these conditions are treated with RECTIV, monitor cardiovascular status and clinical condition. The adverse reactions of RECTIV are likely to be more pronounced in the elderly. Headache - RECTIV produces dose-related headaches, which may be severe. Tolerance to headaches occurs.

ADVERSE REACTIONS: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reaction of RECTIV (nitroglycerin) Ointment 0.4% applied to the anal canal is headache. Headache may be recurrent following each dose. Headaches are typically of short duration and can be treated with an analgesic, e.g. acetaminophen, and are reversible upon discontinuation of treatment. In Study REC-C-001, a double-blind, placebo-controlled trial in patients with a painful chronic anal fissure, the most frequent (≥ 2%) adverse reactions reported were as follows (Table 1): Table 1: Incidence of Adverse Reactions (≥ 2%) in Study REC-C-001 RECTIV Placebo N = 123 N = 124 System Organ Class Patients Events Patients Events Preferred term n (%) n n (%) n Nervous system disorders Headache 79 (64) 938 51 (41) 225 Dizziness 6 (5) 26 0 0

Hypotension: Transient episodes of light-headedness, occasionally related to blood pressure changes, also may occur. Hypotension (including orthostatic hypotension) occurs infrequently, but in some patients may be severe enough to warrant discontinuation of therapy. Allergic Reactions: Flushing, allergic reactions and application site reactions (including drug rash and exfoliative dermatitis) have been reported rarely.

Methemoglobinemia: In rare cases, therapeutic doses of organic nitrates have caused methemoglobinemia (see OVERDOSAGE).

DRUG INTERACTIONS: PDE5 inhibitors - Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. The time course of the interaction appears to be related to the half-life of the PDE5 inhibitor, however, the dose dependence of this interaction has not been studied. Use of RECTIV within a few days of PDE5 inhibitors is contraindicated. Antihypertensives - Patients receiving antihypertensive drugs, betaadrenergic blockers, and other nitrates should be observed for possible additive hypotensive effects when using RECTIV. Marked orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used concomitantly.

Beta-blockers blunt the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects. If beta-blockers are used with RECTIV in patients with angina pectoris, additional hypotensive effects may occur. Aspirin - Coadministration of aspirin (at doses between 500 mg and 1000 mg) and nitroglycerin has been reported to result in increased nitroglycerin maximum concentrations by as much as 67% and AUC by 73% when administered as a single dose. The pharmacological effects of RECTIV may be enhanced by concomitant administration of aspirin. Tissue-type Plasminogen Activator (t-PA) - Intravenous administration of nitroglycerin decreases the thrombolytic effect of tissue-type plasminogen activator (t-PA). Plasma levels of t-PA are reduced when coadministered with nitroglycerin. Therefore, caution should be observed in patients receiving RECTIV during t-PA therapy. Heparin - Although an interaction has been reported between intravenous heparin and intravenous nitroglycerin (resulting in a decrease in the anticoagulant effect of heparin), the data are not consistent. If patients are to receive intravenous heparin and RECTIV concurrently, the anticoagulation status of the patient must be checked. Ergotamine - Oral administration of nitroglycerin

for these patients,” said lead author Ziad Gellad, MD, MPH, assistant professor of medicine, Duke Clinical Research Institute, Durham, N.C. The price of HCV therapy has risen since the introduction of direct-acting antiviral drugs (DAAs) to the market. For example, a 12-week course of telaprevir combined with 36 weeks of

markedly decreases the first-pass metabolism of dihydroergotamine and consequently increases its oral bioavailability. Ergotamine is known to precipitate angina pectoris.

Therefore the possibility of ergotism in patients receiving RECTIV should be considered. Alcohol - The vasodilating effects of nitroglycerin have been shown to be additive to the effects observed with alcohol.

USE IN SPECIFIC POPULATIONS: Pregnancy - Pregnancy Category C - Animal reproduction and teratogenicity studies have not been conducted with RECTIV. Nitroglycerin was not teratogenic when administered by topical or dietary route. There are no adequate and well-controlled studies in pregnant women. RECTIV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Teratology studies in rats and rabbits were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested. A teratogenicity study was conducted in rats with nitroglycerin administered in the diet at levels up to 1% content (approximately 430 mg/kg/day) on days 6 to 15 of gestation. In offspring of the high-dose group, an increased but not statistically significant incidence of diaphragmatic hernias was noted together with decreased hyoid bone ossification. The latter finding probably reflects delayed development, thus indicating no clear evidence of a potential teratogenic effect of nitroglycerin. Nursing Mothers - It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RECTIV is administered to a nursing woman. Pediatric Use - The safety and effectiveness of RECTIV in pediatric patients under 18 years of age have not been established. Geriatric Use - Clinical studies of RECTIV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical data from the published literature indicate that the elderly demonstrate increased sensitivity to nitrates, which may be therapeutic but also manifest by more frequent or severe hypotension and related dizziness or fainting.

Increased sensitivity may reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

OVERDOSAGE: Nitroglycerin toxicity is generally mild. The estimated adult oral lethal dose of nitroglycerin is 200 mg to 1,200 mg. Infants may be more susceptible to toxicity from nitroglycerin. Consultation with a poison center should be considered. Laboratory determinations of serum levels of nitroglycerin and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of nitroglycerin overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of nitroglycerin and its active metabolites. Similarly, it is not known which if any of these substances can usefully be removed from the body by hemodialysis. No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient’s legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.

The use of epinephrine or other arterial vasoconstrictors in this setting is not recommended. In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of RECTIV overdose in these patients may be subtle and difficult, and invasive monitoring may be required. Methemoglobinemia: Methemoglobinemia has been rarely reported with organic nitrates. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate arterial PO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. If methemoglobinemia is present, intravenous administration of methylene blue, 1 to 2 mg/kg of body weight, may be required.

PATIENT COUNSELING INFORMATION: See FDA-approved patient labeling (Patient Information and Instructions for Use) in the full prescribing information. Interaction with PDE5 inhibitors - Advise patient not to use RECTIV with medications for erectile dysfunction such as Viagra (sildenafil), Levitra (vardenafil), and Cialis (tadalafil). These products have been shown to increase the hypotensive effects of RECTIV and other nitrate drugs. Hypotension - Advise patients that treatment with RECTIV may be associated with light-headedness on standing, especially just after rising from a lying or seated position. The effect may be more frequent in patients who have also consumed alcohol, since alcohol use contributes to hypotension. Advise patients to stand up from the supine or sitting position slowly. Headaches - Advise patients that headaches sometimes accompany treatment with RECTIV. For patients who get these headaches, the headaches may indicate the activity of the drug. Tolerance to headaches develops.

Advise patients that if they experience headache they should not alter the schedule of their RECTIV treatment to avoid the occurrence of headache. An analgesic, such as acetaminophen, may be used to prevent or relieve the headaches. Dizziness - Advise patients that dizziness has been reported as a side-effect of treatment with RECTIV. Advise patients not to drive or operate machinery immediately after applying RECTIV. Aptalis Pharma US, Inc, 22 Inverness Center Parkway, Birmingham, Alabama 35242 USA, Tel (800) 472-2634, Fax (205) 991-8426, www.aptalispharma.com Revised: June 2011

pegylated interferon (Peg-IFN) and ribavirin is estimated to cost $85,872, and a full 48-week course of boceprevir-based therapy costs about $71,873. In contrast, the previous standard therapy without DAAs—48 weeks of Peg-IFN alfa and ribavirin—is approximately $36,672.

“Given the significant cost and potential side effects of telaprevir and boceprevir, it is important to ask whether all patients should be offered these agents as first-line therapies,” said George Makar, MD, assistant professor of clinical medicine and associate medical director of the liver transplant program, University of Pennsylvania, Philadelphia, who was not involved in the study.

Dr. Gellad and his team performed a cost-effectiveness comparison of three treatment strategies for HCV genotype 1 patients with the IL28B CC genotype, which is the strongest pretreatment predictor of sustained virologic response (SVR). The investigators included three treatment strategies in their model: • Peg-IFN alfa and ribavirin for 48 weeks, with a 12-week stopping rule for nonresponse and retreatment with telaprevir for nonresponders and relapsers; • A response-guided treatment strategy of Peg-IFN and ribavirin with treatment of 24 or 48 weeks based on rapid virologic response and retreatment with telaprevir for nonresponders and relapsers;

HCV Guideline continued from page 8

influence either the physician’s or patient’s decision to initiate therapy,” the authors said.

Telaprevir and boceprevir are not recommended for use in children and adolescents younger than 18 years because safety and efficacy has not been established in this group.

Additionally, the guidelines do not address several important questions about DAAs, Dr. Charlton said. The report, for example, does not provide detailed and practical information about drug–drug interactions, managing HIV/HCV coinfection and managing side effects, he said.

“Perhaps the highest-impact omission, which was unavoidable, is whether in light of the spectacular report of efficacy and tolerability of PSI-7977 in combination with ribavirin without interferon, patients with early stages of liver disease should be treated at all with boceprevir or telaprevir,” he said. “In our practice, we are already beginning to advise many patients to wait. … A strong case could

AASLD

2011

GastroenteroloGy & endoscopy news • aprIl 2012

• A response-guided treatment strategy of 12 weeks of telaprevir with 24 or 48 weeks of Peg-IFN and ribavirin.

Treatment outcomes were based on data from the IDEAL (The Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy), REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes) and ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir) clinical trials.

The model showed that the efficacy of all three treatment strategies was similar in this group of patients. Quality-adjusted life-years for the three treatments ranged from 19.26 to 19.34 years.

However, costs differed markedly. The total cost associated with a responseguided Peg-IFN and ribavirin regimen amounted to $46,785, by far the lowest, according to the model. The Peg-IFN/ ribavirin regimen for 48 weeks with telaprevir as a retreatment strategy was $54,931. Telaprevir as a front-line therapy amounted to $68,788.

“Telaprevir was less likely than peginterferon/ribavirin to be cost-effective across all willingness-to-pay thresholds,” said Dr. Gellad.

Dr. Gellad said the analysis was not meant to guide treatment decisions at the patient level. “Rather, it was designed to address a policy question at the societal

be made for waiting for the results of the Phase III interferon-free studies.”

The committee cautions that the guidelines are “based on data that are presently limited” and the recommendations may need revision as additional data become available.

“There is a paucity of information for many of the subgroups with the greatest unmet need for treatment (e.g., patients co-infected with HIV and HCV, with decompensated cirrhosis and after liver transplantation),” the committee said. n Dr. Nelson receives research support from Bayer/Onyx, Bristol-Myers Squibb, Genentech/Roche, Gilead, Merck, Pharmasset, Tibotec and Vertex Pharmaceuticals; he serves on the advisory boards of Bayer/ Onyx, Genentech/Roche, Gilead, Merck, Pharmasset and Tibotec; and he is a consultant for Vertex Pharmaceuticals.

Dr. Charlton receives research support from Bristol-Myers Squibb, Genentech/ Roche, Merck and Vertex Pharmaceuticals; he is a consultant for Bristol-Myers Squibb, Genentech/Roche Gilead, Merck and Vertex Pharmaceuticals.

level. … Nonetheless, I hope it does raise some awareness about the judicious use of new and expensive therapies.”

One-way sensitivity analyses revealed that telaprevir became the preferred strategy in a number of scenarios: when the cost of telaprevir fell to less than $1,640 per week, when the likelihood of SVR in patients with nonextended rapid viral response rose greater than 80% and when the likelihood of SVR in relapsers retreated with telaprevir fell to less than 62%.

In Dr. Makar’s practice, he offers

telaprevir and boceprevir to patients with a CC genotype who do not achieve a SVR with four weeks of Peg-IFN and ribavirin alone.

In patients with the IL28B CC genotype, the standard treatment is often successful, with SVR rates around 70% to 80% (Thompson AJ et al. Gastroenterology 2010;139:120-129). DAAs, however, are superior for patients who are nonresponsive or who relapse after dual therapy.

Dr. Makar said the cost-effectiveness analyses in the study will have to be

11

reviewed closely.

“The potential for increased cost and side effects has to be weighted against the higher likelihood of SVR, as well as the much greater potential for shortened therapy,” he said, adding that patients also have to be actively involved in decision making. n Dr. Gellad is a consultant for Merck & Co., and has received grant/research support from Merck & Co., and PENTAX Medical.

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IBS Awareness Month

GastroenteroloGy & endoscopy news • april 2012

Phase II Results Support MuDelta for Diarrhea-Predominant IBS

By Ted Bosworth National Harbor, Md.—A novel medication for the doses of MuDelta were superior to placebo. Over- a biphasic or paired receptor molecule that relieves treatment of irritable bowel syndrome (IBS) has dem- all—whether measured using pain relief, diarrhea or diarrhea and IBS-related pain with a relatively low onstrated sufficient efficacy and safety in multicenter both—the proportion of responders was about twofold risk for constipation. The exact role that the µ-opioid Phase II studies and is now being sent into the regis- higher in the MuDelta groups compared with placebo. receptor agonism and δ-opioid receptor antagonism, tration trials needed for regulatory approval.

After 12 weeks of therapy, the 100- and 200-mg doses which are both associated with some degree of analgeThe new agent, currently dubbed MuDelta, com- remained significantly more effective than placebo. sia, play in producing the effects observed in this trial bines a µ-opioid receptor agonist with a δ-opioid On quality-of-life measures, both the 100- and 200- are unknown, but Dr. Randall characterized the agent receptor antagonist, which together are designed to mg doses were significantly better than placebo overall as “promising.” slow motility while offering concomitant analgesia. and in several specific domains, including mood and According to Michael Camilleri, MD, professor One of the most attractive features of this paired recep- IBS-related disability. of medicine at Mayo Clinic, Rochester, Minn., and a tor molecule is that it acts locally on widely recognized expert on IBS, this the gut and thus avoids the systemic dual receptor activity “is of potential side effects that have plagued previous interest.” He noted that the ability of ‘Many studies have averaged scores so that a patient with bad IBS treatments. Furiex Pharmaceutithe µ-opioid agonist in this compound symptoms on days 1 through 4 but few symptoms on days 5 cals is developing the drug, which has to retard gastrointestinal transit and through 7 would demonstrate moderate disease activity even been granted a fast-track development reduce pain “is consistent with the status by the FDA. effects of other µ-agonists.” The key though symptoms often were significant.’

The Phase II results, presented at advance would be if this compound —Charles Randall, MD the 2011 American College of Gasdoes, in fact, avoid central side effects troenterology meeting, support this like drowsiness or the potential for strategy, according to Charles Ranaddiction. However, he indicated that dall, MD, medical director of clinical the clinical advances of an effect on research, Gastroenterology Clinic of a δ-receptor are less well established, San Antonio and a faculty member of suggesting that “further studies appear the University of Texas Health Science to be required to characterize the abilCenter, San Antonio. ity of the combination of pharmacoIn the study, the most effective doses logic actions on both sensation and of the new agent were consistently more motility.” effective than placebo. The intentStill, Dr. Camilleri characterized to-treat, double-blind, dose-ranging the clinical trial as “quite impressive, Phase II study initially included five despite the apparently small number arms, including four MuDelta dosage of responders based on the FDA-recgroups (ranging from 5 to 200 mg) ommended end points.” He questioned and a placebo group. After a four-week the lack of a clear dose–response interim analysis, the 5-mg dose was curve, but he did indicate that overall discontinued due to lack of activity, response is similar to those reported for leaving doses of 25, 100 and 200 mg in linaclotide, another IBS drug in develthe efficacy and safety analysis that was opment, at the 2011 Digestive Disease conducted at 12 weeks. Although all of Week meeting (Rao et al). While callthe patients initially had diarrhea-preing MuDelta promising, Dr. Camilleri dominant IBS, as defined by the Rome cautioned that the optimal methods criteria, patients also had to demonfor testing new IBS agents are not yet strate an ability to complete a symptom defined. diary over one week before they entered “The composite end points appear a two-week screening. to belittle the potential benefit of these In an effort to control for the notorimedications,” he said. “Further studies ous placebo effect associated with trials of IBS treatAt four weeks, about 50% of placebo patients of the pharmacodynamics and central side effects, as ments, the investigators did not average the rates reported adequate pain relief, but the proportion of well as the clinical efficacy on secondary end points like of symptom relief on patients’ diary cards. Instead, those with adequate pain relief fell in all groups over abdominal pain, bloating, stool consistency and numpatients needed to achieve a sustained reduction in time except in the 100-mg dose group, which contin- ber of bowel movements per week will help clinicians pain as well as an average Bristol Stool Score (BSS) of ued to demonstrate relief throughout the study. understand the role of such an agent in the managen 4 or less on two-thirds of the study days. The rationale About 50% of patients reported adverse events ment of IBS nonconstipated patients.” for this type of evaluation was to reduce the impact of (AEs). Although the rate and type of serious AEs were Dr. Randall received research funding for this trial from fluctuations in disease activity unrelated to treatment. comparable on active therapy and placebo, there was a Furiex Pharmaceuticals. Dr. Camilleri has received “Many studies have averaged scores so that a patient higher rate of discontinuation because of AEs among grant/research support from Albireo, Johnson & Johnson, with bad symptoms on days 1 through 4 but few symp- patients on the 200-mg dose. AEs that appeared to be Rhythm, Takeda/Sucampo, Theravance and Tsumura; he toms on days 5 through 7 would demonstrate moder- related to therapy included abdominal pain, nausea and ate disease activity even though symptoms often were vomiting, dizziness and headache. Constipation was has been a consultant or advisory board member for Adolor, Alkermes, ARYx, AstraZeneca, Dainippon Sumitomo significant,” Dr. Randall explained. more common in patients on the 100-mg dose than Pharma, Eurand, GlaxoSmithKline, Ikaria, Ironwood He also noted that durability of effect is important in those on other doses of active therapy, but this was Pharmaceuticals, Johnson & Johnson, Movetis, NovaSecta, to patients. For this reason, the FDA is increasingly reported in only 6% of patients.

NPS Pharmaceuticals, Ocera, Rhythm, Salix Pharmaceulooking for evidence of sustained relief in considering Based on the results of this study, there are plans to ticals, Shire, SK Life Science, SmartPill, Synergy, Takeda efficacy of new drugs. pursue Phase III studies with the 100-mg dose. AccordPharmaceuticals and Tranzyme Pharma.

The first analysis at four weeks showed that all ing to Dr. Randall, the results support the strategy of

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IBS Awareness Month

IBS continued from page 1

IBS continues to baffle those who suffer from it and those who treat it. Although researchers are hard at work investigating a gut microbe association with IBS, there is at present no full understanding of what causes the disease. And to date, no single medication or class of medications addresses the root cause of IBS. The current fallback is to treat the symptoms.

Mark Pimentel, MD, director of the GI Motility Program and the GI Laboratory at Cedars-Sinai Medical Center, Los Angeles, often gives the analogy that the best treatment for diarrhea IBS is a highly addictive narcotic.

“Morphine will get rid of the diarrhea, you won’t have pain and you won’t remember the bloating,” he said. “I use that as a joke, but the reality is that’s what we’re doing. We’re basically trying to disguise everything so the patients don’t feel the disease they have. We would never dream of doing that with Crohn’s disease.”

In fact, most treatments are little more than a bandage.

Some therapies seem to cause nearly as much harm as good. In research presented at the American College of Gastroenterology annual meeting in 2011, Dr. Pimentel and colleagues compared the number needed to harm (NNH) in five medications most commonly used to treat IBS. Among patients with diarrhea-predominant IBS, the antibiotic rifaxamin was very safe, whereas alosetron and tricyclic antidepressants did not fare so well.

‘Morphine will get rid of the diarrhea, you won’t have pain and you won’t remember the bloating. I use that as a joke, but the reality is that’s what we’re doing.’

—Mark Pimentel, MD “For every two or three patients who benefit from alosetron or tricyclic antidepressants, one will get hurt,” said Dr. Pimentel. “That’s a substantial number.”

The study was recently published in the April issue of the American Journal of Medicine (Shah E et al.

2012;125:381-393).

Role of Psychotherapy Although IBS does not stem from mental dysfunction, evidence suggests early psychological intervention can help patients with moderate to severe IBS cope with their symptoms.

“Changing the way people think about their condition and the way they behave when they have symptoms can really improve symptoms,” said Laurie Keefer, PhD, associate professor of medicine and director of the Center for Psychosocial Research in GI, Northwestern University, Chicago.

But there are a few obstacles to getting patients the proper adjunctive psychological treatment. The first impediment is the discomfort gastroenterologists might feel suggesting mental health therapy for a physical condition.

“A lot of IBS patients don’t want the stigma they have had with physicians who have said, ‘It’s all in your head, there’s nothing we can do. We can either send you to a psychiatrist or you can just live with it,’ ” Dr. Pimentel said.

GastroenteroloGy & endoscopy news • april 2012

Even when the treatment team includes a psychologist, gastroenterologists may be reticent to suggest a psychological intervention.

“Trying to bridge that line between, ‘I’m not trying to tell you it’s all in your head, but I am suggesting you see a psychologist,’ is probably the biggest barrier,” Dr. Keefer said. “The language the doctors use is really important in how they refer patients and whether patients follow up with the recommendation.”

Part of that language could include the fact that psychological intervention for patients with moderate to severe disease is supported by clinical evidence.

“We can tell patients that certain behavioral therapies have been shown to improve IBS symptoms in randomized controlled trials, rather than saying, ‘Go see a shrink and tell him about your stress,’ ” Dr. Keefer said.

Although psychological problems are not the cause of IBS, the condition can lead to feelings of isolation, loneliness and depression, which can escalate symptoms.

Neuroimaging studies suggest IBS patients may have abnormal processing of emotional and cognitive information, which can influence pain perception. Furthermore, people with IBS often display characteristics or behaviors that can make their symptoms worse, such as hypersensitivity, catastrophizing and inflexible problem solving (Labus JS. Neuroimage 2009;47:952-960; Mayer EA et al. Neurogastroenterol Motil 2009;21:579-596; Seminowicz DA et al. Gastroenterology 2010;139:4857; Lackner JM, Quigley BM. Behav Res Ther 2005;43:943-957).

“In sum, understanding the psychological factors influencing IBS symptoms can inform your choice of therapy. A clearer understanding of the options can help you deliver that more quickly and help get your patients the treatment they need,” Dr. Keefer said. “In other words, don’t wait to refer.”

Another challenge to psychological intervention is tailoring therapy to the patient. Several options exist for treating IBS: interpersonal psychotherapy (IPT), relaxation-based therapies, hypnotherapy, mindfulnessbased stress reduction and cognitive-behavioral therapy (CBT).

Patients who benefit the most from IPT tend to be those seeking more traditional therapy, those who are significantly disabled and those who have a history of sexual abuse (Creed F et al. Psychosom Med 2005;67:490499; Hyphantis T et al. Pain 2009;145:196-203). Hypnosis can be a good option for patients who are highly somatic, but not otherwise psychologically distressed, and those who have an understanding of gut physiology and what is going wrong (Gonsalkorale WM et al. Am J Gastroenterol 2002;97:954-961). Patients who feel as though they have some control over their condition may benefit from CBT (Weinland SR et al. Am J Gastroenterol 2010;105:1397-1406).

The final big challenge to getting IBS patients appropriate psychotherapeutic treatment is accessibility and cost. “The question I always get is, ‘Now that I know what to recommend to whom, if there is no GI psychologist in the community, or patients can’t afford it, how do I get these types of services?’ ” Dr. Keefer said.

Dr. Keefer recommends gastroenterologists familiarize themselves with their local psychotherapy practitioners to find out what services they provide and how they bill. Those who provide evidence-based interventions for IBS usually bill patients under medical insurance.

Complementary and Alternative Medicine Because current treatments don’t address all of the

problems of IBS, many patients seek alternatives. According to the 2007 National Health Interview Survey, about 38% of people in the United States incorporate complementary and alternative medicine (CAM) into their pursuit of health. A Kaiser Permanente study showed 35% of

‘We’re basically trying to disguise everything so the patients don’t feel the disease they have. We would never dream of doing that with Crohn’s disease.’

—Mark Pimentel, MD

‘Changing the way people think about their condition and the way they behave when they have symptoms can really improve symptoms.’

—Laurie Keefer, PhD

patients with a functional bowel disease used some form of CAM (Hussain Z, Quigley EM. Aliment Pharmacol Ther 2006;23:465-471; Kong SC et al. J Clin Gastroenterol 2005;39:138-141). Additionally, the National Center for Complementary and Alternative Medicine has identified acupuncture, peppermint oil, probiotics and hypnotherapy to be effective for treating IBS (NCCAM

IBS Awareness Month

GastroenteroloGy & endoscopy news • april 2012

Clinical Digest May 2011; http://nccam.nih.gov/health/ providers/digest/IBS.htm, accessed March 19, 2012).

The efficacy of some of these alternative treatments is up for debate. Although the National Institutes of Health supports the use of acupuncture in address-

‘Trying to bridge that line between, “I’m not trying to tell you it’s all in your head, but I am suggesting you see a psychologist,” is probably the biggest barrier [gastroenterologists face]. The language the doctors use is really important in how they refer patients and whether patients follow up with the recommendation.’

—Laurie Keefer, PhD

ing postoperative and chemotherapy-induced nausea, evidence supporting its use in treating IBS is not that strong.

“A Cochrane meta-analysis of acupuncture in IBS concluded that most trials were of poor quality, were heterogeneous in terms of intervention, controls and outcome measures. It is still inconclusive whether

acupuncture is more effective than sham acupuncture or other interventions for IBS,” said Anthony Lembo, MD, associate professor of medicine, Beth Israel Deaconess Medical Center, Boston (Lim B et al. Cochrane Database Syst Rev 2006;4:CD005111).

Acupuncture trials face many challenges to assessing the practice’s efficacy, such as bias on the part of the acupuncturist, the type of match in sham control, and the heterogeneity of acupuncturist techniques and individualized treatments. To address some of these challenges, several years ago Dr. Lembo and his team conducted a trial of 230 patients assigned to acupuncture or sham acupuncture. Although all patients experienced an improvement in symptoms, there was no difference between the acupuncture and sham groups compared with a waitlisted control group (Lembo AJ et al. Am J Gastroenterol 2009;104:1489-1497).

“It depends on how you look at it,” Dr. Lembo said.

“A patient who was suffering might think being in either of those two arms would be better than doing nothing.”

A possible explanation for this lack of difference between the two groups is the patient–physician relationship and the patient’s pursuit of care, both elements of the placebo effect.

“In patients trying to get better, they are seeking help for their symptoms, watching their diet better, and doing a variety of things that result in nonspecific or placebo effects,” Dr. Lembo said.

According to a systematic review of 14 trials, some controlled and some not, hypnotherapy was found to improve the cardinal symptoms of IBS (Wilson S et al.

Aliment Pharmacol Ther 2006;24:769-780). Probiotics may lead to adaptive immunomodulation and improvement in barrier function in people with IBS, “but the magnitude of benefit and strain and species is not clear,” Dr. Lembo said.

In terms of herbal remedies, peppermint oil, which contains the calcium channel blocker methol, has the most data available. “In 1998 a nice meta-analysis looking at eight trials, five of which were doubleblind randomized controlled trials, found a significant improvement in global symptoms of IBS,” Dr. Lembo said (Ford AC et al. BMJ 2008;337:a2313). Subsequent trials have shown similar positive findings.

With other herbs, however, it’s unclear what works, what doesn’t and what may be harmful. “In 22 studies of different herbs, the conclusion is that herbal medicine should be used with caution,” Dr. Lembo said (Shi J et al. World J Gastroenterol 2008;14:454-462).

Patients have arrived at his office carrying TongXieYaoFang, a Chinese herb marketed on the Internet as Calm Wind. “One meta-analysis showed improvements over conventional therapies, whereas another comparing the herb with probiotics in a small number of patients showed no difference in symptoms,” Dr. Lembo said (Bian Z et al. J Altern Complement Med 2006;12:401-407).

An herbal remedy for functional dyspepsia, STW 5, appeared effective in reducing pain and other IBS symptoms, as did STW 5-11 (Madisch A et al. Aliment Pharmacol Ther 2004;19:271-279). Another herb, Padma Lax, used for thousands of years in Tibet has been known to help symptoms, possibly due to the presence of cascara sagrada, a laxative. But therein lies the rub: In 2002, the FDA declared the agent “not generally recognized as safe and effective” as part of its ongoing over-the-counter product review (www.fda.gov/ohrms/ dockets/98fr/050902a.htm, accessed March 19, 2012).

“Herbs and other therapies don’t go through any type

15

of scrutiny, and we don’t have the information to tell patients whether or not there is a risk; if these are physiologically active treatments, they might have some other effect on the body,” Dr. Lembo said.

Some of these therapies may have a role in treating some patients with IBS, “but high-quality, multicentered studies are required to really define their role in IBS,” Dr. Lembo said. “We also need more data on potential side effects, particularly with the use of herbs.”

Current Medical Research At present, it seems the two hypotheses behind what causes IBS are about to converge. In the last few years, meta-analyses of top papers have shown there is about a one in 10 chance of developing IBS after food poisoning (Halvorson HA et al. Am J Gastroenterol 2006;101:1894-1899; Thabane M, Marshall JK. World J Gastroenterol 2009;15:3591-3596). At the same time, the theory that IBS is driven by bacterial overgrowth has gained ground.

‘Antibiotics not only help patients get better, but they stay better. No other drug for IBS does that. So that’s the novelty of the antibiotic approach because it is treating a cause of IBS, a cause of the symptoms.’

——Mark Pimentel, MD

“For almost a decade, the association between IBS and bacterial overgrowth was believed to be the case based on breath testing,” Dr. Pimentel said. “But in the past three years, two major culture studies have been completed, one just published, that demonstrate by culture absolutely that IBS patients have bacterial overgrowth” (Pyleris E et al. Dig Dis Sci 2012 Jan 20. [Epub ahead of print]; Posserud I et al. Gut 2007;56:802-808).

It’s possible that the two theories are linked.

“We’ve got studies now showing that food poisoning leads to nerve damage of the gut, which leads to bacterial accumulation, which leads to symptoms,” Dr. Pimentel said.

With bacteria playing such a role, it seems logical that antibiotics could be effective. In recently published research, Dr. Pimentel and colleagues demonstrated that about 40% of patients with IBS without constipation experienced significant relief of bloating, pain and watery stools following two weeks of treatment with rifaximin, compared with about 30% in the placebo group (Pimentel M et al. N Engl J Med 2011;364:22-32).

“Antibiotics not only help patients get better, but they stay better,” Dr. Pimentel said. “No other drug for IBS does that. So that’s the novelty of the antibiotic approach because it is treating a cause of IBS, a cause of the symptoms.”

There are concerns with using antibiotics to treat IBS. One specific to using rifaximin to relieve a chronic condition is retreatment: If IBS returns, can it be successfully treated again? Trials are being set up to investigate that question, and FDA approval of rifaximin for IBS hinges on the results. Until then, rifaxamin for IBS is an off-label use, but one, it seems, many gastroenterologists n are enthusiastic about.

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GastroenteroloGy & endoscopy news • april 2012

Mortality from Bariatric surgery found lower at Accredited centers Ability To Care for Critically Ill, Not Procedure Volume, May Be Reason

By Christina Frangou San Francisco—A new study shows a threefold reduction in in-hospital mortality when bariatric surgery is performed at accredited, as opposed to nonaccredited, bariatric centers.

In a report presented at the 2011 Clinical Congress of the American College of Surgeons, researchers studied more than 35,000 bariatric operations performed between October 2007 and December 2009. In-hospital mortality at accredited centers was 0.06% compared with 0.21% at nonaccredited centers (P=0.002), results showed.

“Accreditation status is associated with a distinct improvement in in-hospital mortality,” said lead author Ninh T. Nguyen, MD, professor of surgery,

University of California, Irvine Medical Center, Orange.

When patients’ comorbidities on admission were taken into account, the mortality gap between accredited and nonaccredited centers grew, from a low of 0.04% at accredited centers to a high of 0.48% at nonaccredited centers (P<0.01).

The mortality gap broadened further in patients who remained in the intensive care unit (ICU) for at least one week, which was used as an indicator for the presence and severity of complications.

Of patients treated at nonaccredited centers, 20% did not survive compared with 4.9% of patients with a prolonged ICU stay at accredited centers (P=0.02).

The higher survival rates at accredited centers could be related to the ability of these centers to rescue patients when complications arise, said Dr. Nguyen.

Accreditation status appeared to play a greater role, too, in patients who underwent more complex procedures. Mortality reached 0.25% among patients who underwent gastric bypass at nonaccredited centers compared with 0.06% at

‘Accreditation status is associated with a distinct improvement in in-hospital mortality.’

—Ninh T. Nguyen, MD accredited centers. However, there was no statistically significant difference in mortality among patients undergoing gastric banding (0.11% vs. 0.04%).

In the late 1990s, the popularity of bariatric surgery exploded in the

United States, with utilization rising by more than 400% between 1998 and 2002, according to a report from the Agency for Health Care Policy and Research (Encinosa WE et al. Health Aff 2005;24:1039-1046). Rates have since plateaued. With the sudden growth in the 1990s came concerns about poor outcomes for these elective procedures, particularly for gastric bypass with its known learning curve for surgeons. One study found a 2% mortality rate within 30 days of bariatric surgery and 4.6% within 12 months of surgery (Flum DR et al. JAMA 2005;294:1903-1908). As a result, third-party payers initiated a centers of excellence program in 2004, which eventually led to the development of two accredited bariatric surgery programs: the American Society of see Accredited Centers, page 20

Allergan Halts Sales of Lap-Band to Surgical Centers

on Feb. 2, Allergan Inc., announced that it would no longer sell its Lap-Band Adjustable Gastric Banding System to surgical centers affiliated with the 1-800-GET-THIn marketing company. The device maker, however, will continue to sell the Lap-Band to other medical facilities and bariatric surgeons.

Less than one week after Allergan issued the statement, two Los Angeles–area ambulatory surgery centers—Valley Surgical Center in West Hills and new Life Surgery Center in Beverly Hills—temporarily halted all Lap-Band weight loss surgeries and initiated a thorough review of their surgical procedures.

“Pending the results of a full independent medical and operational review, we have voluntarily stopped scheduling new Lap-Band surgeries at two of our centers,” said a statement from the surgery centers affiliated with the 1-800-GET-THIn marketing firm. “We look forward to sharing the results of this review with Allergan and others to ensure complete confidence.”

Allergan declined to comment on its decision, telling Gastroenterology & Endoscopy News that the company’s corporate policy does not allow it to discuss its customer relationships with third parties.

“While we are disappointed by Allergan’s decision, we remain committed to the health and welfare of our patients interested in weight-loss solutions, of which a Lap-Band implant is one option,” said the surgery centers’ statement, provided to Gastroenterology & Endoscopy News by a lawyer representing the centers. “our experienced surgeons receive certification training from Allergan on proper Lap-Band procedures, and they have performed thousands of successful weight loss surgeries at the centers and other outpatient facilities and

hospitals since 2009.” needless procedures; The news falls on the heels of an FDA reprimand against and one center—the eight California surgical centers and the 1-800-GET-THIn Beverly Hills Surgery marketing firm regarding an aggressive surgical weight Center—covered up loss marketing campaign. As detailed in the February events leading to the issue of Gastroenterology & Endoscopy News, warn- death of a patient. ing letters from the FDA were sent to the companies in Additionally, the December for failing to inform consumers about the seri- California Department ous risks associated with the weight loss surgery (see of Insurance plans to “FDA Squeezes California Surgery Centers, Marketing explore accusations Firm for Improper Promotion of Gastric Banding,” by Vic- that the centers subtoria Stern. Gastroenterology & Endoscopy News February mitted false insurance lap-Band Adjustable 2012;63:3,6,7). claims.

Gastric Banding System Several of the companies are also facing other accusations. Two former employees and 11 patients of the surgical centers filed a lawsuit in January claiming that the centers performed LapBand and other medical procedures with unqualified staff, in unsanitary facilities and using unsafe equipment. Specifically, the lawsuit alleges that centers did not preserve equipment or own ventilators large enough for obese patients; had a high incidence of postoperative infections because of poor sanitation; employed nurses as surgeons and allowed unsu- the fdA has accused eight surgical centers affiliated with the 1-800-getthiN marketing company of misleading advertising regarding Allergan’s pervised administration Lap-Band surgical weight loss procedure. Billboards like this one are pepof anesthesia; carried out pered along highways in southern California.

Photo: Glenn Koenig/Los Angeles Times. Copyright, 2011 Los Angeles Times. reprinted with permission.

By ViCtoria stern

Photo courtesy of Allergan

Decision Follows FDA Warning About Misleading Lap-Band Ad Campaigns

PRINTER-FRIENDLY VERSION AT GASTROENDONEWS.COM

Pancreatic Exocrine Insufficiency Part 1 of 2: Pathogenic and Diagnostic Considerations SHADEAH LAILA SULEIMAN VIVEK KADIYALA, MD DARWIN L. CONWELL, MD, MS Center for Pancreatic Disease Brigham and Women’s Hospital Division of Gastroenterology, Hepatology, and Endoscopy Harvard Medical School Boston, Massachusetts

I

n this 2-part review, Part 1 covers the epidemiologic factors, pathogenic

mechanisms, and current diagnostic strategies of pancreatic exocrine insuf-

ficiency (PEI); Part 2 will cover treatment approaches for patients with PEI, including the proper use of currently FDA-approved pancrelipase preparations.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

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The exocrine pancreas plays an essential physiologic role in maintaining digestive health, nutrition, and proper patterns of growth. Pancreatic exocrine secretion of digestive enzymes breaks down ingested food into micronutrients for absorption into the circulatory system. A disruption of this process by pancreatic ductal blockage, parenchymal destruction, or surgical resection may lead to PEI. Vulnerable patients who have lost more than 90% of pancreatic function exhibit steatorrhea and are at risk for short- and long-term nutritional deficiencies and complications that compromise clinical outcomes.1 Utilization of pancreas function tests in at-risk patients allows for accurate diagnosis of PEI, which is critical to initiating effective disease management and limiting complications of maldigestion. Although dietary modifications are helpful, most patients with PEI require individualized, lifelong support with pancreatic enzyme replacement therapy (PERT). Proper dosage, timing, and adherence to exogenous pancreatic enzyme replacements are essential to optimize efficacy and minimize adverse effects that may impact life expectancy and patient quality of life. Improper use of PERT by clinicians or patients may also exacerbate disease complications, increasing healthcare expenditures and the overall economic burden of PEI.

Epidemiology and Burden of PEI PEI develops most commonly in children with cystic fibrosis (CF) or adults with advanced-stage chronic pancreatitis (CP).2 As shown in the Table, other causes of pancreatic exocrine dysfunction include pancreatic diseases such as hereditary pancreatitis, tropical pancreatitis, severe acute necrotizing pancreatitis, acute recurrent pancreatitis, and chronic main pancreatic duct obstruction, including pancreatic cancer. Metabolic disorders, such as hypercalcemia and hyperlipoproteinemia;2 extrapancreatic illnesses, such as celiac disease, Crohnâ&#x20AC;&#x2122;s disease, primary biliary cirrhosis, and sclerosing cholangitis; and, rarely, isolated enzyme deficiencies observed in pediatric patients have been associated with PEI.3,4 PEI is also common after pancreatic and gastric surgical procedures, notably including pancreatic resection. The clinical and economic burden attributable to PEI is difficult to determine and has not been clearly established in medical literature. However, since individuals with CF and CP require PERT to remedy enzyme insufficiencies,5-7 PEI prevalence and costs can be extrapolated from epidemiologic data available for CF and CP patient populations.

CYSTIC FIBROSIS CF is the most common lethal genetic defect occurring in the Caucasian population.8 The global incidence of CF varies among races, and in the United States

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ranges from 1 in 2,500 to 1 in 3,500 live births in the Caucasian population.8,9 CF currently affects approximately 30,000 adults and children in the United States.10 Although the cost of care is variable, the mean annual cost of care for a patient with CF has been estimated at $7,524.9 CF is inherited in an autosomal recessive pattern localized to chromosome 7, which encodes the cystic fibrosis transmembrane conductance regulator (CFTR).

Dysfunction of CFTR leads to the clinical manifestations of CF.11 Although the pulmonary complications are more evident, in the pancreas this mutation alters chloride transport from pancreatic ductal cells causing viscous proteinaceous secretions which block the pancreas ducts. This eventually leads to scarring and progressive pancreatic insufficiency.11,12 Other common gastrointestinal manifestations of CF include gastroesophageal reflux disease, small bowel overgrowth, rectal prolapse, hepatobiliary disease, intussusception, meconium ileus, and distal intestinal obstructive syndrome (DIOS).13 Approximately 50% of children with CF exhibit pancreatic insufficiency at birth, and another 25% develop pancreatic dysfunction within the first 6 months of life.14,15 Of the remaining 25% of children with CF, at least 15% will develop PEI later in childhood or young adulthood, leaving up to only 10% of children with CF who will have sufficient pancreatic activity for the duration of their lives.15 Although pancreatic sufficiency in CF patients is generally associated with better clinical outcomes, it does not imply normal pancreatic function and is still associated with a risk for developing DIOS or CF-related diabetes.13,16 It is estimated that more than 90% of children with CF require PERT as a life-sustaining intervention for PEI.17 Expected survival rates for individuals with CF has improved with the use of PERT, as well as advances in pulmonary care and recognition of early signs of malnutrition.18 The median age of survival for people with CF has risen to 37 years, with more than 40% of individuals with CF being 18 years of age or older.10 The rising life expectancy of individuals with CF augments the opportunity to effectively treat the disease and manage gastrointestinal symptoms as well as other associated sequelae (ie, metabolic bone disease).

CHRONIC PANCREATITIS CP is caused by chronic inflammation of the pancreas associated with genetic, autoimmune, and environmental factors and occurs more frequently in male adults.2 The incidence ranges from 3 to 9 cases per 100,000 individuals and increases with age.19,20 The data on prevalence is scarce but is estimated at 28.5 to 41.8 cases per 100,000 persons. The gradual rise in incidence observed in some countries may be attributed to earlier diagnosis and/or increasing alcohol consumption.19,21-23

Table. Etiologies of Pancreatic Exocrine Insufficiency69 Mechanism

Etiology

Decreased lipase production and delivery, increased lipase destruction

Chronic pancreatitis, cystic fibrosis, diabetes

Pancreatic duct obstruction

Periampullary tumor, pancreatic head cancer, IPMN, benign tumors

Decreased endogenous lipase stimulation and production

Celiac disease, Crohn’s disease, Shwachman–Diamond syndrome

Motility disorders (decreased contact time, interaction with chyme, and stimulation of pancreatic enzymes)

Gastrectomy, gastric bypass, extensive small bowel resection

IPMN, intraductal papillary mucinous neoplasm

Alcohol abuse accounts for 70% to 80% of CP cases.24 PEI and symptoms of maldigestion usually develop after approximately 10 to 15 years of chronic alcoholic abuse25 and vary according to CP disease severity and duration; prevalence of PEI is estimated at 30% for mild CP and up to 85% for severe CP.26 Idiopathic PEI accounts for 10% of adult CP cases.25 Management of patients with CP involves significant annual healthcare expenditures, accounting for more than 122,000 outpatient visits and over 56,000 hospitalizations in the United States, with total treatment costs estimated at $2.1 billion in 1998.27,28 Emerging epidemiological data from the North American Pancreatitis Study Group has improved our understanding of the etiologic factors at play in CP in the United States, implicating smoking as a dose-dependent, causal co-factor for CP. The combined effect of smoking and alcohol is synergistic and contributes profoundly to development and progression of the disease.

Pathogenesis of PEI Loss of exocrine function in patients with CF and CP results from the inflammatory destruction of pancreatic ductal and acinar cells, causing a reduction in the quantity of enzymes available to digest carbohydrates, proteins, and fats and consequently resulting in maldigestion and malabsorption.

THE DIGESTIVE PROCESS

AND

FAT MALABSORPTION

Suboptimal carbohydrate, protein, and fat digestion processes underlie the clinical symptoms of PEI and are among the diagnostic criteria for the condition. Carbohydrate digestion starts in the mouth with salivary

amylase and continues at the brush border of the small intestine with both intestinal oligosaccharidases and pancreatic amylase secretions.29 Protein digestion begins in the stomach with hydrochloric acid activation of pepsin and continues at the brush border with pancreatic and intestinal proteolytic enzymes.29 Despite loss of pancreatic function, carbohydrate and protein digestion are well maintained in individuals with PEI, as the digestive system is capable of compensating for PEI. In contrast, lipid digestion involves a more complex, multistep process of emulsification and ultimately fatty acid hydrolysis, the latter process being highly dependent on pancreatic lipase. Thus, exogenous therapeutic intervention is necessary to rescue the functional deficiency.29 In healthy individuals, dietary fat is first modified by lingual and gastric lipase in the stomach. Bile salts subsequently solubilize the lipolytic products through the formation of micelles for further hydrolysis in the small intestine by pancreatic lipase. Lipase then breaks down the lipids into long-chain fatty acids and monoglycerides in a neutralized chymal environment maintained by duct cell bicarbonate secretion.29 Following absorption across the intestinal barrier, micelles are converted back into chylomicrons (lipoprotein particles), which circulate in the lymphatic system and return to the circulatory system for delivery to the body.29 Fat absorption is particularly affected in individuals with PEI for several reasons.30 The functional ability of the pancreas to synthesize and secrete lipase is impaired earlier and more severely than its other enzymes, particularly in the course of CP.30-32 The pancreas is the primary source of lipase secretion for the digestion of

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dietary fat, with intragastric lipase digestion accounting for approximately only 10% of total lipid digestion.29 However, in patients with PEI, intragastric lipase digestion may account for more than 90% of total lipase activity but cannot compensate for loss of pancreatic lipase secretion.33 Additionally, the insufficient pancreas does not secrete an adequate concentration of sodium bicarbonate, which protects pancreatic enzymes from denaturation by gastric acid and establishes an optimal pH (~8) for pancreatic enzyme activity. The resulting low duodenal pH impairs lipid solubilization by inactivating the bile acids, a complication further exacerbated by the denaturation of the pancreatic enzymes, notable at pH 5 or lower.34,35 Lastly, lipase is more susceptible to proteolytic degradation than other enzymes, including amylase.36,37 Lipase activity declines rapidly during small intestinal transit and is active for relatively short periods of time in both healthy individuals and patients with PEI.36-38 Thus, lipolysis is a complicated process for which pancreatic secretion of bicarbonate and lipolytic enzymes is essential and, once impaired, results in maldigestion and malabsorption, necessitating extrinsic pancreatic enzyme supplementation.

SIGNS

AND

SYMPTOMS

OF

PEI

The primary clinical sign of PEI is steatorrhea—loose, fatty, pale, malodorous stool resulting from lipid maldigestion. Unabsorbed fat and oil droplets in stool that stick to the toilet bowl or that are difficult to flush are highly suggestive of PEI. This is a late manifestation of pancreas dysfunction, typically occurring after 90% of exocrine glandular function is lost.1 Other clinical symptoms that may be suggestive of PEI include malnutrition, growth retardation, or delayed maturation related to nutritional failure; hyperproteinemia with severe edema; decreased muscle mass; and abdominal distension and pain. A small number of patients exhibit fat-soluble vitamin (A, D, E, and K) deficiencies.39 Noticeable digression from weight and height curves plotted during routine pediatric well-visits should also be considered in the context of other symptoms of PEI.40 Recent evidence also implicates PEI with associated metabolic bone disease and osteoporosis.41

Diagnostic Tests To Assess Pancreatic Function Upon clinical suspicion of pancreatic dysfunction following a complete physical examination, family history, and differential diagnosis, accurate assessment of exocrine function with direct or indirect pancreas function tests is necessary to confirm pancreatic status and initiate appropriate therapy. Pancreas function tests assess pancreatic secretory reserve and are used to diagnose early disease, to monitor disease progression, and to assess the efficacy of PERT in order to

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tailor therapy.42-44 Pancreatic function tests are similar in diagnostic utility across age groups.

Infrequently used in clinical practice, direct (invasive) pancreas function tests require placement of doublelumen gastroduodenal tubes for pancreatic fluid collection following intravenous cholecystokinin (CCK) or secretin stimulation.45 The extracted fluid is analyzed quantitatively for enzyme and bicarbonate production.

Direct tests are highly accurate for PEI, particularly in early CP, because they detect subtle changes in pancreatic function before the development of overt steatorrhea and morphologic changes observed on imaging tests. Direct tests have been reported to be more than 90% sensitive and specific for detection of PEI.45 The major limitations of direct pancreatic function testing have been the cumbersome nature of the test and the difficulty of pancreatic fluid collection with the gastroduodenal tube method.46 Thus, they have only been available at select research centers with dedicated gastroenterology laboratory personnel.47 Over the past several years, endoscopic collection methods have been developed which have simplified pancreatic fluid collection. These techniques have made the test more suitable for widespread clinical use, including screening patients with chronic pain syndromes for pancreatic disease.48,49 With these newer approaches, the upper endoscope is used instead of the gastroduodenal tube to: 1) directly aspirate pancreas fluid (endoscopic pancreatic function testing [ePFT]);48 2) facilitate placement of a modified Dreiling tube (endoscopy-assisted);49 or 3) facilitate placement of a Liguory tube.50,51 Some centers also directly cannulate the pancreas duct during endoscopic retrograde cholangiopancreatography; this carries some risk for procedure-induced pancreatitis and may not be as accurate as other diagnostic methods.52 Furthermore, these newer methods have promoted the use of a hospital autoanalyzer in place of back-titration methods to analyze fluids.53,54 Both the application of an endoscopic collection method and the adoption of an autoanalyzer to systematize pancreatic fluid analysis have markedly increased the use of pancreas function testing in the United States.

The ePFT method of direct pancreas fluid aspiration from the duodenum is the most studied and validated endoscopic method of pancreatic function testing.55,56 It causes minimal harm to the patient and does not induce pancreatitis. Secretin-, CCK-, and combined secretinCCK-stimulated ePFT methods have been developed.57 Additionally, a shortened “screening” method has been reported to rapidly assess patients with chronic pain syndromes who have a low likelihood of having pancreatic disease.58 Aspirated pancreas fluid samples are kept on ice and transported to the hospital laboratory for autoanalyzer analysis of electrolyte and/or enzyme

concentration. Peak pancreas fluid bicarbonate concentrations less than 80 meq/L in the secretin test and peak lipase concentrations less than 780,000 IU/L in CCK-stimulated ePFT are diagnostic of PEI. In general, investigators have preferentially relied on indirect (noninvasive) methods to circumvent the challenges associated with direct pancreatic function tests.

Clinically available indirect tests of pancreatic function include fecal fat analysis, fecal chymotrypsin analysis, acid steatocrit analysis, and fecal elastase analysis.59-62 Most indirect tests are sensitive for moderate- and latestage PEI but lack sensitivity for early disease detection. However, they are adequate for the assessment of steatorrhea, a manifestation of significant loss of pancreatic function.49 The 72-hour fecal fat collection test with calculation of a coefficient of fat absorption is the gold standard for the assessment of fat malabsorption.63 The test requires a 5-day diet of 100 g of fat per day, with stool collections performed throughout the last 72 hours of the diet.63 Fecal fat excretion exceeding 7 g per day is abnormal but not sensitive or specific for PEI, as other gastrointestinal diseases also may be associated with steatorrhea.63 The fecal fat test is inconvenient, unpleasant for patients, and prone to laboratory error and sample loss; therefore, it is primarily used in research settings.63 The fecal elastase-1 test is emerging globally as the most commonly utilized noninvasive test for PEI assessment and also is gaining widespread recognition in the United States.64 Elastase-1, a specific protease synthesized by pancreatic acinar cells, is a useful tool for the evaluation of insufficiency because it is stable in stool, unaffected by PERT, and correlates well with stimulated pancreas function tests.64 The fecal elastase-1 test is an enzyme-linked immunosorbent assay that uses monoclonal antibodies against two different epitopes of human pancreatic elastase. It has a superior overall diagnostic accuracy when compared with chymotrypsin (92% vs 82%), and measurements may be reproduced for approximately 7 days post-collection.64 As with other indirect pancreas function tests, stool dilution can cause false-positive results.64 Fecal elastase-1 testing has gained popularity in CF clinics and is now commonly used as evidence of PEI in infants screened for CF to confirm the need for PERT.65 Mild and severe PEI diagnoses are based on a fecal elastase-1 value of less than 200 mcg per gram of stool and 100 mcg per gram of stool, respectively.61 Despite radiologic and endoscopic advances, a diagnostic test that can detect early PEI prior to clinically evident symptoms of steatorrhea is currently unavailable.1 Diagnostic methods sensitive for early disease are an active area of research and include recent advances in magnetic resonance imaging and secretin-stimulated magnetic resonance cholangiopancreatography

as well as endoscopic ultrasound, which correlate pancreatic function with duct morphology in moderate to advanced disease.66,67 Simplification of endoscopic direct function tests as well as further advances in radiologic imaging would potentially offer diagnostic possibilities less cumbersome and better tolerated by patients, thereby broadening the availability and clinical use of direct tests for the early detection of PEI.47,68

Conclusion Ongoing epidemiologic study is establishing the incidence and prevalence of PEI in the United States and more clearly defining its etiologic risk factors. Despite recent advances in direct pancreas function testing, a point-of-care diagnostic test that can detect early PEI prior to clinically evident symptoms of steatorrhea is still lacking.1 The patients identified may be started on pancreatic enzyme replacement therapy (PERT) early in the course of the disease in hopes of retarding the complications of long-term malnutrition.

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47. Stevens T, Conwell DL, Zuccaro G, et al. Electrolyte composition of endoscopically collected duodenal drainage fluid after synthetic porcine secretin stimulation in healthy subjects. Gastrointest Endosc. 2004;60(3):351-355.

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2nd ed. New York, NY: Raven Press; 1993: 665-706.

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53. Patel S, Vargo JJ, Khandwala F, et al. Deep sedation occurs frequently during elective endoscopy with meperidine and midazolam. Am J Gastroenterol. 2005;100(12):2689-2695.

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57. Stevens T, Conwell DL, Zuccaro G Jr, Lewis SA, Love TE. The efficiency of endoscopic pancreatic function testing is optimized using duodenal aspirates at 30 and 45 minutes after intravenous secretin. Am J Gastroenterol. 2007;102(2):297-301.

58. Stevens T, Parsi MA. Update on endoscopic pancreatic function testing. World J Gastroenterol. 2011;17(35):3957-3961.

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60. Lankisch PG. Now that fecal elastase is available in the United States, should clinicians start using it? Curr Gastroenterol Rep. 2004;6(2):126-131.

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68. Conwell DL, Zuccaro G, Purich E, et al. The effect of moderate sedation on exocrine pancreas function in normal healthy subjects: a prospective, randomized, cross-over trial using the synthetic porcine secretin stimulated Endoscopic Pancreatic Function Test (ePFT). Am J Gastroenterol. 2005;100(5):1161-1166.

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AUTHOR DISCLOSURES—Ms. Suleiman and Dr. Conwell have no conflicts of interest. Dr. Kadiyala did not report any conflicts of interest.

DISCLAIMER—This review is designed to be a summary of information and represents the opinions of the author(s). Although detailed, the review is not exhaustive. Readers are strongly urged to consult any relevant primary literature, the complete prescribing information available in the package insert of each drug, and the appropriate clinical protocols. No liability will be assumed for the use of this review, and the absence of typographical errors is not guaranteed. Copyright © 2012, McMahon Publishing, 545 West 45th Street, 8th Floor, New York, NY 10036. Printed in the USA. All rights reserved, including right of reproduction, in whole or in part, in any form.

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to submit their outcomes to a central database.

Accredited Centers continued from page 16

Metabolic and Bariatric Surgeryâ&#x20AC;&#x2122;s Center of Excellence program, which was started in 2004 and requires a minimum of 125 cases a year; and the American College of Surgeonsâ&#x20AC;&#x2122; Bariatric Surgery Center Network, which was initiated in 2005 and grants Level 1 status to centers that perform more than 125 cases a year and Level 2 status to those that do more than 25 lower-risk cases a year. Both programs require surgeons and centers

Study Details Investigators in the current study set out to measure the effect of accreditation status on perioperative outcomes, using data collected by the University Health System Consortium Database, an alliance of 114 academic medical centers and 255 of their affiliated hospitals. Over the study period, 35,284 bariatric procedures were reported. Of these, 89% were completed at accredited hospitals, reflecting the

tremendous growth of the accreditation programs.

The 71 accredited hospitals studied performed a mean of 197 cases per year, much higher than the mean 39 cases reported by nonaccredited hospitals. The 43 nonaccredited centers treated more women (80.2% vs. 77.7%, respectively) and a greater proportion of black (19.5% vs. 13.2%, respectively) and Hispanic (7.1% vs. 5.3%, respectively) patients than the accredited centers. Demographics were similar in all other aspects, including disease severity.

HIGHLIGHTS OF PRESCRIBING INFORMATION

Gastroduodenal (Dreiling)Tube Collection Method(1):

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These highlights do not include all the information needed to use ChiRhoStimÂŽ safely and effectively. See full prescribing information for ChiRhoStimÂŽ.

Ă&#x160;Ă&#x20AC;>`Â&#x2C6;Â&#x153;ÂŤ>ÂľĂ&#x2022;i]Ă&#x160;`Â&#x153;Ă&#x2022;LÂ?iÂ&#x2021;Â?Ă&#x2022;Â&#x201C;iÂ&#x2DC;Ă&#x160;Ă&#x152;Ă&#x2022;LiĂ&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;ÂŤ>Ă&#x192;Ă&#x192;i`Ă&#x160;Ă&#x152;Â&#x2026;Ă&#x20AC;Â&#x153;Ă&#x2022;}Â&#x2026;Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;Â&#x201C;Â&#x153;Ă&#x2022;Ă&#x152;Â&#x2026;Ă&#x160;vÂ&#x153;Â?Â?Â&#x153;Ă&#x153;Â&#x2C6;Â&#x2DC;}Ă&#x160;>Ă&#x160;ÂŁĂ&#x201C;Â&#x2021;ÂŁxĂ&#x160; Â&#x2026;Â&#x153;Ă&#x2022;Ă&#x20AC;Ă&#x160;v>Ă&#x192;Ă&#x152;°Ă&#x160;Ă&#x160;1Â&#x2DC;`iĂ&#x20AC;Ă&#x160;yĂ&#x2022;Â&#x153;Ă&#x20AC;Â&#x153;Ă&#x192;VÂ&#x153;ÂŤÂ&#x2C6;VĂ&#x160;VÂ&#x153;Â&#x2DC;Ă&#x152;Ă&#x20AC;Â&#x153;Â?]Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;Â&#x153;ÂŤiÂ&#x2DC;Â&#x2C6;Â&#x2DC;}Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;ÂŤĂ&#x20AC;Â&#x153;Ă?Â&#x2C6;Â&#x201C;>Â?Ă&#x160;Â?Ă&#x2022;Â&#x201C;iÂ&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160; tube is placed in the gastric antrum and the opening of the distal lumen just beyond Ă&#x152;Â&#x2026;iĂ&#x160;ÂŤ>ÂŤÂ&#x2C6;Â?Â?>Ă&#x160;Â&#x153;vĂ&#x160;6>Ă&#x152;iĂ&#x20AC;°Ă&#x160;Ă&#x160;/Â&#x2026;iĂ&#x160;ÂŤÂ&#x153;Ă&#x192;Â&#x2C6;Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Â&#x2C6;Â&#x2DC;}Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;Ă&#x152;Ă&#x2022;LiĂ&#x160;Â&#x201C;Ă&#x2022;Ă&#x192;Ă&#x152;Ă&#x160;LiĂ&#x160;VÂ&#x153;Â&#x2DC;wĂ&#x20AC;Â&#x201C;i`Ă&#x160;>Â&#x2DC;`Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;Ă&#x152;Ă&#x2022;LiĂ&#x160; secured prior to synthetic human secretin testing. Intermittent negative pressure of Ă&#x201C;xÂ&#x2021;{äĂ&#x160;Â&#x201C;Â&#x201C; }Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;>ÂŤÂŤÂ?Â&#x2C6;i`Ă&#x160;Ă&#x152;Â&#x153;Ă&#x160;LÂ&#x153;Ă&#x152;Â&#x2026;Ă&#x160;Â?Ă&#x2022;Â&#x201C;iÂ&#x2DC;Ă&#x192;Ă&#x160;>Â&#x2DC;`Ă&#x160;Â&#x201C;>Â&#x2C6;Â&#x2DC;Ă&#x152;>Â&#x2C6;Â&#x2DC;i`Ă&#x160;Ă&#x152;Â&#x2026;Ă&#x20AC;Â&#x153;Ă&#x2022;}Â&#x2026;Â&#x153;Ă&#x2022;Ă&#x152;Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;Ă&#x152;iĂ&#x192;Ă&#x152;°Ă&#x160;Ă&#x160;7Â&#x2026;iÂ&#x2DC;Ă&#x160; duodenal contents have a pH of *Ă&#x160;Ă&#x2C6;]Ă&#x160;>Ă&#x160;L>Ă&#x192;iÂ?Â&#x2C6;Â&#x2DC;iĂ&#x160;Ă&#x192;>Â&#x201C;ÂŤÂ?iĂ&#x160;Â&#x153;vĂ&#x160;`Ă&#x2022;Â&#x153;`iÂ&#x2DC;>Â?Ă&#x160;yĂ&#x2022;Â&#x2C6;`Ă&#x192;Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;VÂ&#x153;Â?Â?iVĂ&#x152;i`Ă&#x160; for a 10 minute period. A test dose of ChiRhoStimÂŽ 0.2 mcg if using the 16 mcg vial (0.1 mL) or 0.4 mcg if using the 40 mcg vial (0.1 mL) is injected intravenously to test for possible allergies. After one minute, if there are no signs of allergic reaction,

Â&#x2026;Â&#x2C6;,Â&#x2026;Â&#x153;-Ă&#x152;Â&#x2C6;Â&#x201C;Ă Ă&#x160;>Ă&#x152;Ă&#x160;>Ă&#x160;`Â&#x153;Ă&#x192;iĂ&#x160;Â&#x153;vĂ&#x160;ä°Ă&#x201C;Ă&#x160;Â&#x201C;V}Ă&#x2030;Â&#x17D;}Ă&#x160;Â&#x153;vĂ&#x160;LÂ&#x153;`Ă&#x17E;Ă&#x160;Ă&#x153;iÂ&#x2C6;}Â&#x2026;Ă&#x152;Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;Â&#x2C6;Â&#x2DC;Â?iVĂ&#x152;i`Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x152;Ă&#x20AC;>Ă&#x203A;iÂ&#x2DC;Â&#x153;Ă&#x2022;Ă&#x192;Â?Ă&#x17E;Ă&#x160; Â&#x153;Ă&#x203A;iĂ&#x20AC;Ă&#x160;ÂŁĂ&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;i°Ă&#x160;Ă&#x160; Ă&#x2022;Â&#x153;`iÂ&#x2DC;>Â?Ă&#x160;yĂ&#x2022;Â&#x2C6;`Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;VÂ&#x153;Â?Â?iVĂ&#x152;i`Ă&#x160;vÂ&#x153;Ă&#x20AC;Ă&#x160;Ă&#x2C6;äĂ&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;iĂ&#x192;Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x20AC;i>vĂ&#x152;iĂ&#x20AC;°Ă&#x160;Ă&#x160;/Â&#x2026;iĂ&#x160;>Ă&#x192;ÂŤÂ&#x2C6;Ă&#x20AC;>Ă&#x152;iĂ&#x160; Â&#x2C6;Ă&#x192;Ă&#x160;`Â&#x2C6;Ă&#x203A;Â&#x2C6;`i`Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x152;Â&#x153;Ă&#x160;vÂ&#x153;Ă&#x2022;Ă&#x20AC;Ă&#x160;VÂ&#x153;Â?Â?iVĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;ÂŤiĂ&#x20AC;Â&#x2C6;Â&#x153;`Ă&#x192;Ă&#x160;Â&#x153;vĂ&#x160;wvĂ&#x152;iiÂ&#x2DC;Ă&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;iĂ&#x192;Ă&#x160;i>VÂ&#x2026;°Ă&#x160;Ă&#x160;/Â&#x2026;iĂ&#x160;`Ă&#x2022;Â&#x153;`iÂ&#x2DC;>Â?Ă&#x160;Â?Ă&#x2022;Â&#x201C;iÂ&#x2DC;Ă&#x160; of the tube is cleared with an injection of air after collection of each sample. Wide variation in volume of the aspirate is indicative of incomplete aspiration. Each Ă&#x192;>Â&#x201C;ÂŤÂ?iĂ&#x160;Â&#x153;vĂ&#x160;`Ă&#x2022;Â&#x153;`iÂ&#x2DC;>Â?Ă&#x160;yĂ&#x2022;Â&#x2C6;`Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;Ă&#x152;Â&#x153;Ă&#x160;LiĂ&#x160;VÂ&#x2026;Â&#x2C6;Â?Â?i`Ă&#x160;>Â&#x2DC;`Ă&#x160;Ă&#x192;Ă&#x2022;LĂ&#x192;iÂľĂ&#x2022;iÂ&#x2DC;Ă&#x152;Â?Ă&#x17E;Ă&#x160;>Â&#x2DC;>Â?Ă&#x17E;âi`Ă&#x160;vÂ&#x153;Ă&#x20AC;Ă&#x160;Ă&#x203A;Â&#x153;Â?Ă&#x2022;Â&#x201C;iĂ&#x160;>Â&#x2DC;`Ă&#x160; bicarbonate concentration. Exocrine pancreas dysfunction typically associated with VÂ&#x2026;Ă&#x20AC;Â&#x153;Â&#x2DC;Â&#x2C6;VĂ&#x160;ÂŤ>Â&#x2DC;VĂ&#x20AC;i>Ă&#x152;Â&#x2C6;Ă&#x152;Â&#x2C6;Ă&#x192;Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;Â&#x2C6;Â&#x2DC;`Â&#x2C6;V>Ă&#x152;i`Ă&#x160;Â&#x2C6;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;ÂŤi>Â&#x17D;Ă&#x160;LÂ&#x2C6;V>Ă&#x20AC;LÂ&#x153;Â&#x2DC;>Ă&#x152;iĂ&#x160;VÂ&#x153;Â&#x2DC;ViÂ&#x2DC;Ă&#x152;Ă&#x20AC;>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;vÂ&#x153;Ă&#x20AC;Ă&#x160;>Â&#x2DC;Ă&#x17E;Ă&#x160;Ă&#x192;>Â&#x201C;ÂŤÂ?iĂ&#x160; < 80 mEq/L.

Ă&#x160;}Ă&#x20AC;i>Ă&#x152;iĂ&#x20AC;Ă&#x160;Ă&#x152;Â&#x2026;>Â&#x2DC;Ă&#x160;Â&#x2DC;Â&#x153;Ă&#x20AC;Â&#x201C;>Â?Ă&#x160;Ă&#x203A;Â&#x153;Â?Ă&#x2022;Â&#x201C;iĂ&#x160;Ă&#x20AC;iĂ&#x192;ÂŤÂ&#x153;Â&#x2DC;Ă&#x192;iĂ&#x160;Ă&#x152;Â&#x153;Ă&#x160;Ă&#x192;iVĂ&#x20AC;iĂ&#x152;Â&#x2C6;Â&#x2DC;Ă&#x160;Ă&#x192;Ă&#x152;Â&#x2C6;Â&#x201C;Ă&#x2022;Â?>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;]Ă&#x160;Ă&#x153;Â&#x2026;Â&#x2C6;VÂ&#x2026;Ă&#x160;Â&#x201C;>Ă&#x17E;Ă&#x160;Â&#x201C;>Ă&#x192;Â&#x17D;Ă&#x160; coexisting pancreatic disease, is occasionally encountered in patients with alcoholic or other liver disease. Results of secretin stimulation tests in these patients should thus be interpreted with caution.

ChiRhoStimÂŽ

(Human Secretin for Injection) ChiRhoStimÂŽ (Human Secretin) Injection, lyophilized powder for intravenous use, 16 mcg and 40 mcg vials Initial U.S. Approval: 2004 ------------------------ RECENT MAJOR CHANGES --------------------------------------------------Dosage and Administration (2.0) 06/2007 ------------------------ INDICATIONS AND USAGE ---------------------------------------------------ChiRhoStimÂŽ injectables are indicated for: UĂ&#x160;-Ă&#x152;Â&#x2C6;Â&#x201C;Ă&#x2022;Â?>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;ÂŤ>Â&#x2DC;VĂ&#x20AC;i>Ă&#x152;Â&#x2C6;VĂ&#x160;Ă&#x192;iVĂ&#x20AC;iĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x192;]Ă&#x160;Â&#x2C6;Â&#x2DC;VÂ?Ă&#x2022;`Â&#x2C6;Â&#x2DC;}Ă&#x160;LÂ&#x2C6;V>Ă&#x20AC;LÂ&#x153;Â&#x2DC;>Ă&#x152;i]Ă&#x160;Ă&#x152;Â&#x153;Ă&#x160;>Â&#x2C6;`Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160; diagnosis of exocrine pancreas dysfunction (1.1) UĂ&#x160;-Ă&#x152;Â&#x2C6;Â&#x201C;Ă&#x2022;Â?>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;}>Ă&#x192;Ă&#x152;Ă&#x20AC;Â&#x2C6;Â&#x2DC;Ă&#x160;Ă&#x192;iVĂ&#x20AC;iĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Ă&#x152;Â&#x153;Ă&#x160;>Â&#x2C6;`Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;`Â&#x2C6;>}Â&#x2DC;Â&#x153;Ă&#x192;Â&#x2C6;Ă&#x192;Ă&#x160;Â&#x153;vĂ&#x160;}>Ă&#x192;Ă&#x152;Ă&#x20AC;Â&#x2C6;Â&#x2DC;Â&#x153;Â&#x201C;>Ă&#x160;­£°Ă&#x201C;ÂŽ UĂ&#x160; >VÂ&#x2C6;Â?Â&#x2C6;Ă&#x152;>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Â&#x2C6;`iÂ&#x2DC;Ă&#x152;Â&#x2C6;wV>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;>Â&#x201C;ÂŤĂ&#x2022;Â?Â?>Ă&#x160;Â&#x153;vĂ&#x160;6>Ă&#x152;iĂ&#x20AC;Ă&#x160;>Â&#x2DC;`Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;>VViĂ&#x192;Ă&#x192;Â&#x153;Ă&#x20AC;Ă&#x17E;Ă&#x160;ÂŤ>ÂŤÂ&#x2C6;Â?Â?>Ă&#x160; during endoscopic retrograde cholangiopancreatography (ERCP) (1.3) ------------------------ DOSAGE AND ADMINISTRATION ------------------------------------------Stimulation of pancreatic secretions, including bicarbonate to aid in the diagnosis of exocrine pancreas dysfunction (2.1) UĂ&#x160;ä°Ă&#x201C;Ă&#x160;Â&#x201C;V}Ă&#x2030;Â&#x17D;}Ă&#x160;LÂ&#x153;`Ă&#x17E;Ă&#x160;Ă&#x153;iÂ&#x2C6;}Â&#x2026;Ă&#x152;Ă&#x160;LĂ&#x17E;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x152;Ă&#x20AC;>Ă&#x203A;iÂ&#x2DC;Â&#x153;Ă&#x2022;Ă&#x192;Ă&#x160;Â&#x2C6;Â&#x2DC;Â?iVĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;Ă&#x203A;iĂ&#x20AC;Ă&#x160;ÂŁĂ&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;i°Ă&#x160;-Ă&#x152;Â&#x2C6;Â&#x201C;Ă&#x2022;Â?>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160; gastrin secretion to aid in the diagnosis of gastrinoma (2.2) UĂ&#x160;ä°{Ă&#x160;Â&#x201C;V}Ă&#x2030;Â&#x17D;}Ă&#x160;LÂ&#x153;`Ă&#x17E;Ă&#x160;Ă&#x153;iÂ&#x2C6;}Â&#x2026;Ă&#x152;Ă&#x160;LĂ&#x17E;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x152;Ă&#x20AC;>Ă&#x203A;iÂ&#x2DC;Â&#x153;Ă&#x2022;Ă&#x192;Ă&#x160;Â&#x2C6;Â&#x2DC;Â?iVĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;Ă&#x203A;iĂ&#x20AC;Ă&#x160;ÂŁĂ&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;i° >VÂ&#x2C6;Â?Â&#x2C6;Ă&#x152;>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Â&#x2C6;`iÂ&#x2DC;Ă&#x152;Â&#x2C6;wV>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;>Â&#x201C;ÂŤĂ&#x2022;Â?Â?>Ă&#x160;Â&#x153;vĂ&#x160;6>Ă&#x152;iĂ&#x20AC;Ă&#x160;>Â&#x2DC;`Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;>VViĂ&#x192;Ă&#x192;Â&#x153;Ă&#x20AC;Ă&#x17E;Ă&#x160;ÂŤ>ÂŤÂ&#x2C6;Â?Â?>Ă&#x160; during endoscopic retrograde cholangiopancreatography (ERCP) (2.3) UĂ&#x160;ä°Ă&#x201C;Ă&#x160;Â&#x201C;V}Ă&#x2030;Â&#x17D;}Ă&#x160;LÂ&#x153;`Ă&#x17E;Ă&#x160;Ă&#x153;iÂ&#x2C6;}Â&#x2026;Ă&#x152;Ă&#x160;LĂ&#x17E;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x152;Ă&#x20AC;>Ă&#x203A;iÂ&#x2DC;Â&#x153;Ă&#x2022;Ă&#x192;Ă&#x160;Â&#x2C6;Â&#x2DC;Â?iVĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;Ă&#x203A;iĂ&#x20AC;Ă&#x160;ÂŁĂ&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;i° ------------------------ DOSAGE FORMS AND STRENGTHS --------------------------------------ChiRhoStimÂŽ is available in two strengths: UĂ&#x160; Ă&#x192;Ă&#x160;>Ă&#x160;Â?Ă&#x17E;Â&#x153;ÂŤÂ&#x2026;Â&#x2C6;Â?Â&#x2C6;âi`Ă&#x160;Ă&#x192;Ă&#x152;iĂ&#x20AC;Â&#x2C6;Â?iĂ&#x160;ÂŤÂ&#x153;Ă&#x153;`iĂ&#x20AC;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x160;£äĂ&#x160;Â&#x201C; Ă&#x160;Ă&#x203A;Â&#x2C6;>Â?Ă&#x192;Ă&#x160;VÂ&#x153;Â&#x2DC;Ă&#x152;>Â&#x2C6;Â&#x2DC;Â&#x2C6;Â&#x2DC;}Ă&#x160;ÂŁĂ&#x2C6;Ă&#x160;Â&#x201C;V}Ă&#x160;Â&#x153;vĂ&#x160;Â&#x2026;Ă&#x2022;Â&#x201C;>Â&#x2DC;Ă&#x160; Ă&#x192;iVĂ&#x20AC;iĂ&#x152;Â&#x2C6;Â&#x2DC;°Ă&#x160;Ă&#x160;,iVÂ&#x153;Â&#x2DC;Ă&#x192;Ă&#x152;Â&#x2C6;Ă&#x152;Ă&#x2022;Ă&#x152;iĂ&#x160;Ă&#x153;Â&#x2C6;Ă&#x152;Â&#x2026;Ă&#x160;nĂ&#x160;Â&#x201C; Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x192;>Â?Â&#x2C6;Â&#x2DC;iĂ&#x160;vÂ&#x153;Ă&#x20AC;Ă&#x160;Â&#x2C6;Â&#x2DC;Â?iVĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Ă&#x152;Â&#x153;Ă&#x160;Ă&#x17E;Â&#x2C6;iÂ?`Ă&#x160;>Ă&#x160;wÂ&#x2DC;>Â?Ă&#x160; concentration of 2 mcg of human secretin/mL (3.1) UĂ&#x160; Ă&#x192;Ă&#x160;>Ă&#x160;Â?Ă&#x17E;Â&#x153;ÂŤÂ&#x2026;Â&#x2C6;Â?Â&#x2C6;âi`Ă&#x160;Ă&#x192;Ă&#x152;iĂ&#x20AC;Â&#x2C6;Â?iĂ&#x160;ÂŤÂ&#x153;Ă&#x153;`iĂ&#x20AC;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x160;£äĂ&#x160;Â&#x201C; Ă&#x160;Ă&#x203A;Â&#x2C6;>Â?Ă&#x192;Ă&#x160;VÂ&#x153;Â&#x2DC;Ă&#x152;>Â&#x2C6;Â&#x2DC;Â&#x2C6;Â&#x2DC;}Ă&#x160;{äĂ&#x160;Â&#x201C;V}Ă&#x160;Â&#x153;vĂ&#x160;Â&#x2026;Ă&#x2022;Â&#x201C;>Â&#x2DC;Ă&#x160; Ă&#x192;iVĂ&#x20AC;iĂ&#x152;Â&#x2C6;Â&#x2DC;°Ă&#x160;Ă&#x160;,iVÂ&#x153;Â&#x2DC;Ă&#x192;Ă&#x152;Â&#x2C6;Ă&#x152;Ă&#x2022;Ă&#x152;iĂ&#x160;Ă&#x153;Â&#x2C6;Ă&#x152;Â&#x2026;Ă&#x160;£äĂ&#x160;Â&#x201C; Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x192;>Â?Â&#x2C6;Â&#x2DC;iĂ&#x160;vÂ&#x153;Ă&#x20AC;Ă&#x160;Â&#x2C6;Â&#x2DC;Â?iVĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Ă&#x152;Â&#x153;Ă&#x160;Ă&#x17E;Â&#x2C6;iÂ?`Ă&#x160;wÂ&#x2DC;>Â?Ă&#x160; concentration of 4 mcg of human secretin /mL (3.2) ------------------------ CONTRAINDICATIONS ---------------------------------------------------------Patients suffering from acute pancreatitis should not receive ChiRhoStimÂŽ until the acute episode has subsided (4).

------------------------ WARNINGS AND PRECAUTIONS -------------------------------------------UĂ&#x160; Â?Â?iĂ&#x20AC;}Â&#x2C6;VĂ&#x160;,i>VĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x192;Ă&#x160;­x°£Ž° UĂ&#x160;6>}Â&#x153;Ă&#x152;Â&#x153;Â&#x201C;Ă&#x17E;Ă&#x160;Â&#x153;Ă&#x20AC;Ă&#x160; Â&#x2DC;y>Â&#x201C;Â&#x201C;>Ă&#x152;Â&#x153;Ă&#x20AC;Ă&#x17E;Ă&#x160; Â&#x153;Ă&#x153;iÂ?Ă&#x160; Â&#x2C6;Ă&#x192;i>Ă&#x192;iĂ&#x160;­x°Ă&#x201C;Ž° UĂ&#x160; Â?VÂ&#x153;Â&#x2026;Â&#x153;Â?Â&#x2C6;VĂ&#x160;Â&#x153;Ă&#x20AC;Ă&#x160;"Ă&#x152;Â&#x2026;iĂ&#x20AC;Ă&#x160; Â&#x2C6;Ă&#x203A;iĂ&#x20AC;Ă&#x160; Â&#x2C6;Ă&#x192;i>Ă&#x192;iĂ&#x160;­x°Ă&#x17D;Ž° ------------------------Ă&#x160; 6 ,- Ă&#x160;, / " -Ă&#x160; --------------------------------------------------------- Â&#x153;Ă&#x192;Ă&#x152;Ă&#x160;VÂ&#x153;Â&#x201C;Â&#x201C;Â&#x153;Â&#x2DC;Ă&#x160;>`Ă&#x203A;iĂ&#x20AC;Ă&#x192;iĂ&#x160;Ă&#x20AC;i>VĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x192;Ă&#x160;­Â&#x20AC;ä°xÂŻÂŽĂ&#x160;>Ă&#x20AC;iĂ&#x160;Â&#x2DC;>Ă&#x2022;Ă&#x192;i>]Ă&#x160;yĂ&#x2022;Ă&#x192;Â&#x2026;Â&#x2C6;Â&#x2DC;}]Ă&#x160;>L`Â&#x153;Â&#x201C;Â&#x2C6;Â&#x2DC;>Â?Ă&#x160;ÂŤ>Â&#x2C6;Â&#x2DC;]Ă&#x160; and vomiting (6). /Â&#x153;Ă&#x160;Ă&#x20AC;iÂŤÂ&#x153;Ă&#x20AC;Ă&#x152;Ă&#x160;-1-* / Ă&#x160; 6 ,- Ă&#x160;, / " -]Ă&#x160;VÂ&#x153;Â&#x2DC;Ă&#x152;>VĂ&#x152;Ă&#x160; Â&#x2026;Â&#x2C6;,Â&#x2026;Â&#x153; Â?Â&#x2C6;Â&#x2DC;]Ă&#x160; Â&#x2DC;V°Ă&#x160;>Ă&#x152;Ă&#x160;Ă&#x17D;ä£Â&#x2021;{Ă&#x2021;Ă&#x2C6;Â&#x2021; 8388 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

------------------------ DRUG INTERACTIONS ---------------------------------------------------------/Â&#x2026;iĂ&#x160;VÂ&#x153;Â&#x2DC;VÂ&#x153;Â&#x201C;Â&#x2C6;Ă&#x152;>Â&#x2DC;Ă&#x152;Ă&#x160;Ă&#x2022;Ă&#x192;iĂ&#x160;Â&#x153;vĂ&#x160;>Â&#x2DC;Ă&#x152;Â&#x2C6;VÂ&#x2026;Â&#x153;Â?Â&#x2C6;Â&#x2DC;iĂ&#x20AC;}Â&#x2C6;VĂ&#x160;>}iÂ&#x2DC;Ă&#x152;Ă&#x192;Ă&#x160;Â&#x201C;>Ă&#x17E;Ă&#x160;Â&#x201C;>Â&#x17D;iĂ&#x160;ÂŤ>Ă&#x152;Â&#x2C6;iÂ&#x2DC;Ă&#x152;Ă&#x192;Ă&#x160; hyporesponsive, i.e., may produce a false result (7). Results of secretin testing in these patients should be interpreted with caution.

------------------------USE IN SPECIFIC POPULATIONS --------------------------------------------The safety evaluation of ChiRhoStimÂŽ in geriatric patients showed no difference vĂ&#x20AC;Â&#x153;Â&#x201C;Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;Ă&#x192;>viĂ&#x152;Ă&#x17E;Ă&#x160;iĂ&#x203A;>Â?Ă&#x2022;>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;}iÂ&#x2DC;iĂ&#x20AC;>Â?Ă&#x160;ÂŤÂ&#x153;ÂŤĂ&#x2022;Â?>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;­n°xŽ°Ă&#x160; See 17 for PATIENT COUNSELING INFORMATION Revised: 6/2007

The patient should fast for at least 12 hours prior to beginning the test. Prior to injection of ChiRhoStimÂŽ, two blood samples are drawn for determination of fasting serum gastrin levels (baseline values). Subsequently, a test dose of ChiRhoStimÂŽ 0.2 mcg if using the 16 mcg vial (0.1 mL) or 0.4 mcg if using the 40 mcg vial (0.1 mL) is injected intravenously to test for possible allergies. If there are no signs of allergic reaction,

Â&#x2026;Â&#x2C6;,Â&#x2026;Â&#x153;-Ă&#x152;Â&#x2C6;Â&#x201C;Ă Ă&#x160;>Ă&#x152;Ă&#x160;>Ă&#x160;`Â&#x153;Ă&#x192;iĂ&#x160;Â&#x153;vĂ&#x160;ä°{Ă&#x160;Â&#x201C;V}Ă&#x2030;Â&#x17D;}Ă&#x160;Â&#x153;vĂ&#x160;LÂ&#x153;`Ă&#x17E;Ă&#x160;Ă&#x153;iÂ&#x2C6;}Â&#x2026;Ă&#x152;Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;Â&#x2C6;Â&#x2DC;Â?iVĂ&#x152;i`Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x152;Ă&#x20AC;>Ă&#x203A;iÂ&#x2DC;Â&#x153;Ă&#x2022;Ă&#x192;Â?Ă&#x17E;Ă&#x160;Â&#x153;Ă&#x203A;iĂ&#x20AC;Ă&#x160;ÂŁĂ&#x160; Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;iĂ&#x2020;Ă&#x160;ÂŤÂ&#x153;Ă&#x192;Ă&#x152;Â&#x2021;Â&#x2C6;Â&#x2DC;Â?iVĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;LÂ?Â&#x153;Â&#x153;`Ă&#x160;Ă&#x192;>Â&#x201C;ÂŤÂ?iĂ&#x192;Ă&#x160;>Ă&#x20AC;iĂ&#x160;VÂ&#x153;Â?Â?iVĂ&#x152;i`Ă&#x160;>vĂ&#x152;iĂ&#x20AC;Ă&#x160;ÂŁ]Ă&#x160;Ă&#x201C;]Ă&#x160;x]Ă&#x160;£ä]Ă&#x160;>Â&#x2DC;`Ă&#x160;Ă&#x17D;äĂ&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;iĂ&#x192;Ă&#x160;vÂ&#x153;Ă&#x20AC;Ă&#x160; determination of serum gastrin concentrations.

Gastrinoma is strongly indicated in patients who show an increase in serum gastrin concentrations of 110 pg/mL over basal level on any of the post injection samples. Ă&#x201C;°Ă&#x17D;Ă&#x160; >VÂ&#x2C6;Â?Â&#x2C6;Ă&#x152;>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160; `iÂ&#x2DC;Ă&#x152;Â&#x2C6;wV>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160; Â&#x201C;ÂŤĂ&#x2022;Â?Â?>Ă&#x160;Â&#x153;vĂ&#x160;6>Ă&#x152;iĂ&#x20AC;Ă&#x160;>Â&#x2DC;`Ă&#x160; VViĂ&#x192;Ă&#x192;Â&#x153;Ă&#x20AC;Ă&#x17E;Ă&#x160;*>ÂŤÂ&#x2C6;Â?Â?>Ă&#x160; Ă&#x2022;Ă&#x20AC;Â&#x2C6;Â&#x2DC;}Ă&#x160; Endoscopic Retrograde Cholangiopancreatography (ERCP) to aid in cannulation of the pancreatic duct: ä°Ă&#x201C;Ă&#x160;Â&#x201C;V}Ă&#x2030;Â&#x17D;}Ă&#x160;LÂ&#x153;`Ă&#x17E;Ă&#x160;Ă&#x153;iÂ&#x2C6;}Â&#x2026;Ă&#x152;Ă&#x160;LĂ&#x17E;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x152;Ă&#x20AC;>Ă&#x203A;iÂ&#x2DC;Â&#x153;Ă&#x2022;Ă&#x192;Ă&#x160;Â&#x2C6;Â&#x2DC;Â?iVĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;Ă&#x203A;iĂ&#x20AC;Ă&#x160;ÂŁĂ&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;i° `Â&#x201C;Â&#x2C6;Â&#x2DC;Â&#x2C6;Ă&#x192;Ă&#x152;Ă&#x20AC;>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160; Â&#x2026;Â&#x2C6;,Â&#x2026;Â&#x153;-Ă&#x152;Â&#x2C6;Â&#x201C;Ă Ă&#x160;Â&#x201C;>Ă&#x17E;Ă&#x160;LiĂ&#x160;}Â&#x2C6;Ă&#x203A;iÂ&#x2DC;Ă&#x160;Ă&#x153;Â&#x2026;iÂ&#x2DC;Ă&#x160;`Â&#x2C6;vwVĂ&#x2022;Â?Ă&#x152;Ă&#x17E;Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;iÂ&#x2DC;VÂ&#x153;Ă&#x2022;Â&#x2DC;Ă&#x152;iĂ&#x20AC;i`Ă&#x160;LĂ&#x17E;Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160; iÂ&#x2DC;`Â&#x153;Ă&#x192;VÂ&#x153;ÂŤÂ&#x2C6;Ă&#x192;Ă&#x152;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x160;Â&#x2C6;`iÂ&#x2DC;Ă&#x152;Â&#x2C6;vĂ&#x17E;Â&#x2C6;Â&#x2DC;}Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;>Â&#x201C;ÂŤĂ&#x2022;Â?Â?>Ă&#x160;Â&#x153;vĂ&#x160;6>Ă&#x152;iĂ&#x20AC;Ă&#x160;vÂ&#x153;Ă&#x20AC;Ă&#x160;Ă&#x203A;>Ă&#x20AC;Â&#x2C6;Â&#x153;Ă&#x2022;Ă&#x192;Ă&#x160;Ă&#x20AC;i>Ă&#x192;Â&#x153;Â&#x2DC;Ă&#x192;Ă&#x160;Â&#x2C6;Â&#x2DC;VÂ?Ă&#x2022;`Â&#x2C6;Â&#x2DC;}\Ă&#x160;>Â&#x2DC;>Ă&#x152;Â&#x153;Â&#x201C;Â&#x2C6;VĂ&#x160; deformity secondary to prior surgery, radiation therapy, peptic ulcer disease, tumors, etc. or in identifying the accessory papilla in patients with pancreas divisum. A test dose of ChiRhoStimÂŽ 0.2 mcg if using the 16 mcg vial (0.1 mL) or 0.4 mcg if using the 40 mcg vial (0.1 mL) is injected intravenously to test for possible allergies. If there are no signs of >Â?Â?iĂ&#x20AC;}Â&#x2C6;VĂ&#x160;Ă&#x20AC;i>VĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;]Ă&#x160;>Ă&#x160;`Â&#x153;Ă&#x192;iĂ&#x160;Â&#x153;vĂ&#x160;ä°Ă&#x201C;Ă&#x160;Â&#x201C;V}Ă&#x2030;Â&#x17D;}Ă&#x160;Â&#x153;vĂ&#x160;LÂ&#x153;`Ă&#x17E;Ă&#x160;Ă&#x153;iÂ&#x2C6;}Â&#x2026;Ă&#x152;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x152;Ă&#x20AC;>Ă&#x203A;iÂ&#x2DC;Â&#x153;Ă&#x2022;Ă&#x192;Â?Ă&#x17E;Ă&#x160;Â&#x153;Ă&#x203A;iĂ&#x20AC;Ă&#x160;ÂŁĂ&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;iĂ&#x160;Â&#x201C;>Ă&#x17E;Ă&#x160; LiĂ&#x160;>`Â&#x201C;Â&#x2C6;Â&#x2DC;Â&#x2C6;Ă&#x192;Ă&#x152;iĂ&#x20AC;i`Ă&#x160;>Â&#x2DC;`Ă&#x160;Ă&#x153;Â&#x2C6;Â?Â?Ă&#x160;Ă&#x20AC;iĂ&#x192;Ă&#x2022;Â?Ă&#x152;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x160;Ă&#x203A;Â&#x2C6;Ă&#x192;Â&#x2C6;LÂ?iĂ&#x160;iĂ?VĂ&#x20AC;iĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;ÂŤ>Â&#x2DC;VĂ&#x20AC;i>Ă&#x152;Â&#x2C6;VĂ&#x160;yĂ&#x2022;Â&#x2C6;`Ă&#x160;vĂ&#x20AC;Â&#x153;Â&#x201C;Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;Â&#x153;Ă&#x20AC;Â&#x2C6;wViĂ&#x192;Ă&#x160;Â&#x153;vĂ&#x160; Ă&#x152;Â&#x2026;iĂ&#x192;iĂ&#x160;ÂŤ>ÂŤÂ&#x2C6;Â?Â?>iĂ&#x160;iÂ&#x2DC;>LÂ?Â&#x2C6;Â&#x2DC;}Ă&#x160;Ă&#x152;Â&#x2026;iÂ&#x2C6;Ă&#x20AC;Ă&#x160;Â&#x2C6;`iÂ&#x2DC;Ă&#x152;Â&#x2C6;wV>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;>Â&#x2DC;`Ă&#x160;v>VÂ&#x2C6;Â?Â&#x2C6;Ă&#x152;>Ă&#x152;Â&#x2C6;Â&#x2DC;}Ă&#x160;Ă&#x152;Â&#x2026;iÂ&#x2C6;Ă&#x20AC;Ă&#x160;V>Â&#x2DC;Â&#x2DC;Ă&#x2022;Â?>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;°

1 INDICATIONS AND USAGE

Because of a potential allergic reaction to ChiRhoStimÂŽ patients should receive an intravenous test dose of 0.1 mL of the respective reconstituted vial. If no signs of allergic reaction are noted after one minute, the recommended dose may be injected slowly over 1 minute. A test dose is especially important in patients with a history of atopic allergy and/or asthma. Appropriate measures for the treatment of acute hypersensitivity reactions should be immediately available. No allergic reactions were observed after the Ă&#x152;iĂ&#x192;Ă&#x152;Ă&#x160;`Â&#x153;Ă&#x192;iĂ&#x160;Â&#x153;Ă&#x20AC;Ă&#x160;vĂ&#x2022;Â?Â?Ă&#x160;`Â&#x153;Ă&#x192;iĂ&#x160;Â&#x153;vĂ&#x160;Ă&#x192;Ă&#x17E;Â&#x2DC;Ă&#x152;Â&#x2026;iĂ&#x152;Â&#x2C6;VĂ&#x160;Â&#x2026;Ă&#x2022;Â&#x201C;>Â&#x2DC;Ă&#x160;Ă&#x192;iVĂ&#x20AC;iĂ&#x152;Â&#x2C6;Â&#x2DC;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x160;xn{Ă&#x160;ÂŤ>Ă&#x152;Â&#x2C6;iÂ&#x2DC;Ă&#x152;Ă&#x192;Ă&#x160;>Â&#x2DC;`Ă&#x160;Ă&#x203A;Â&#x153;Â?Ă&#x2022;Â&#x2DC;Ă&#x152;iiĂ&#x20AC;Ă&#x192;°

ä°Ă&#x201C;Ă&#x160;Â&#x201C;V}Ă&#x2030;Â&#x17D;}Ă&#x160;LÂ&#x153;`Ă&#x17E;Ă&#x160;Ă&#x153;iÂ&#x2C6;}Â&#x2026;Ă&#x152;Ă&#x160;LĂ&#x17E;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x152;Ă&#x20AC;>Ă&#x203A;iÂ&#x2DC;Â&#x153;Ă&#x2022;Ă&#x192;Ă&#x160;Â&#x2C6;Â&#x2DC;Â?iVĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;Ă&#x203A;iĂ&#x20AC;Ă&#x160;ÂŁĂ&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;i°

Nausea Flushing Early removal of Dreiling tube Abdominal pain Vomiting Increased heart rate Mild Pancreatitis Upset stomach Anxiety Burning in stomach or abdomen Clammy skin Decreased O2 saturation Diarrhea Faintness Hypotension Infiltrated IV Oral secretions increased Sedation Slow heart rate (57 bpm) Tingling in legs Unresponsive Warm sensation in abdomen Warm sensation in face

ä°{Ă&#x160;Â&#x201C;V}Ă&#x2030;Â&#x17D;}Ă&#x160;LÂ&#x153;`Ă&#x17E;Ă&#x160;Ă&#x153;iÂ&#x2C6;}Â&#x2026;Ă&#x152;Ă&#x160;LĂ&#x17E;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x152;Ă&#x20AC;>Ă&#x203A;iÂ&#x2DC;Â&#x153;Ă&#x2022;Ă&#x192;Ă&#x160;Â&#x2C6;Â&#x2DC;Â?iVĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;Ă&#x203A;iĂ&#x20AC;Ă&#x160;ÂŁĂ&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;i°

ChiRhoStimÂŽ 16 mcg vial: Dissolve the contents of the ChiRhoStimÂŽ 16 mcg vial in 8 mL of Sodium Chloride Injection USP, to yield a concentration of 2 mcg/mL°Ă&#x160;-Â&#x2026;>Â&#x17D;iĂ&#x160;Ă&#x203A;Â&#x2C6;}Â&#x153;Ă&#x20AC;Â&#x153;Ă&#x2022;Ă&#x192;Â?Ă&#x17E;Ă&#x160;Ă&#x152;Â&#x153;Ă&#x160;iÂ&#x2DC;Ă&#x192;Ă&#x2022;Ă&#x20AC;iĂ&#x160; dissolution. Use immediately after reconstitution and discard any unused portion.

2.1 Stimulation of Pancreatic Secretions, Including Bicarbonate to Aid in the Diagnosis of Exocrine Pancreas Dysfunction:

6 ,- Ă&#x160;, / " -Ă&#x160;7 / Ă&#x160; , "-/ Ă Adverse Reaction

2.2 Stimulation of Gastrin Secretion to Aid in Diagnosis of Gastrinoma:

2.4 ADMINISTRATION

2 DOSAGE AND ADMINISTRATION

TABLE 1

After assessment of patients for sedation and analgesia, a test dose of ChiRhoStimÂŽ 0.2 mcg if using the 16 mcg vial (0.1 mL) or 0.4 mcg if using the 40 mcg vial (0.1 mL) is injected intravenously to test for possible allergies. After one minute, if there are Â&#x2DC;Â&#x153;Ă&#x160;Ă&#x192;Â&#x2C6;}Â&#x2DC;Ă&#x192;Ă&#x160;Â&#x153;vĂ&#x160;>Â?Â?iĂ&#x20AC;}Â&#x2C6;VĂ&#x160;Ă&#x20AC;i>VĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;]Ă&#x160; Â&#x2026;Â&#x2C6;,Â&#x2026;Â&#x153;-Ă&#x152;Â&#x2C6;Â&#x201C;Ă Ă&#x160;>Ă&#x152;Ă&#x160;>Ă&#x160;`Â&#x153;Ă&#x192;iĂ&#x160;Â&#x153;vĂ&#x160;ä°Ă&#x201C;Ă&#x160;Â&#x201C;V}Ă&#x2030;Â&#x17D;}Ă&#x160;Â&#x153;vĂ&#x160;LÂ&#x153;`Ă&#x17E;Ă&#x160;Ă&#x153;iÂ&#x2C6;}Â&#x2026;Ă&#x152;Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160; injected intravenously over 1 minute. An upper endoscopy is performed with conscious Ă&#x192;i`>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;]Ă&#x160;>vĂ&#x152;iĂ&#x20AC;Ă&#x160;Ă&#x152;Â&#x153;ÂŤÂ&#x2C6;V>Â?Ă&#x160;>Â&#x2DC;iĂ&#x192;Ă&#x152;Â&#x2026;iĂ&#x152;Â&#x2C6;V°Ă&#x160;Ă&#x160; Â?Â?Ă&#x160;}>Ă&#x192;Ă&#x152;Ă&#x20AC;Â&#x2C6;VĂ&#x160;yĂ&#x2022;Â&#x2C6;`Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;>Ă&#x192;ÂŤÂ&#x2C6;Ă&#x20AC;>Ă&#x152;i`Ă&#x160;Ă&#x152;Â&#x2026;Ă&#x20AC;Â&#x153;Ă&#x2022;}Â&#x2026;Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;iÂ&#x2DC;`Â&#x153;Ă&#x192;VÂ&#x153;ÂŤiĂ&#x160;>Â&#x2DC;`Ă&#x160; discarded. After small bowel intubation to the junction of the second and third portion of Ă&#x152;Â&#x2026;iĂ&#x160;`Ă&#x2022;Â&#x153;`iÂ&#x2DC;Ă&#x2022;Â&#x201C;]Ă&#x160;yĂ&#x2022;Â&#x2C6;`Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;>Ă&#x192;ÂŤÂ&#x2C6;Ă&#x20AC;>Ă&#x152;i`Ă&#x160;vÂ&#x153;Ă&#x20AC;Ă&#x160;ÂŁĂ&#x160;Ă&#x152;Â&#x153;Ă&#x160;Ă&#x17D;Ă&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;iĂ&#x192;Ă&#x160;>Â&#x2DC;`Ă&#x160;VÂ&#x153;Â?Â?iVĂ&#x152;i`Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x160;xĂ&#x160;Ă&#x192;iÂŤ>Ă&#x20AC;>Ă&#x152;iĂ&#x160;Ă&#x192;ÂŤiVÂ&#x2C6;Â&#x201C;iÂ&#x2DC;Ă&#x160; Ă&#x152;Ă&#x20AC;>ÂŤĂ&#x192;Ă&#x160;>Ă&#x152;Ă&#x160;L>Ă&#x192;iÂ?Â&#x2C6;Â&#x2DC;iĂ&#x160;­äŽ]Ă&#x160;ÂŁx]Ă&#x160;Ă&#x17D;ä]Ă&#x160;{x]Ă&#x160;>Â&#x2DC;`Ă&#x160;Ă&#x2C6;äĂ&#x160;Â&#x201C;Â&#x2C6;Â&#x2DC;Ă&#x2022;Ă&#x152;iĂ&#x192;Ă&#x160;>vĂ&#x152;iĂ&#x20AC;Ă&#x160;Ă&#x192;iVĂ&#x20AC;iĂ&#x152;Â&#x2C6;Â&#x2DC;Ă&#x160;Â&#x2C6;Â&#x2DC;Â?iVĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;°Ă&#x160;Ă&#x160;/Â&#x2026;iĂ&#x160;ÂŤ>Ă&#x152;Â&#x2C6;iÂ&#x2DC;Ă&#x152;Ă&#x192;Ă&#x160; remain intubated with the upper endoscope for one hour in the left lateral decubitus ÂŤÂ&#x153;Ă&#x192;Â&#x2C6;Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;°Ă&#x160;Ă&#x160; Â&#x153;Â?Ă&#x2022;Ă&#x192;iĂ&#x192;Ă&#x160;Â&#x153;vĂ&#x160;Â&#x201C;iÂŤiĂ&#x20AC;Â&#x2C6;`Â&#x2C6;Â&#x2DC;iĂ&#x160;>Â&#x2DC;`Ă&#x160;Â&#x201C;Â&#x2C6;`>âÂ&#x153;Â?>Â&#x201C;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x160;>Ă&#x160;Ă&#x201C;x\ÂŁĂ&#x160;Â&#x201C;}Ă&#x160;Ă&#x20AC;>Ă&#x152;Â&#x2C6;Â&#x153;Ă&#x160;>Ă&#x20AC;iĂ&#x160;>`Â&#x201C;Â&#x2C6;Â&#x2DC;Â&#x2C6;Ă&#x192;Ă&#x152;iĂ&#x20AC;i`Ă&#x160; to maintain analgesia and sedation during the 1-hour procedure. Each sample of `Ă&#x2022;Â&#x153;`iÂ&#x2DC;>Â?Ă&#x160;yĂ&#x2022;Â&#x2C6;`Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;Ă&#x152;Â&#x153;Ă&#x160;LiĂ&#x160;VÂ&#x2026;Â&#x2C6;Â?Â?i`Ă&#x160;>Â&#x2DC;`Ă&#x160;Ă&#x192;Ă&#x2022;LĂ&#x192;iÂľĂ&#x2022;iÂ&#x2DC;Ă&#x152;Â?Ă&#x17E;Ă&#x160;>Â&#x2DC;>Â?Ă&#x17E;âi`Ă&#x160;vÂ&#x153;Ă&#x20AC;Ă&#x160;Ă&#x203A;Â&#x153;Â?Ă&#x2022;Â&#x201C;iĂ&#x160;>Â&#x2DC;`Ă&#x160;LÂ&#x2C6;V>Ă&#x20AC;LÂ&#x153;Â&#x2DC;>Ă&#x152;iĂ&#x160; concentration. Exocrine pancreas dysfunction typically associated with chronic ÂŤ>Â&#x2DC;VĂ&#x20AC;i>Ă&#x152;Â&#x2C6;Ă&#x152;Â&#x2C6;Ă&#x192;Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;Â&#x2C6;Â&#x2DC;`Â&#x2C6;V>Ă&#x152;i`Ă&#x160;Â&#x2C6;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;ÂŤi>Â&#x17D;Ă&#x160;LÂ&#x2C6;V>Ă&#x20AC;LÂ&#x153;Â&#x2DC;>Ă&#x152;iĂ&#x160;VÂ&#x153;Â&#x2DC;ViÂ&#x2DC;Ă&#x152;Ă&#x20AC;>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;vÂ&#x153;Ă&#x20AC;Ă&#x160;>Â&#x2DC;Ă&#x17E;Ă&#x160;Ă&#x192;>Â&#x201C;ÂŤÂ?iĂ&#x160;Â?Ă&#x160;näĂ&#x160;Â&#x201C; ÂľĂ&#x2030; °

1 INDICATIONS AND USAGE 1.1 Stimulation of pancreatic secretions, including bicarbonate to aid in the diagnosis of Exocrine Pancreas Dysfunction 1.2 Stimulation of gastrin secretion to aid in the diagnosis of gastrinoma £°Ă&#x17D;Ă&#x160; >VÂ&#x2C6;Â?Â&#x2C6;Ă&#x152;>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Â&#x2C6;`iÂ&#x2DC;Ă&#x152;Â&#x2C6;wV>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;>Â&#x201C;ÂŤĂ&#x2022;Â?Â?>Ă&#x160;Â&#x153;vĂ&#x160;6>Ă&#x152;iĂ&#x20AC;Ă&#x160;>Â&#x2DC;`Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;>VViĂ&#x192;Ă&#x192;Â&#x153;Ă&#x20AC;Ă&#x17E;Ă&#x160;ÂŤ>ÂŤÂ&#x2C6;Â?Â?>Ă&#x160; during endoscopic retrograde cholangiopancreatography (ERCP) 2 DOSAGE AND ADMINISTRATION 2.1 Stimulation of pancreatic secretions, including bicarbonate to aid in the diagnosis of Exocrine Pancreas Dysfunction 2.2 Stimulation of gastrin secretion to aid in the diagnosis of gastrinoma Ă&#x201C;°Ă&#x17D;Ă&#x160; >VÂ&#x2C6;Â?Â&#x2C6;Ă&#x152;>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Â&#x2C6;`iÂ&#x2DC;Ă&#x152;Â&#x2C6;wV>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;>Â&#x201C;ÂŤĂ&#x2022;Â?Â?>Ă&#x160;Â&#x153;vĂ&#x160;6>Ă&#x152;iĂ&#x20AC;Ă&#x160;>Â&#x2DC;`Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;>VViĂ&#x192;Ă&#x192;Â&#x153;Ă&#x20AC;Ă&#x17E;Ă&#x160;ÂŤ>ÂŤÂ&#x2C6;Â?Â?>Ă&#x160; during endoscopic retrograde cholangiopancreatography (ERCP) 2.4 Administration 3 DOSAGE FORMS AND STRENGTHS 3.1 ChiRhoStimÂŽ single dose 16 mcg/10 ml vial 3.2 ChiRhoStimÂŽ single dose 40 mcg/10 mL vial 4 CONTRAINDICATIONS xĂ&#x160;7 , -Ă&#x160; Ă&#x160;*, 1/ " x°£Ă&#x160; Â?Â?iĂ&#x20AC;}Â&#x2C6;VĂ&#x160;,i>VĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x192; x°Ă&#x201C;Ă&#x160;6>}Â&#x153;Ă&#x152;Â&#x153;Â&#x201C;Ă&#x17E;Ă&#x160;Â&#x153;Ă&#x20AC;Ă&#x160; Â&#x2DC;y>Â&#x201C;Â&#x201C;>Ă&#x152;Â&#x153;Ă&#x20AC;Ă&#x17E;Ă&#x160; Â&#x153;Ă&#x153;iÂ?Ă&#x160; Â&#x2C6;Ă&#x192;i>Ă&#x192;i x°Ă&#x17D;Ă&#x160; Â?VÂ&#x153;Â&#x2026;Â&#x153;Â?Â&#x2C6;VĂ&#x160;Â&#x153;Ă&#x20AC;Ă&#x160;"Ă&#x152;Â&#x2026;iĂ&#x20AC;Ă&#x160; Â&#x2C6;Ă&#x203A;iĂ&#x20AC;Ă&#x160; Â&#x2C6;Ă&#x192;i>Ă&#x192;i Ă&#x2C6;Ă&#x160; 6 ,- Ă&#x160;, / " 7 DRUG INTERACTIONS ÂŁxĂ&#x160;, , 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Supplied 16.2 Storage 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed.

1.1 Stimulation of pancreatic secretions, including bicarbonate, to aid in the diagnosis of pancreatic exocrine dysfunction, 1.2 Stimulation of gastrin secretion to aid in the diagnosis of gastrinoma, and £°Ă&#x17D;Ă&#x160; >VÂ&#x2C6;Â?Â&#x2C6;Ă&#x152;>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;Â&#x2C6;`iÂ&#x2DC;Ă&#x152;Â&#x2C6;wV>Ă&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;>Â&#x201C;ÂŤĂ&#x2022;Â?Â?>Ă&#x160;Â&#x153;vĂ&#x160;6>Ă&#x152;iĂ&#x20AC;Ă&#x160;>Â&#x2DC;`Ă&#x160;>VViĂ&#x192;Ă&#x192;Â&#x153;Ă&#x20AC;Ă&#x17E;Ă&#x160;ÂŤ>ÂŤÂ&#x2C6;Â?Â?>Ă&#x160;`Ă&#x2022;Ă&#x20AC;Â&#x2C6;Â&#x2DC;}Ă&#x160; endoscopic retrograde cholangiopancreatography (ERCP).

Mild to moderate adverse reactions have been noted for synthetic human secretin in VÂ?Â&#x2C6;Â&#x2DC;Â&#x2C6;V>Â?Ă&#x160;Ă&#x192;Ă&#x152;Ă&#x2022;`Â&#x2C6;iĂ&#x192;Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x160;xĂ&#x17D;Ă&#x17D;Ă&#x160;ÂŤ>Ă&#x152;Â&#x2C6;iÂ&#x2DC;Ă&#x152;Ă&#x192;Ă&#x160;>Â&#x2DC;`Ă&#x160;xÂŁĂ&#x160;Â&#x2026;i>Â?Ă&#x152;Â&#x2026;Ă&#x17E;Ă&#x160;Ă&#x203A;Â&#x153;Â?Ă&#x2022;Â&#x2DC;Ă&#x152;iiĂ&#x20AC;Ă&#x192;°Ă&#x160;Ă&#x160;/Ă&#x153;Â&#x153;Ă&#x160;Ă&#x192;iĂ&#x203A;iĂ&#x20AC;iĂ&#x160;>`Ă&#x203A;iĂ&#x20AC;Ă&#x192;iĂ&#x160;Ă&#x20AC;i>VĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x192;]Ă&#x160; nausea and abdominal pain, occurred in one patient. Table 1 details the type and number of patients with adverse reactions.

Endoscopic Collection Method: Endoscopic Pancreatic FunctionTest (ePFT)(2-4):

FULL PRESCRIBING INFORMATION: CONTENTS*

ChiRhoStimÂŽ is indicated for:

Ă&#x2C6;Ă&#x160; 6 ,- Ă&#x160;, / " -

ChiRhoStimÂŽ 40 mcg vial: Dissolve the contents of the ChiRhoStimÂŽ 40 mcg vial in 10 mL of Sodium Chloride Injection USP, to yield a concentration of 4 mcg/mL°Ă&#x160;Ă&#x160;-Â&#x2026;>Â&#x17D;iĂ&#x160;Ă&#x203A;Â&#x2C6;}Â&#x153;Ă&#x20AC;Â&#x153;Ă&#x2022;Ă&#x192;Â?Ă&#x17E;Ă&#x160;Ă&#x152;Â&#x153;Ă&#x160;iÂ&#x2DC;Ă&#x192;Ă&#x2022;Ă&#x20AC;iĂ&#x160; dissolution. Use immediately after reconstitution and discard any unused portion.

For both strengths, the reconstituted drug product should be inspected visually prior to administration. If particulate matter or discoloration is seen, the product should be discarded.

3 DOSAGE FORMS AND STRENGTHS ChiRhoStimÂŽ is available in two strengths: 3.1 As a lyophilized sterile powder in 10 mL vials containing 16 mcg of human secretin.

3.2 As a lyophilized sterile powder in 10 mL vials containing 40 mcg of human secretin.

4 CONTRAINDICATIONS Patients suffering from acute pancreatitis should not receive ChiRhoStimÂŽ until the acute episode has subsided. xĂ&#x160;7 , -Ă&#x160; Ă&#x160;*, 1/ " x°£Ă&#x160; Â?Â?iĂ&#x20AC;}Â&#x2C6;VĂ&#x160;,i>VĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;Ă&#x192;

x°Ă&#x201C;Ă&#x160;6>}Â&#x153;Ă&#x152;Â&#x153;Â&#x201C;Ă&#x17E;Ă&#x160;Â&#x153;Ă&#x20AC;Ă&#x160; Â&#x2DC;y>Â&#x201C;Â&#x201C;>Ă&#x152;Â&#x153;Ă&#x20AC;Ă&#x17E;Ă&#x160; Â&#x153;Ă&#x153;iÂ?Ă&#x160; Â&#x2C6;Ă&#x192;i>Ă&#x192;i *>Ă&#x152;Â&#x2C6;iÂ&#x2DC;Ă&#x152;Ă&#x192;Ă&#x160;Ă&#x153;Â&#x2026;Â&#x153;Ă&#x160;Â&#x2026;>Ă&#x203A;iĂ&#x160;Ă&#x2022;Â&#x2DC;`iĂ&#x20AC;}Â&#x153;Â&#x2DC;iĂ&#x160;Ă&#x203A;>}Â&#x153;Ă&#x152;Â&#x153;Â&#x201C;Ă&#x17E;Ă&#x160;Â&#x153;Ă&#x20AC;Ă&#x160;Ă&#x153;Â&#x2026;Â&#x153;Ă&#x160;Â&#x2026;>Ă&#x203A;iĂ&#x160;Â&#x2C6;Â&#x2DC;y>Â&#x201C;Â&#x201C;>Ă&#x152;Â&#x153;Ă&#x20AC;Ă&#x17E;Ă&#x160;LÂ&#x153;Ă&#x153;iÂ?Ă&#x160;`Â&#x2C6;Ă&#x192;i>Ă&#x192;iĂ&#x160; may be hyporesponsive to secretin stimulation. This response does not indicate pancreatic disease, and results of secretin stimulation tests in these patients should be interpreted with caution.

N = 584 Incidence (Patients) 11(11) 4 (4) 3 (3) 3 (3) 3 (3) 2 (2) 2 (2) 2 (2) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1)

"vĂ&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;xn{Ă&#x160;ÂŤ>Ă&#x152;Â&#x2C6;iÂ&#x2DC;Ă&#x152;Ă&#x192;Ă&#x160;>Â&#x2DC;`Ă&#x160;Â&#x2026;i>Â?Ă&#x152;Â&#x2026;Ă&#x17E;Ă&#x160;Ă&#x203A;Â&#x153;Â?Ă&#x2022;Â&#x2DC;Ă&#x152;iiĂ&#x20AC;Ă&#x192;Ă&#x160;Ă&#x152;Ă&#x20AC;i>Ă&#x152;i`Ă&#x160;Ă&#x153;Â&#x2C6;Ă&#x152;Â&#x2026;Ă&#x160; Â&#x2026;Â&#x2C6;,Â&#x2026;Â&#x153;-Ă&#x152;Â&#x2C6;Â&#x201C;Ă ]Ă&#x160;>Ă&#x160;Ă&#x152;Â&#x153;Ă&#x152;>Â?Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x201C;Â&#x2122;Ă&#x160; ÂŤ>Ă&#x152;Â&#x2C6;iÂ&#x2DC;Ă&#x152;Ă&#x192;Ă&#x160;­xÂŻÂŽĂ&#x160;Â&#x2026;>`Ă&#x160;>Ă&#x152;Ă&#x160;Â?i>Ă&#x192;Ă&#x152;Ă&#x160;Â&#x153;Â&#x2DC;iĂ&#x160;>`Ă&#x203A;iĂ&#x20AC;Ă&#x192;iĂ&#x160;Ă&#x20AC;i>VĂ&#x152;Â&#x2C6;Â&#x153;Â&#x2DC;°Ă&#x160;Ă&#x160; 7 DRUG INTERACTIONS /Â&#x2026;iĂ&#x160;VÂ&#x153;Â&#x2DC;VÂ&#x153;Â&#x201C;Â&#x2C6;Ă&#x152;>Â&#x2DC;Ă&#x152;Ă&#x160;Ă&#x2022;Ă&#x192;iĂ&#x160;Â&#x153;vĂ&#x160;>Â&#x2DC;Ă&#x152;Â&#x2C6;VÂ&#x2026;Â&#x153;Â?Â&#x2C6;Â&#x2DC;iĂ&#x20AC;}Â&#x2C6;VĂ&#x160;>}iÂ&#x2DC;Ă&#x152;Ă&#x192;Ă&#x160;Â&#x201C;>Ă&#x17E;Ă&#x160;Â&#x201C;>Â&#x17D;iĂ&#x160;ÂŤ>Ă&#x152;Â&#x2C6;iÂ&#x2DC;Ă&#x152;Ă&#x192;Ă&#x160;Â&#x2026;Ă&#x17E;ÂŤÂ&#x153;Ă&#x20AC;iĂ&#x192;ÂŤÂ&#x153;Â&#x2DC;Ă&#x192;Â&#x2C6;Ă&#x203A;iĂ&#x160;Ă&#x152;Â&#x153;Ă&#x160; secretin stimulation and may produce a false result. Any results of secretin stimulation tests in these patients should thus be interpreted with caution. ÂŁxĂ&#x160;, , £°Ă&#x160; Ă&#x20AC;iÂ&#x2C6;Â?Â&#x2C6;Â&#x2DC;}Ă&#x160; °Ă&#x160;Ă&#x160;*>Â&#x2DC;VĂ&#x20AC;i>Ă&#x152;Â&#x2C6;VĂ&#x160;Ă&#x192;iVĂ&#x20AC;iĂ&#x152;Â&#x153;Ă&#x20AC;Ă&#x17E;Ă&#x160;Ă&#x152;iĂ&#x192;Ă&#x152;Â&#x2C6;Â&#x2DC;}Ă&#x160;Â&#x2C6;Â&#x2DC;Ă&#x160;ÂŁÂ&#x2122;Ă&#x2021;{°Ă&#x160; Ă&#x2022;Ă&#x152;°Ă&#x160;ÂŁÂ&#x2122;Ă&#x2021;xĂ&#x2020;ÂŁĂ&#x2C6;­nÂŽ\Ă&#x2C6;xĂ&#x17D;Â&#x2021;Ă&#x2021;° Ă&#x201C;°Ă&#x160;-Ă&#x152;iĂ&#x203A;iÂ&#x2DC;Ă&#x192;Ă&#x160;/]Ă&#x160; Â&#x153;Â&#x2DC;Ă&#x153;iÂ?Â?Ă&#x160; ]Ă&#x160;<Ă&#x2022;VV>Ă&#x20AC;Â&#x153;Ă&#x160; Ă&#x160; Ă&#x20AC;]Ă&#x160;6>Â&#x2DC;Ă&#x160; iÂ&#x2DC;Ă&#x152;iĂ&#x160; ]Ă&#x160;*Ă&#x2022;Ă&#x20AC;Â&#x2C6;VÂ&#x2026;Ă&#x160; ]Ă&#x160; Â&#x2026;>Â&#x2DC;`Ă&#x153;>Â?>Ă&#x160; ]Ă&#x160; iÂ&#x2C6;Â&#x2DC;Ă&#x160;-°Ă&#x160; A randomized crossover study of secretin-stimulated endoscopic and dreiling tube pancreatic function test methods in healthy subjects. Am J Gastroenterol. 2006 iLĂ&#x2020;£ä£­Ă&#x201C;ÂŽ\Ă&#x17D;xÂŁÂ&#x2021;x° 3.Yadav D, Chari ST.The Endoscopic Pancreatic Exocrine FunctionTest (ePFT): Can it be Ă&#x152;Â&#x2026;iĂ&#x160; iĂ&#x153;Ă&#x160;Âş Â&#x153;Â?`Ă&#x160;-Ă&#x152;>Â&#x2DC;`>Ă&#x20AC;`œĂ&#x160; >Ă&#x192;Ă&#x152;Ă&#x20AC;Â&#x153;iÂ&#x2DC;Ă&#x152;iĂ&#x20AC;Â&#x153;Â?Â&#x153;}Ă&#x17E;Ă&#x160;Ă&#x201C;ääĂ&#x2C6;Ă&#x160;"VĂ&#x152;Ă&#x2020;ÂŁĂ&#x17D;£­{ÂŽ\ÂŁĂ&#x17D;{Â&#x2122;Â&#x2021;ÂŁĂ&#x17D;xä° {°Ă&#x160; Â&#x153;Â&#x2DC;Ă&#x153;iÂ?Â?Ă&#x160; ]Ă&#x160;<Ă&#x2022;VV>Ă&#x20AC;Â&#x153;Ă&#x160; ]Ă&#x160;*Ă&#x2022;Ă&#x20AC;Â&#x2C6;VÂ&#x2026;Ă&#x160; ]Ă&#x160; iÂ&#x2C6;Â&#x2DC;Ă&#x160;-]Ă&#x160;6>Â&#x2DC;Â?iÂ&#x2DC;Ă&#x152;iĂ&#x160; ]Ă&#x160;6>Ă&#x20AC;}Â&#x153;Ă&#x160; ]Ă&#x160; Ă&#x2022;Â&#x201C;Â&#x153;Ă&#x152;Ă&#x160; ]Ă&#x160;"½Â?>Ă&#x2022;}Â&#x2026;Â?Â&#x2C6;Â&#x2DC;Ă&#x160; C,Trolli P.The effect of moderate sedation on exocrine pancreas function in normal healthy subjects: a prospective, randomized, cross-over trial using the synthetic porcine secretin stimulated Endoscopic Pancreatic FunctionTest (ePFT). Am J Gastroenterol. Ă&#x201C;ääxĂ&#x160; >Ă&#x17E;Ă&#x2020;­xÂŽ\ÂŁÂŁĂ&#x2C6;ÂŁÂ&#x2021;Ă&#x2C6;° x°Ă&#x160; Â&#x153;Ă&#x20AC;ÂŤiĂ&#x192;]Ă&#x160; °Ă&#x160;>Â&#x2DC;`Ă&#x160; Ă&#x2022;Ă&#x152;Ă&#x152;Ă&#x160;6°Ă&#x160;"Â&#x2DC;Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;LÂ&#x2C6;Â&#x153;Â?Â&#x153;}Â&#x2C6;V>Â?Ă&#x160;>Ă&#x192;Ă&#x192;>Ă&#x17E;Ă&#x160;Â&#x153;vĂ&#x160;Ă&#x192;iVĂ&#x20AC;iĂ&#x152;Â&#x2C6;Â&#x2DC;°Ă&#x160;/Â&#x2026;iĂ&#x160;Ă&#x20AC;iviĂ&#x20AC;iÂ&#x2DC;ViĂ&#x160;Ă&#x192;Ă&#x152;>Â&#x2DC;`>Ă&#x20AC;`°Ă&#x160; VĂ&#x152;>Ă&#x160; *Â&#x2026;Ă&#x17E;Ă&#x192;Â&#x2C6;Â&#x153;Â?Ă&#x160;-V>Â&#x2DC;`°Ă&#x160;ÂŁÂ&#x2122;Ă&#x2C6;Ă&#x2C6;Ă&#x160; >Ă&#x20AC;Ă&#x2020;Ă&#x2C6;Ă&#x2C6;­Ă&#x17D;ÂŽ\Ă&#x17D;ÂŁĂ&#x2C6;Â&#x2021;Ă&#x201C;x° Ă&#x2C6;°Ă&#x160; Â&#x2026;iĂ&#x17E;Ă&#x160;79]Ă&#x160; Â&#x2026;>Â&#x2DC;}Ă&#x160;/Â&#x2021; ]Ă&#x160;-iVĂ&#x20AC;iĂ&#x152;Â&#x2C6;Â&#x2DC;°Ă&#x160; Â&#x2DC;\Ă&#x160; >Ă&#x192;Â&#x2C6;Â&#x2DC;Ă&#x160; °Ă&#x160; `Â&#x2C6;Ă&#x152;Â&#x153;Ă&#x20AC;°Ă&#x160; >Â&#x2DC;`LÂ&#x153;Â&#x153;Â&#x17D;Ă&#x160;Â&#x153;vĂ&#x160; Â&#x2C6;Â&#x153;Â?Â&#x153;}Â&#x2C6;V>Â?Â?Ă&#x17E;Ă&#x160; VĂ&#x152;Â&#x2C6;Ă&#x203A;iĂ&#x160; *iÂŤĂ&#x152;Â&#x2C6;`iĂ&#x192;°Ă&#x160; Â?Ă&#x192;iĂ&#x203A;Â&#x2C6;iĂ&#x20AC;]Ă&#x160; Â&#x201C;Ă&#x192;Ă&#x152;iĂ&#x20AC;`>Â&#x201C;°Ă&#x160;Ă&#x201C;ääĂ&#x2C6;Ă&#x2020;ÂŁÂŁÂŁxÂ&#x2021;ÂŁÂŁĂ&#x201C;Ă&#x201C;° 7. Whitcomb DC. Neurohormonal Control of the Exocrine Pancreas. In:Greeley JR G, editor. Endocrinology of the Gastrointestinal System.Totowa NJ:Humana Press. ÂŁÂ&#x2122;Â&#x2122;nĂ&#x2020;Ă&#x201C;Ă&#x17D;Â&#x2122;Â&#x2021;Ă&#x201C;xn° 8. Deveney, C.W., et al. Use of Calcium and Secretin in the Diagnosis of Gastrinoma ­<Â&#x153;Â?Â?Â&#x2C6;Â&#x2DC;}iĂ&#x20AC;Â&#x2021; Â?Â?Â&#x2C6;Ă&#x192;Â&#x153;Â&#x2DC;Ă&#x160;-Ă&#x17E;Â&#x2DC;`Ă&#x20AC;Â&#x153;Â&#x201C;iŽ°Ă&#x160; Â&#x2DC;Â&#x2DC;Ă&#x160; Â&#x2DC;Ă&#x152;iĂ&#x20AC;Â&#x2DC;Ă&#x160; i`°Ă&#x160;ÂŁÂ&#x2122;Ă&#x2021;Ă&#x2021;Ă&#x160; iVĂ&#x2020;nĂ&#x2021;­Ă&#x2C6;ÂŽ\Ă&#x2C6;näÂ&#x2021;Ă&#x2C6;° 16 HOW SUPPLIED/STORAGE AND HANDLING

Â&#x2026;Â&#x2C6;,Â&#x2026;Â&#x153;-Ă&#x152;Â&#x2C6;Â&#x201C;Ă Ă&#x160;ÂŁĂ&#x2C6;Ă&#x160;Â&#x201C;V}Ă&#x160;Ă&#x203A;Â&#x2C6;>Â?Ă&#x160;

Ă&#x160;Â&#x203A;Ă&#x160;Ă&#x2C6;Ă&#x2021;äĂ&#x2C6;Ă&#x2C6;Â&#x2021;ääxÂ&#x2021;ä£ ChiRhoStimÂŽ 40 mcg vial NDC # 67066-007-01 16.1 Supplied ChiRhoStimÂŽ is supplied in two strengths: As a lyophilized sterile powder in vials containing 16 mcg of human secretin.

As a lyophilized sterile powder in vials containing 40 mcg of human secretin.

16.2 Storage The unreconstituted product should be stored at -20°C (freezer). Expiration date is Â&#x201C;>Ă&#x20AC;Â&#x17D;i`Ă&#x160;Â&#x153;Â&#x2DC;Ă&#x160;Ă&#x152;Â&#x2026;iĂ&#x160;Â?>LiÂ?°Ă&#x160;Ă&#x160;*Ă&#x20AC;Â&#x153;Ă&#x152;iVĂ&#x152;Ă&#x160;vĂ&#x20AC;Â&#x153;Â&#x201C;Ă&#x160;Â?Â&#x2C6;}Â&#x2026;Ă&#x152;° 17 PATIENT COUNSELING INFORMATION Since there is no data on pregnant or nursing mothers, physicians should discuss these matters with the patient before using this product.

Â&#x2026;Â&#x2C6;,Â&#x2026;Â&#x153;-Ă&#x152;Â&#x2C6;Â&#x201C;Ă Ă&#x160;Â&#x2C6;Ă&#x192;Ă&#x160;>Ă&#x160;Ă&#x20AC;i}Â&#x2C6;Ă&#x192;Ă&#x152;iĂ&#x20AC;i`Ă&#x160;Ă&#x152;Ă&#x20AC;>`iÂ&#x201C;>Ă&#x20AC;Â&#x17D;Ă&#x160;Â&#x153;vĂ&#x160; Â&#x2026;Â&#x2C6;,Â&#x2026;Â&#x153; Â?Â&#x2C6;Â&#x2DC;]Ă&#x160; Â&#x2DC;V° Manufactured for: ChiRhoClin, Inc Ă&#x2022;Ă&#x20AC;Ă&#x152;Â&#x153;Â&#x2DC;Ă&#x192;Ă&#x203A;Â&#x2C6;Â?Â?i]Ă&#x160; Ă&#x160;Ă&#x201C;änĂ&#x2C6;Ă&#x2C6;Â&#x2021;Ă&#x2C6;ÂŁĂ&#x201C;Â&#x2122; ääx* xäĂ&#x2C6;

Approximately 60% of patients treated in both kinds of hospitals had minor severity, whereas the remainder had moderate to major severity of illness when admitted.

When investigators compared outcomes based on the admission severity of illness, they found a greater difference in mortality. In-hospital mortality was 0.46% among patients with moderate and major severity treated at nonaccredited centers. For the same group of patients, the mortality rate was 0.10% at accredited centers.

Investigators believe that the improved outcomes were not related to higher volume of surgery performed at accredited centers but rather to â&#x20AC;&#x153;their ability to manage patients with a higher severity of illness and their ability to recognize and rescue the patient when major complications arise,â&#x20AC;? said Dr. Nguyen.

Significance Questioned One expert questioned whether the findings are significant. Edward Livingston, MD, professor of surgery at UT Southwestern Medical Center, Dallas, and a contributing editor for the Journal of the American Medical Association, pointed out that the mortality difference is extremely small, and might not be accurate because investigators did not include body mass index (BMI) in their analysis. â&#x20AC;&#x153;This canâ&#x20AC;&#x2122;t be risk-adjusted if you do not account for BMI.â&#x20AC;?

He argued that the figures suggest that 250 patients would need to be operated on at a center versus a nonaccredited center of excellence to benefit one patient.

At $100,000 per year for accreditation, â&#x20AC;&#x153;thatâ&#x20AC;&#x2122;s a lot of money to try to save one life, if in fact, the results are true. â&#x20AC;&#x153;The math would suggest that it would cost $25 million to save one life, which is beyond the bounds of the $50,000 cost to offset one quality-adjusted year of life that is generally accepted as the threshold for cost-effectiveness,â&#x20AC;? he said.

Dr. Nguyen agreed the difference was small but argued that it is clinically significant. â&#x20AC;&#x153;When we are talking about mortality, itâ&#x20AC;&#x2122;s a clinically relevant parameter.â&#x20AC;?

Both accredited and nonaccredited centers had identical results in terms of overall complications (2.3% for both), and similar results for ICU stay (8% vs. 7.3%) and 30-day readmission (2% vs. 2.5%). However, mean hospital length of stay was 0.3 days shorter at accredited centers (2.4Âą3.1 vs. 2.7Âą4.2 days; P<0.01) and mean costs were $3,758 less ($13,203Âą$4,028 vs. $16,961Âą$9,172; P<0.01).

The study was not designed to measure outcomes beyond the period of hospitalization. As such, 30-day and one-year mortality were not assessed. Moreover, the results are based on outcomes from academic and teaching hospitals and might n not reflect the overall population.

21

GastroenteroloGy & endoscopy news • april 2012

From the Literature

Bariatric Surgery Associated With Reduced Risk For Cardiovascular-related Events, Mortality

By George Ochoa

Compared with usual care, bariatric surgery is associated with a reduced number of cardiovascular (CV) deaths and a lower incidence of CV events in obese adults, according to the results of a Swedish study published in the Jan. 4 issue of the Journal of the American Medical Association (Sjöström L et al.

2012;307:56-65).

In the ongoing, nonrandomized, prospective, controlled trial, 2,010 obese patients underwent bariatric surgery (gastric bypass, banding or vertical banded gastroplasty) and 2,037 matched control patients received usual care. Patients were recruited over a 13-year period (from Sept. 1, 1987 to Jan. 31, 2001) and followed for a median of 14.7 years. Patients had a body mass index (BMI) of at least 34 kg/m2 in men and at least 38 kg/m2 in women.

‘The main finding, based on predefined aims, is that bariatric surgery is in fact reducing the incidence of CV events.’

—Lars Sjöström, MD, PhD

There were 28 CV deaths in the surgery group versus 49 in the control group (adjusted hazard ratio [Hr], 0.47; 95% confidence interval [CI], 0.29-0.76; P=0.002). Also, the number of total firsttime fatal or nonfatal CV events (myocardial infarction or stroke, whichever came first) was lower in the surgery group (199 events) than in the control group (234 events; adjusted Hr, 0.67; 95% CI, 0.540.83; P<0.001).

“The main finding, based on predefined aims, is that bariatric surgery is in fact reducing the incidence of CV

events,” said lead author Lars Sjöström, MD, PhD, professor, Institute of Internal Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden. “This will further strengthen the position of bariatric surgery as an important obesity treatment.”

In post hoc analyses, a higher baseline insulin concentration, but not

preoperative BMI, was associated with a better outcome of bariatric surgery on CV events. Weight loss after surgery was not related to a reduced incidence of CV events. Dr. Sjöström expressed hope that his study findings will “stimulate further research trying to identify mechanisms behind weight change–independent favorable effects of bariatric surgery.”

Dr� Sjöström reported the following financial disclosures: unrestricted Swedish Obese Subjects grants from Sanofi-aventis and Johnson & Johnson since 2007; lecture and consulting fees from AstraZeneca, Biovitrum, Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann LaRoche, Johnson & Johnson, Lenimen, Merck, Novo Nordisk, Sanofi-aventis and Servier; and stock in Lenimen� He is also chairman of the board for Lenimen�

22

GastroenteroloGy & endoscopy news • april 2012

New Studies Show Plateauing Rates of Obesity, Conflicting With Earlier Data

By George Ochoa Two new articles by researchers from the Centers for Disease Control and Prevention (CDC) suggest that obesity has been plateauing in the United States in recent years, in contrast to the rising trend that has long characterized the problem.

Although this news would appear to be promising, it conflicts with other studies that suggest obesity rates are not only rising but will continue to increase for years to come.

The new articles, which report that obesity trends are leveling off, are based on data from the National Health and Nutrition Examination Survey (NHANES).

One trial found that from 2009 to 2010, obesity prevalence in adults aged 20 years or older was 35.5% among men and 35.8% among women, with no significant change compared with 2003 to 2008 (P=0.08 for men and P=0.24 for women; Flegal KM et al. JAMA 2012;307:491-497). Over the 12-year period from 1999 to 2010, obesity did not increase significantly among women (annual change in odds ratio [AOR], 1.01; 95% confidence interval [CI], 1.00-1.03; P=0.07), but did slightly for men (AOR, 1.04; 95% CI, 1.021.06; P<0.001). Additionally, increases in obesity were statistically significant for non-Hispanic black and Mexican American women (P=0.04 and P=0.046, respectively).

“There’s been no [large or notable] change in recent years,” said Cynthia L. Ogden, PhD, MRP, epidemiologist and branch chief in the Division of Health and Nutrition Examination Surveys, National Center for Health Statistics, CDC, Hyattsville, Md., and lead author of the study.

The other study found no difference in obesity prevalence among men or women between 2007-2008 and 2009-2010 (P=0.62 and P=0.65, respectively). The obesity prevalence in children and adolescents between 2009 and 2010 was 16.9% (Ogden CL et al. JAMA 2012;307:483490). But the analysis over a 12-year period indicated a significant increase in obesity prevalence from 1999-2000 to 2009-2010 in males aged 2 to 19 years (OR, 1.05; 95% CI, 1.01-1.10) but not in females (OR, 1.02; 95% CI, 0.98-1.07).

Overall, the plateau of obesity rates represents a marked change from the past, the study authors noted, reporting a substantial increase in population prevalence of obesity of almost 8% from 1980 to 1994, and a similar increase from 1994 to 2000.

“Our data suggest [obesity among U.S. adults] is plateauing,” said Katherine M. Flegal, PhD, senior research scientist, National Center for Health Statistics, and investigator on both studies.

The results from several other recent studies, however, conflict with those from the JAMA articles. A 2011 Lancet article projected that there will be 65 million

more obese adults in the United States by 2030 (Wang YC et al. 378:815-825).

Additionally, a study presented at the 2011 American Heart Association Scientific Sessions by Mark Huffman, MD, MPH, used trends based on NHANES data from 1988 to 2008 to make forward linear projections to 2020. Applying these methods, the researchers estimated that

43% of men and 42% of women would be obese by 2020.

Dr. Huffman, assistant professor in the Departments of Preventive Medicine and Medicine-Cardiology, Northwestern University Feinberg School of Medicine, Chicago, said in an email that

23

GastroenteroloGy & endoscopy news • april 2012

‘Note that both the current prevalence as well as our projections of obesity prevalence are both unacceptably high … necessitating population- and individual-level interventions.’

—Mark Huffman, MD, MPH he stands by his 2020 estimates “based on past projections.” He observed that an increasing obesity trend among males aged 2 to 19 years between 1999 and 2010 “may increase the prevalence of obesity among adults 20 years and older, despite recent trends. Note that both the current

prevalence as well as our projections of obesity prevalence are both unacceptably high and lead to substantial premature death and disability, necessitating population- and individual-level interventions.”

Michael Nusbaum, MD, chief of bariatric surgery, Morristown Medical

Center, Morristown, N.J., and president, New Jersey chapter of the American Society for Metabolic and Bariatric Surgery, observed that “the level of rise in obesity has decreased. The growth curve has started to flatten out, though not completely.” But, he added, “There’s such a push against obesity, we should be seeing a decrease and we aren’t.” An obesity prevalence rate of about 35% “is alarming and we shouldn’t downplay it.”

Asked about studies projecting a continuing increase in obesity, Dr. Flegal said, “We don’t predict the future.” But

lead author of the Lancet study, Y. Claire Wang, MD, ScD, assistant professor, Department of Health Policy & Management, Columbia Mailman School of Public Health, New York City, asked: “Can we really avoid making any projections? Or are we equally confident that the trend will go flat from now on so we don’t need to anticipate or prepare for the increase in disease burdens?” n Drs. Flegal, Huffman, Nusbaum, Ogden and Wang reported no relevant financial disclosures.

25

GastroenteroloGy & endoscopy news • april 2012

From the Literature

Teammate Support Spurs Individual Weight Loss in Online Fitness Competition least 5% of their body weight tended to be on the same team (P<0.001). Those who reported being more highly influenced by their peers had an increased likelihood of achieving a 5% weight loss (odds ratio, 1.20). Additionally, team captains lost more weight than team members, possibly due to their increased motivation and engagement in the campaign.

By ViCtoria stern Social pressures are known to affect how we dress or interact with others, but these peer influences also may help us lose weight.

According to a new study, team members who participated in a weight loss competition significantly influenced each other’s weight loss (Leahey TM et al. Obesity 2012 Feb 7. [Epub ahead of print]). Investigators found that participants not only lost similar amounts of weight, but also reported that the support and encouragement from their teammates helped motivate them to shed the pounds.

“This is the first study to show that in these team-based campaigns, who’s on your team really matters,” said lead author Tricia Leahey, PhD, researcher with The Miriam Hospital’s Weight Control and Diabetes research Center and assistant professor of psychiatry and human behavior at Alpert Medical School, both in Providence, r.I. “Being surrounded by others with similar health goals all working to achieve the same thing may have really helped people with their weight loss efforts.”

In recent years, online team-based weight loss interventions have been popping up with more frequency to help encourage weight loss in large groups of people. This study is the first to examine the effects of teammates on individual weight loss during one such competition.

The findings are based on the results of the Shape Up rhode Island 2009 campaign, a 12-week online program open to adult residents of the state. Participants joined a team and competed with others in weight loss, physical activity and pedometer steps. The program included 3,330 individuals who were overweight or obese. There were 987 teams; 76% of participants were women with an average body mass index of 31.2 kg/m2 (±5.3 kg/m2).

The investigators found that overweight or obese individuals who completed the competition reported losing 4.2% (±3.4%) of their initial body weight.

Weight loss was similar among teammates (P<0.001), and those who lost at

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Questions, comments, suggestions?

Contact the Editor 212.957.5300 x277 cgordon@mcmahonmed.com

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26 Lifesaver continued from page 1

Medicine (Zauber AG et al. 2012;366:687-696) give strong support to the hypothesis that screening colonoscopy and polypectomy reduces mortality associated with colorectal cancer (CRC).

“We’re very pleased,” said Sidney J. Winawer, MD, Paul Sherlock Chair in Medicine, Memorial-Sloan Kettering Cancer Center, New York City, and one of the lead NPS researchers. “This paper is consistent with the paper we published in 1993, which showed a reduction in incidence of colon cancer as a result of colonoscopy and polypectomy. The question then was were we preventing lethal cancers? Now we’ve demonstrated both an incidence reduction and a mortality reduction, so that’s a powerful combination.”

The study included 2,602 patients who were referred for initial colonoscopy at an NPS center between 1980 and 1990 and whose procedures included the removal of adenomas. During a median follow-up of 15.8 years, 1,246 subjects died, and 12 deaths were attributable to CRC. With an estimated CRC mortality rate of 25.4% in the general population as estimated from the Surveillance, Epidemiology, and End Results program, these findings suggest that colonoscopy with polypectomy results in a 53% reduction in CRC-related deaths, the authors said.

“This supports what we’ve always suspected; that colonoscopy would lead to a decrease in mortality,” said Lisa Richardson, MD, MPH, associate director for science, Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, in Atlanta. “When you look back over the past 10 or 15 years, there’s been quite a decrease in CRC mortality and incidence because of CRC screening, so it is exciting to see more data to support that.”

Deaths from CRC have indeed diminished over the past two decades, as have deaths from lung, prostate and breast cancer, according to another recent study (Siegel R et al. CA Cancer J Clin 2012;62:10-29). Although it’s likely that the decrease in lung cancer mortality is associated with a drop in tobacco smoking, for the other three cancer sites it seems logical that better screening and earlier detection and treatments have had a significant effect.

“The reduction in deaths is no doubt related to improved treatment, and probably also to earlier detection, finding more tumors in earlier stages where our treatments are more effective,” said Durado Brooks, MD, MPH, director, Prostate and Colorectal Cancers, American Cancer Society. “But certainly it is believed that screening has played a significant role in the decrease in incidence and the decrease in death rates that we’ve seen in CRC across the country.”

New Data Challenge Naysayers The timing of the study and the flurry of positive news coverage it generated could not be more fortuitous, as cancer screening procedures have come under increasing scrutiny in recent years. The last time colonoscopy caught so much attention from the lay press was on the

GastroenteroloGy & endoscopy news • april 2012

heels of a study that suggested the procedure misses more cancers than people thought (Baxter NN et al. Ann Intern Med 2009;150:1-8). And colonoscopy has not stood alone in negative publicity—the age recommendation for the first mammogram to screen for breast cancer was challenged in 2010 (US Preventive Services Task

‘This study is groundbreaking because it ends the argument about whether or not removing adenomatous polyps translates into saving lives.’

—David Greenwald, MD

‘This paper supports the clinical practice of screening colonoscopy in this difficult time when all screening is being challenged.’

—Sidney J. Winawer, MD

Force. Ann Intern Med 2009;151:716-726), and testing for prostate-specific antigen to screen for prostate cancer was recently dismissed as ineffective (Luckmann R. Ann Intern Med 2011;154:JC1-JC2).

The new data from the NPS paper quiet doubts regarding the effectiveness of colonoscopy as a screening method for CRC. “This paper supports the clinical practice of screening colonoscopy in this difficult time when all screening is being challenged,” Dr. Winawer said. “Our study demonstrates that if you remove polyps, you reduce incidence and mortality. If we did not demonstrate that, there would be no point in doing screening colonoscopy.”

“This study is groundbreaking because it ends the argument about whether or not removing adenomatous polyps translates into saving lives,” Dr. Greenwald added.

Quality and Access Still Hurdles A caveat of the new study is that the colonoscopies performed in the NPS were of the highest caliber. The procedures were done by some of the top endoscopists in the country who were instructed to clear the colon with a high degree of confidence.

“If that was not the case, the protocol called for a repeat colonoscopy,” Dr. Winawer said. “We had a fairly high repeat rate of 13% for a second colonoscopy, and occasionally there was a third colonoscopy performed.

So that did influence the outcome.”

These findings certainly validate the potential of colonoscopy to reduce both the incidence of and death from colon cancer—but the degree to which the study’s findings will translate to the general population remains to be seen.

“In order to [duplicate] the results from studies like this, it will be necessary for all colonoscopy screening to be of the highest quality, and that means excellent preparations and well-trained colonoscopists,” Dr. Greenwald said.

“High-quality screening is the goal.

There’s no point in being screened if the screen is not of high quality.”

Quality is a top priority, but so are access to and compliance with available screening modalities. An article published in the same issue of The New England Journal of Medicine compared fecal immunochemical testing with colonoscopy and found the latter to be superior in identifying polyps (Quintero E et al. N Engl J Med 2012;366:697-706). However, compliance with both tests was abysmal, and for colonoscopy was particularly poor (see, “Colonoscopy Versus FIT: Similar Rates of Cancer Detection, but Compliance an Issue,” page 27). In the United States, although the proportion of people eligible for CRC screening who get screened has climbed substantially in the past decade, at 65.4%, it still falls short of the CDC’s Healthy People 2020 goal of 70.5% (Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 2011;60:884-889).

Ongoing trials—including the Barcelona trial, the NordICC (Nordic Initiative on Colorectal Cancer) trial and the Veterans Affairs trial—are attempting to answer questions about the effectiveness of screening colonoscopy in the general population. It will be some time, however, before those trials have been concluded and their findings published. For now, the NPS data stand as strong evidence in support of screening colonoscopy and polypectomy.

“Through its previous work, the NPS showed that we could decrease the incidence of colon cancers by removing polyps. But this study is certainly the largest and longest-term follow-up of this group of increasedrisk patients, and I think it clearly shows a decrease in the likelihood of people dying of colon cancer after having a polyp removed,” Dr. Brooks affirmed. “This study is very important in supporting what we had believed, but had not had the hard data to indisputably n document.”

None of the doctors interviewed for this article reported any relevant conflicts of interest.

APRIL 2012

Brought to You by

REPORT Redefining the Protocol for Managing Hemorrhoids Management Strategy

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roundtable discussion among leading colorectal surgeons on the appropriate use of medical therapy for the management of hemorrhoidal disease was held on July 28, 2011 in Chicago, Illinois. The discussion resulted in a consensus that there is a need to redefine the role of medical therapy as the foundation of the management of hemorrhoidal disease.

Most current treatment algorithms present hemorrhoid management in a linear fashion, starting with medical therapy and progressing to office or surgical procedures depending on the type and severity of symptomatic hemorrhoids. This approach gives the impression that medical therapy is reserved only as an initial therapy for mild hemorrhoidal disease.

However, as Glenn Parker, MD, chief of the Division

Faculty Stephen Cohen, MD, FACS, FASCRS Colorectal Surgeon Atlanta Colon and Rectal Surgery, P.A. Marietta, Georgia

Sanjay Jobanputra, MD, FACS Colorectal Surgeon North Shore University Hospital Manhasset, New York

Anne Le, MD Colorectal Surgeon Colorectal Surgical Associates Houston, Texas

Glenn Parker, MD, FACS, FASCRS Chief, Division of Colon and Rectal Surgery Director, Gastrointestinal Oncology Jersey Shore University Medical Center Oakhurst, New Jersey

Supported by

Gary Siemons, MD, FACS, FASCRS Colorectal Surgeon Virtua Health System Centennial Surgical Center Voorhees, New Jersey

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Thrombosed Excision

External

Large All symptomatic hemorrhoids Internal grades I-IV External Mixed Medical management

Hemorrhoidectomy

Internal

Mixed

Grades I-III Office procedures Rubber band ligation Infrared coagulation Sclerotherapy

Grades III-IV Surgical procedures Hemorrhoidectomy Stapled hemorrhoidopexy HAL/THD

Refractory or unable to tolerate

Figure 1. Hemorrhoid management algorithm.

Medical therapy may be used throughout disease management. Practice parameters describing patient evaluation, hemorrhoid classification and grading, and use of procedures have been published by the American Society of Colon and Rectal Surgeons.

HAL, hemorrhoid arterial ligation; THD, transanal hemorrhoidal dearterialization Based on reference 1.

of Colon and Rectal Surgery and director of Gastrointestinal Oncology at Jersey Shore University Medical Center in Oakhurst, New Jersey, said, “We should not view surgery as necessarily a failure of medical management or as a reason not to use it again.” In practice, medical therapy should be the cornerstone of therapy for nearly all types and severities of symptomatic hemorrhoids throughout disease management, with procedural or surgical treatments added as needed depending on the type and severity of hemorrhoidal disease (Figure 1).1 As Gary Siemons, MD, colorectal surgeon at the Centennial Surgical Center in Voorhees, New Jersey, said, “Medical management is the hallmark of treatment because most patients are going to

2

respond to it.” Medical therapy can be used in combination with and after any procedural treatments. It should be the primary modality for management of hemorrhoidal disease because it is the only approach that addresses the underlying causes.

According to Dr. Parker, “You have to correct the underlying cause, that’s why medical management is the foundation.”

Hemorrhoidal Disease: Multifactorial Etiology and Pathogenesis Hemorrhoids are believed to contribute to anal continence, and hemorrhoidal symptoms are a result of the deterioration of

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Table 1. Etiology and Pathogenesis of Symptomatic Hemorrhoids Elevated anal sphincter pressure Bowel habits Constipation Pregnancy Aging Weakened supporting connective tissue Possible hereditary component

Table 2. Medical Management Fluid 6-8 eight-ounce glasses of water per day Fiber Up to 30 g/d total dietary fiber Topical Anti-inflammatory analgesic Sitz bath Flavonoids Based on references 3 and 5.

Chronic venous insufficiency Stagnation, stasis of blood, and clotting in prolapsed tissue Inflammatory response that results in dilation and increased permeability and fragility Based on references 2-4.

the normal anatomic structure of hemorrhoids. Hemorrhoids are composed of blood vessels and connective tissue stroma, covered by the epithelial lining of the anal canal. The blood vessels form a plexus of arteriovenous shunts. The hemorrhoidal cushions are anchored by connective tissue fibers that start in the epithelial lining and penetrate the internal sphincter.2 The vascular cushions congest during a Valsalva maneuver or when intra-abdominal pressure is increased, intensifying the action of the anal sphincter and enabling the anal canal to remain closed. Decongestion is achieved by a rapid decrease in anal tone and allows rapid emptying of the rectal content.3 A lowfiber diet can produce hard stools and constipation resulting in repeated and prolonged straining that may contribute to the development of hemorrhoidal symptoms (Table 1). Straining to complete evacuation serves to congest the vascular cushions and may contribute to the downward displacement of the hemorrhoids.

Aging also is thought to be one of the primary factors contributing to symptomatic hemorrhoids. Connective tissue becomes weak, disintegrated, loose, and broken in older individuals. The weakened connective tissue fibers are not able to anchor the hemorrhoids against the downward active forces in the anal canal. As the cushions are displaced downward, the external hemorrhoids start to bulge inside and outside of the anal canal.2

One of the pathogenic processes now understood to be implicated in symptomatic hemorrhoids is chronic venous insufficiency (CVI).4 “CVI is probably more of a factor than the medical community in general understands,” Dr. Siemons said. Stagnation, stasis of blood, and clotting develop in the vascular plexuses of the prolapsed anal cushions. Stasis activates white cells to release inflammatory mediators and cause an inflammatory response that results in dilation and increased permeability and fragility of the vessel wall. The anal cushions therefore are easily injured by the passage of stool and may begin to bleed.4 It is unclear if CVI is a causative factor, contributes to pathogenesis, or both. “It’s a vicious cycle. A little bit of incompetence leads to more dilatation, more inflammatory reaction. It’s probably an initiating factor and becomes more and more prominent over time,” said Dr. Siemons.

The Role of Medical Management The goal of medical therapy is to manage symptoms by addressing the underlying causes of elevated anal pressure and CVI in order to decrease strain on the hemorrhoidal cushions (Table 2). “Stop treating just symptoms,” said Dr. Siemons, “and try to intervene in the pathogenesis of hemorrhoids.” One component of medical therapy involves dietary changes. Patients should be advised to drink 6 to 8 eight-ounce glasses of water per day. The patient’s diet should include 25 to 30 g of fiber per day. Other therapies that can relieve symptoms include topical anti-inflammatory agents, topical analgesics, and sitz baths. Epsom salt and plastic sitz baths that fit over standard sized toilets can be found at most pharmacies.

Another important facet of medical management, often overlooked in the United States, is the use of flavonoids.

Flavonoids are derived from citrus and manage the metabolic aspects of CVI through multiple mechanisms. Flavonoids

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improve venous tone by inhibiting norepinephrine degradation.

They also inhibit the inflammatory response to maintain the integrity of the capillary endothelium and reduce edema.4,5 In the United States, the level of dietary flavonoid intake is low due to the relatively small amount of fruits and vegetables consumed by Americans.6-8 Hesperidin, a flavanone related to diosmin, was found to increase the efficacy of vitamin C in the treatment of scurvy, which has venous fragility as part of its presentation.9,10 It was discovered in a hospital setting that if this flavonoid was withheld from hospital patients who were given vitamin C, they still developed capillary fragility, which is part of CVI.11 This finding suggests a distinct dietary requirement for flavanones for the management of CVI, especially after a diagnosis of hemorrhoids is made.

Vasculera™, a specially formulated medical food indicated for the dietary management of CVI disorders under physician supervision, is marketed in the United States as one component of the Analpram Advanced ® Kit. Each tablet of Vasculera™ contains 600 mg of diosmin, the primary ingredient, and 30 mg of alka4-complex, a buffering agent that helps manage gastrointestinal (GI) effects associated with high-dose flavonoids. Dosing is 1 tablet 3 times daily for 4 days, followed by 1 tablet twice daily for 9 days. Vasculera™ can then be taken as a maintenance dose if necessary for the management of hemorrhoids. The ingredients in Vasculera™ are Generally Recognized as Safe (GRAS), and there are no known cases of overuse.5 Diosmin has been demonstrated to manage hemorrhoid symptoms, including bleeding,12,13 and the alka4-complex has been shown to buffer acidic venous pH.14 The Analpram Advanced® Kit also comes with Analpram HC ® (hydrocortisone acetate 2.5% and pramoxine HCl 1%) Cream 2.5% and AloeClean™ aloe-infused wipes. Anal wipes containing astringents (eg, witch hazel) are not recommended because they can cause perianal irritation with extended use.

An Integrated Approach Because all types and severities of hemorrhoidal disease share the same underlying causes, medical therapy should be considered in most cases. Medical therapy may be used alone, prior to procedures, or in combination with office

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procedures. Medical therapy alone may be effective for patients who refuse procedures or for whom procedures are contraindicated and also may help manage hemorrhoidal disease while waiting for test results or scheduling a procedure. “Medical management does not necessarily stop,” said Stephen Cohen, MD, colorectal surgeon at Atlanta Colon and Rectal Surgery, P.A., in Marietta, Georgia. “You continue with the medical management as you do the treatment, versus the old-fashioned way, where you stop doing everything because you’ve done a hemorrhoidectomy.” In fact, patients often benefit [from] a continuation of medical therapy after office procedures or surgery to speed their recovery and help prevent recurrence. “We’re looking at a spectrum of disease,” said Dr. Parker. “As we treat the disease process we’re going to shift gears.” Patients who have improved with medical therapy alone also may benefit from continued medical management that can prevent recurrence by managing the metabolic aspects of CVI. An integrated approach, built around medical management, presents an opportunity to address the underlying cause of hemorrhoidal disease from the very beginning of treatment, and to continue to address it for as long as the patient requires treatment.

Conclusion Hemorrhoidal disease is a common and often chronic condition. Medical management can be an important component of therapeutic plans for symptomatic hemorrhoids because it is the only approach that addresses the underlying causes. Because all types and severities of hemorrhoidal disease share the same underlying causes, medical therapy should be considered in most cases. Depending on disease severity, medical therapy can be integrated with procedural approaches and also may help manage hemorrhoidal disease while waiting for test results or scheduling a procedure. An important facet of medical management is the use of a flavonoid such as diosmin that manages the metabolic aspects of CVI through multiple mechanisms. Disease management that includes medical therapy, with an unwavering focus on underlying causes, presents the best opportunity for longterm success.

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Managing an Underlying Cause of Hemorrhoids: Chronic Venous Insufficiency Chronic Venous Insufficiency

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ymptomatic hemorrhoids are part of the spectrum of CVI disorders, which also includes varicose veins of the lower limbs. CVI is the deficient return of venous blood flow leading to metabolic imbalances that cause inflammation in the venous walls and supporting tissues. As Anne Le, MD, colorectal surgeon at Colorectal Surgical Associates in Houston, Texas, said, “It’s an abnormality in the blood flow which leads to a chronic inflammatory state.” CVI is caused by venous hypertension (VH), which results from dilation of veins and valvular incompetence.4 It is unclear whether CVI is a causative factor in hemorrhoidal disease, contributes to pathogenesis, or both. “It’s a vicious cycle. A little bit of incompetence leads to more dilation, more inflammatory reaction. It’s probably an initiating factor and becomes more and more prominent over time,” said Dr. Siemons. VH aggravates these metabolic imbalances leading to further metabolic changes (Figure 2). These changes promote further inflammation in vascular tissue leading to edema and tissue damage.

Downward displacement of hemorrhoids caused by straining and aging also can contribute to CVI and VH. Hemorrhoids are composed of blood vessels and connective tissue stroma, covered by the epithelial lining of the anal canal.

The hemorrhoidal cushions are anchored by connective tissue fibers that start in the epithelial lining and penetrate the internal sphincter.2 Hard stools and constipation may result in repeated and prolonged straining that can contribute to the downward displacement of the hemorrhoids. Furthermore, the connective tissue becomes weak, disintegrated, loose, and broken in older individuals. The weakened connective tissue fibers are not able to anchor the hemorrhoids.

As the cushions are displaced downward, the hemorrhoids start to bulge inside and outside of the anal canal.2 Blood begins to pool in the hemorrhoids, and contributes to the cascade of events associated with the metabolic imbalances of CVI. Stagnation, stasis of blood, and clotting develop in the vascular plexuses of the prolapsed anal cushions. These changes in blood flow cause an increased expression of adhesion molecules on the endothelium. Leukocytes bind to the adhesion

Stasis, thrombosis, inflammation, and bleeding

CVI

Venous hypertension

Inside a normal hemorrhoid

Inside a symptomatic hemorrhoid

Figure 3. Chronic venous insufficiency.

Figure 2. Role of CVI in the pathogenesis of hemorrhoidal disease.

CVI, chronic venous insufficiency

Blood stasis in the vascular plexuses of the prolapsed anal cushions lead to white blood cell infiltration of the venous walls and release of inflammatory mediators.

The resulting inflammatory response causes dilation and increased permeability and fragility of the vessel wall.

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OH O O

HO CH3

HO HO

O

OO

OH

OCH3

OCH3

Diosmetin

O

HO

OH HO OH

OH

O

O

OH

Liver O-R OCH3 O-R

O

R-O

O

Diosmetin glucuronides

Figure 4. Chemical structure of diosmin.

Diosmin is metabolized into active forms diosmentin and diosmentin glucuronides.

Based on references 16-22.

Table 3. Metabolic Effects of Diosmin That Manage CVI Smooth muscle contractility

Inhibits norepinephrine degradation

Antiinflammatory

Scavenges reactive oxygen species

Increases lymphatic vessel contraction frequency and amplitude

Inhibits production of inflammatory mediators: prostaglandin E2, prostaglandin F2b, thromboxane B2 CVI, chronic venous insufficiency

6

molecules, infiltrate the venous walls, and release inflammatory mediators such as oxygen-free radicals, prostaglandins, and thromboxane.15,16 The resulting inflammatory response causes dilation and increased vessel permeability and fragility (Figure 3).

The anal cushions are therefore easily injured by the passage of stool and may begin to bleed.4 Traditionally, hemorrhoidal disease has been treated by a combination of medical management, office procedures, and surgical procedures. Medical management has included increased water and fiber intake, topical anti-inflammatory and analgesic agents, and sitz baths.

Increases in water and fiber intake address the increased anal pressure associated with constipation and straining, an underlying cause of hemorrhoids. Topical anti-inflammatory and analgesic agents, and sitz baths, help alleviate symptoms but do not address the causes of the disease. Likewise, procedural and surgical approaches alter the normal anatomy of the hemorrhoids without rectifying the underlying causes.

Management of CVI Looking at all of the current treatment modalities, it is apparent that none of them addresses CVI. The recent introduction in the United States of a diosmin flavonoid as part of a medical food product provides a tool to manage CVI under physician supervision. Diosmin is a naturally occurring flavonoid that has vasoconstrictive and anti-inflammatory properties in the vascular plexuses of hemorrhoids (Figure 4).16-22 Diosmin

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is manufactured by extracting the flavonoid hesperidin from citrus rinds, which is then converted to diosmin.23 The mechanism of action of diosmin is 2-fold (Table 3). First, diosmin inhibits the degradation of norepinephrine, enhancing venous and lymphatic tone by increasing smooth muscle contractility to improve drainage and reduce edema.24 Second, diosmin manages the response to VH by scavenging reactive oxygen species and inhibiting the production of inflammatory mediators.25 “Diosmin improves the metabolic aspects of CVI,” said Sanjay Jobanputra, MD, colorectal surgeon at North Shore University Hospital in Manhasset, New York. Both activities may help protect the endothelial cells lining the vessels from damage associated with oxidative stress and inflammation.

“What we’re trying to do is break the vicious cycle of metabolic changes,” said Dr. Parker.

D/H Placebo a

Bleeding

b

Pain

b

Discomfort b

Discharge

b

Proctitis 0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Severity score

The efficacy of diosmin was evaluated in 2 randomized, doubleblind, placebo-controlled trials. In the first trial, 100 patients with a history of hemorrhoidal disease who were actively suffering from an acute episode were randomized to the control group or received 3 tablets of 500 mg diosmin twice a day for 4 days, followed by 2 tablets (90% diosmin/10% hesperidin) twice a day for 3 days.12 Groups were matched for sex, age, weight, risk factors, characteristics of the current episode, and number of previous acute attacks. Patients with an associated anal fistula or permanent prolapse were excluded from the study.

The primary outcome was symptom severity at day 7. At study end, there was a statistically significant improvement in bleeding, pain, discomfort, discharge, and swelling in the diosmin group compared with the placebo group (Figure 5).

According to Dr. Cohen, “If you look at day 7 of the surgeon examining the patient, everything that they looked at— bleeding, pain, discomfort, discharge—was significantly better using the medication.” Overall improvement in symptoms was greater in the diosmin group at day 2, and continued to increase through day 7 (Figure 6). This outcome was supported by the finding that topical and systemic analgesic use diminished in the diosmin group relative to the placebo group starting at day 3 (Figure 7). Furthermore, using the prior year as baseline, patients in the diosmin group experienced a significant improvement in the duration and intensity of acute episodes compared with placebo (Figure 8).

Adverse events (AEs) were primarily mild GI distress, and there were no serious AEs. “The study shows that it works.

It’s efficacious, early stage, and then there’s a longer-term study,” said Dr. Cohen.

The second clinical trial examined the efficacy of diosmin over a longer period of time. One hundred twenty patients with symptomatic hemorrhoids having had an acute episode within the last 2 months were randomized to the control group or received 2 tablets (500 mg; 90% diosmin/10% hesperidin) twice daily for 2 months.13 Groups were matched for sex,

Figure 5. Comparative symptomatology at day 7.

Values expressed as mean ± SEM. Scores are based on clinical examination where 0 = null, 1 = mild, 2 = significant, and 3 = severe. a

P=0.006.

b

P<0.01.

D/H, diosmin/hesperidin; SEM, standard error of the mean

D/H Placebo

3

a a

Improvement Score

Efficacy of Diosmin in the Management of Symptomatic Hemorrhoids as Part of CVI

a

2 a a

1 a

0 2

3

4

5

6

7

Day

Figure 6. Improvement in overall symptomatology.

Values expressed as mean ± SEM. Scores are based on patient logs where 0 = no improvement, 1 = mild improvement, 2 = significant improvement, and 3 = disappearance. a

P<0.001.

D/H, diosmin/hesperidin; SEM, standard error of the mean

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A

D/H Placebo

2.5

B

3.0 2.5

Utilization per Day

2.0

Utilization per Day

D/H Placebo

1.5 a

1.0

a a

0.5

2.0

*

1.5

a a

1.0

a a

0.5 a

a

0.0

1

0

2

3

4

5

6

7

0.0

0

Day

1

2

3

4

5

6

a

7

Day

Figure 7. Topical and systemic medication utilization.

(A) Topical analgesic use (lidocaine 5%). (B) Systemic analgesic use (glafenineb 200 mg). a

P<0.05.

b

Glafenine is an NSAID available previously in Europe; currently withdrawn in most countries.

D/H, diosmin/hesperidin; NSAID, nonsteroidal anti-inflammatory drug

Diosmin Placebo 22.5 a Duration 75.5

10.2 a Intensity 61.2 0

10

20

30

40

50

60

70

80

Patients without a decrease in symptomatology, %

Figure 8. Comparison of acute episodes before and after start of treatment.

The reduction in duration and intensity of episodes is based on patient comparison with previous episodes before start of study. a

8

P<0.05.

age, percentage of patients with a history of symptomatic hemorrhoids greater than 3 years, and the number, duration, and severity of acute episodes on entry. Patients with permanent irreducible prolapse, external thrombosed hemorrhoid, anal fissure, or previous hemorrhoidectomy were excluded.

Efficacy outcomes measured the effect of diosmin on both acute and chronic hemorrhoidal symptoms. Acute episodes during the 2-month treatment period were shorter, milder, and less frequent in the diosmin group compared with the placebo group (Table 4). Furthermore, the percentage of patients with 1 or more acute episodes was significantly lower in the diosmin group (40% vs 76%; P<0.05). After treatment for 2 months, the mean scores for chronic clinical features were decreased significantly more in the diosmin group (Figure 9).

The pooled chronic clinical feature scores also were significantly lower for the diosmin group compared with placebo at the end of the study (1.1±0.2 vs 4.0±0.5 for symptoms; P<0.01; and 0.9±0.2 vs 2.0±0.3 for signs; P<0.01).

Furthermore, the percentage of improved patients in the diosmin group was significantly higher for each chronic clinical feature compared with placebo (Figure 10). Therapy was tolerated to a similar degree in both groups, and no significant AEs were noted. “There’s an issue of CVI in hemorrhoidal disease and now there’s a product that will help with this problem,” said Dr. Cohen.

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Table 4. Characteristics of Acute Episodes D/H

Placebo

P valuea

Frequency (n)

0.6±0.1

2.1±0.2

<0.01

Duration (days)

2.6±0.1

4.6±0.4

<0.01

Severity

1.1±0.2

1.6±0.1

<0.01

Values expressed as mean ± SEM. Severity was scored on a scale of 1 to 3, with 1 the least severe. a P<0.01, c2 test.

D/H, diosmin/hesperidin; SEM, standard error of the mean

Diosmin

Placebo

2.5

2.5

Erythema

Erythema

Edema

2.0

Edema

2.0

1.5

Tenesmus Pruritus

1.0

Bleeding on examination

0.5

Pain Mean Sccore

Mean Score

Pain 1.5

Tenesmus Pruritus

1.0

Bleeding on examination

0.5

Discharge Bleeding

0

Inclusion

2 months

Discharge Bleeding

0

Inclusion

2 months

Figure 9. Change in mean scores per clinical feature in each group.a Scores based on a scale of 0 to 3, with 0 = none and 3 = severe. Comparisons between groups were based on 2-way analysis of variance. There was no significant difference between groups at inclusion; at 2 months. a

P<0.01, symptom improvement in each category.

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D/H Placebo Pain

98 a

Tenesmus

98 a

Edema

98 a

Discharge

97 a

Erythema Bleeding on examination Bleeding

95 a

Pruritus

86 a

94 a 91 a 0

20

40

60

80

100

Improved patients at 2 months, %

Figure 10. Proportion of improved patients after 2 months. a

P<0.01, c2 test.

D/H, diosmin/hesperidin

Use of Diosmin in the Medical Management of Chronic Symptomatic Hemorrhoids as Part of CVI Diosmin, marketed as part of Vasculera™ (diosmiplex), is available as one component of the Analpram Advanced® Kit. Diosmiplex is a medical food defined as “a food which is formulated to be consumed or administered enterally under the supervision of a physician, and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.”

Each tablet of Vasculera™ contains 600 mg of 95% diosmin,

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5% hesperidin, and 30 mg of alka4-complex, a buffering agent that helps manage GI effects associated with highdose flavonoids.16 The absorption of diosmin is improved by micronization of the particles to less than 2 mm in diameter.4 The ingredients in Vasculera™ are GRAS. Dosing is 1 tablet 3 times daily for 4 days, followed by 1 tablet twice daily for 9 days.16 The Analpram Advanced ® Kit also comes with Analpram HC® (hydrocortisone acetate 2.5% and pramoxine HCl 1%) Cream 2.5% and AloeClean™ aloe-infused wipes. As Dr. Cohen said, “It’s a real advantage that everything comes together. It makes it easy for patients.” Anal wipes containing astringents (eg, witch hazel) are not recommended because they can cause perianal irritation with extended use.

Conclusion Medical management including diosmin should be at the core of any management plan for symptomatic hemorrhoids because it is the only approach that addresses the underlying causes of the chronic disease state. “Stop treating just symptoms and try to intervene in the pathogenesis of hemorrhoids,” said Dr. Siemons. CVI is an underappreciated chronic contributor to symptomatic hemorrhoids. As Dr. Siemons said, “CVI is probably more of a factor than the medical community in general understands.” CVI can now be managed with diosmin under physician supervision. Diosmin has been demonstrated to manage the metabolic aspects of CVI by improving venous tone and inhibiting the production of inflammatory mediators.

“You have chronic venous stasis leading to an inflammatory cycle, which leads to breakdown of blood vessels and bleeding, and that’s why you use Vasculera™,” said Dr. Parker. In clinical studies, diosmin improves the clinical features associated with symptomatic hemorrhoids, including bleeding, pain, and inflammation as part of CVI.12 The use of diosmin and other medical management approaches should be the foundation of any treatment plan that also may incorporate procedural or surgical therapies, depending on disease grade and severity.

As Dr. Cohen said, “I’ve heard for years, ‘Why can’t you make a pill to take care of my hemorrhoids?’ Patients feel like they’re really doing something for their hemorrhoids.”

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Clinical Experience with Medical Management of Symptomatic Hemorrhoids Management Strategy

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edical therapy is defined as including the use of increased water and fiber intake, flavonoids, topical anti-inflammatory and anesthetic agents, and sitz baths.

Flavonoids are naturally occurring compounds derived from citrus that have vasoconstrictive and anti-inflammatory properties in the vascular plexuses of hemorrhoids.16 A consensus was reached that medical therapy including flavonoids may be appropriate and should be considered for all types and severities of symptomatic hemorrhoids because it is the only approach that addresses the underlying causes of symptomatic hemorrhoids as part of the chronic disease state. These causes include elevated anal pressure and CVI, the deficient return of venous blood flow leading to a vicious cycle of VH, inflammation, and metabolic changes.4,16 Topical antiinflammatory agents, topical analgesics, and sitz baths may be appropriate in managing symptoms but do not address underlying causes. The consensus developed by roundtable participants is reflected in the treatment algorithm shown in Figure 1. One option that can be included in medical management is the use of flavonoids. The flavonoid diosmin has been demonstrated in randomized, placebo-controlled, double-blind clinical trials to manage hemorrhoidal symptoms, including bleeding, inflammation, pain, anal discomfort, tenesmus, and anal discharge.12,13 Unfortunately, no specific guidance has been published on the application of flavonoids in the various clinical scenarios that are likely to be encountered. Recently, a medical food that has diosmin as its primary ingredient has been introduced in the United States.

It is marketed as Vasculera™ (diosmiplex), and is available as one component of the Analpram Advanced ® Kit, which also includes topical anti-inflammatory and anesthetic agents, and aloe-infused wipes. Vasculera™ is indicated for the clinical dietary management of CVI under physician supervision.

To help define appropriate uses of medical management, roundtable participants shared their experiences using the Analpram Advanced ® Kit in the management of symptomatic hemorrhoids.

The Analpram Advanced® Kit The Analpram Advanced® Kit includes Vasculera™, Analpram HC® (hydrocortisone acetate 2.5% and pramoxine HCl 1%) Cream 2.5% and AloeClean™ aloe-infused wipes. According to Dr. Cohen, “It’s a real advantage that everything comes together. Patients get one Kit, they take the pills, and the cream and wipes are there. It makes it easy for them.” Each tablet of Vasculera™ contains 600 mg of 95% diosmin/5% hesperidin and 30 mg of alka4-complex, a buffering agent that helps manage GI effects associated with high-dose flavonoids.2 The ingredients in Vasculera™ are GRAS. Dosing is 1 tablet 3 times daily for 4 days, followed by 1 tablet twice daily for 9 days.4 The following clinical scenarios exemplify the consensus of the roundtable that medical therapy, including the use of flavonoids, should be the cornerstone of therapy for nearly all types and severities of symptomatic hemorrhoids throughout management of chronic disease, with procedural or surgical treatments added as needed depending on the type and severity of hemorrhoidal disease.

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Clinical Scenario:

Medical Management Alone

T

he goal of medical management is to address the underlying causes of elevated anal pressure and CVI in order to decrease strain on the hemorrhoidal cushions. Many patients will respond to medical management alone and its consistent use also may expand the pool of patients who respond well without requiring procedural approaches. In the following case example, the Analpram Advanced® Kit was successfully used as part of medical management for a patient with a history of chronic rectal bleeding.

Case 1 Stephen Cohen, MD, FACS, FASCRS Introduction A 56-year-old man presented with a complaint of a 5-year history of bleeding per rectum. He described bright red blood when he wipes, with a little bit in the stool. There was no complaint of pain, prolapse, or other symptoms. A recent colonoscopy was normal. His hemoglobin level was 11.5 g/dL, which is just slightly below normal. The rectal exam was normal. There was very little in the way of prolapsed tissue, and no evidence of fissures, abscesses, or tumors.

Diagnosis, Treatment, and Outcome The patient was diagnosed with moderately bleeding grade I hemorrhoids. He was already taking a fiber product and was not happy using Proctofoam-HC® because he considered it messy and ineffective, and he was unhappy with the applicator. The patient was started on the Analpram Advanced® Kit. Bleeding continued for the first 3 days, and then stopped, with an occasional blood-tinged wipe at days 10 through 14. Bleeding has not resumed 6 months post-treatment.

Discussion “This is someone who does not need an operation or any kind of office therapy,” said Dr. Cohen. “He is a perfect candidate for medical therapy and the Analpram Advanced® Kit to stop the bleeding. His main concern was bleeding. In this case, there wasn’t anything to band. In the past—before the Analpram Advanced® Kit— I would have just done fiber, fluids—see you back in 6 weeks and hopefully things will stop. If you have trouble down the line, it’s something either we can do in the office or we’ll put you on a repeat of the medication you had—see you back in a year.” The only treatment for bleeding grade I hemorrhoids is medical management or infrared coagulation [IRC], and IRC is only indicated once every 90 days. You don’t band unless you have to.”

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Clinical Scenario:

Medical Management of Underlying Disease to Avoid Procedures or Manage Symptoms Prior to Procedures

E

ven with medical management, patients often may need additional treatment. The need to add procedural approaches will depend on disease grade and severity. Medical therapy can be integrated with procedural approaches and also may help manage hemorrhoidal disease as part of CVI while waiting for test results or scheduling a procedure. Additionally, some patients who may be candidates for an office or surgical procedure may wish to defer or avoid a procedure, or the procedure may be contraindicated. In the following cases, the Analpram Advanced® Kit was used to manage underlying disease, thus avoiding procedures or managing symptoms prior to a procedure.

Case 2

Case 3

Sanjay Jobanputra, MD, FACS

Anne Le, MD

Introduction

Introduction

A 32-year-old woman presented with a complaint of severe anal pain for the preceding 24 hours, during which time she had used Preparation H ®, and a lump around her anus. The lump was located in the left lateral area and was between the size of a pea and a grape. The area was too tender for a rectal examination using an anoscope. She had a history of mild bleeding with bowel movements off and on for many years. She also complained of some mild constipation.

A 48-year-old man presented with painless rectal bleeding with bowel movements. The patient had a history of IV drug use and was HIV positive. His CD4 count was 410, his viral load was nondetectable, and he was currently on Atripla®.

His father had colon cancer at age 79. A rectal examination revealed grade III hemorrhoids with reducible prolapse and moderate swelling and inflammation in all 3 positions.

Diagnosis, Treatment, and Outcome The patient was diagnosed with a thrombosed external hemorrhoid and bleeding, likely caused by internal hemorrhoidal disease. The patient was offered local excision because the pain was so acute. She refused excision and opted for a more conservative approach that included the Analpram Advanced® Kit, increased water and fiber intake, and a stool softener. Compliance was excellent. She had resolution of pain within 24 hours. When she returned for follow-up at 2 weeks there was complete resolution of the thrombosed external hemorrhoid. The patient continued to have occasional bleeding, stating that it may have improved a little. A rectal examination using an anoscope revealed grade II internal hemorrhoids. She was offered rubber band ligation but declined, saying that she was pleased with the results.

Discussion Dr. Jobanputra said, “[The patient] absolutely did not want excision; she wanted to try something else. If you look at the normal results, some people will be better within 24 to 48 hours, but it seemed like maybe it improved, sped up a little. If she had been agreeable I would still have excised her, but I feel a little more comfortable not excising … because people seem to be getting resolution a little quicker. If we’re not going to excise then I will see them in 2 weeks just to make sure everything is fine. If they do progress to something then we put them on a follow-up schedule; otherwise I see them in about 3 months.”

Diagnosis, Treatment, and Outcome This patient’s rectal bleeding was presumably caused by internal, prolapsed hemorrhoids, but given his family history a colonoscopy was recommended prior to invasive treatment of the hemorrhoids. In the meantime, the patient was treated with the Analpram Advanced ® Kit to help diminish the rectal bleeding. The colonoscopy was normal.

After the colonoscopy the patient was reevaluated for his hemorrhoid disease. He still had some bleeding, although it was significantly better. He was very happy with his results, but he also complained of anal fullness and continued to have prolapse on examination, which was not improved.

He was offered rubber band ligation, and the procedure was successful. The Analpram Advanced ® Kit was not prescribed during the ligation.

Discussion According to Dr. Le, “He hadn’t had any colon cancer screening. His HIV disease was very well controlled, he didn’t have the sexual risk factors, and he was healthy otherwise.

So my thought process was that with the family history of colon cancer he needed to go ahead and get that done.

That’s what I do in my practice—rule out proximal sources of bleeding, especially if you have risk factors. I scheduled him for a colonoscopy, but in the meantime with the bleeding that he was having, which was of significance, especially to him, I placed him on the Analpram Advanced® Kit as a temporizing measure. We got him scheduled for the colonoscopy, and while he was on the Kit waiting for his colonoscopy the bleeding actually improved and I was able to do the colonoscopy.”

13

REPORT

Clinical Scenario:

Medical Management in Combination with Office Procedures

D

epending on disease severity, medical therapy can be used in combination with most procedural treatments and can be continued after those procedures. An integrated approach, built around medical management, presents an opportunity to address the underlying cause of hemorrhoidal disease from the very beginning of treatment, and to continue to address it as long as the patient requires treatment for the chronic condition. The following case illustrates the use of the Analpram Advanced® Kit in combination with rubber band ligation as a part of medical management of the underlying chronic disease.

Case 4 Stephen Cohen, MD, FACS, FASCRS Introduction A 48-year-old woman presented with an 8-month history of rectal pressure, prolapse with bowel movements, and the occasional need to manually reduce the protruding tissue. She was experiencing mild rectal discomfort when sitting for long periods of time and with bowel movements on occasion. Her normal once-daily bowel habit had not changed. She had experienced a recent bout of diarrhea but was now better. She takes fiber daily and has had only one episode of bright red blood on straining. She used Anusol-HC® suppositories daily for 3 days, but felt they were messy, painful, and not helpful. Bleeding and problems with hygiene prompted her to seek treatment. Rectal examination revealed symptomatic internal hemorrhoids of moderate severity in all 3 locations.

There were some small external skin tags, but no evidence of fissures or abscesses. A recent colonoscopy was normal.

Diagnosis, Treatment, and Outcome The patient was diagnosed with grade II to III hemorrhoids, with inflammation all the way around the anal canal. She was prescribed the Analpram Advanced ® Kit and fiber, and went through 3 banding procedures, each 2 weeks apart. After the 2-week course of the Kit and the first band her symptoms were almost completely resolved and her bleeding had improved. Prolapse and hygiene problems were improved by the final procedure.

Discussion “This is a very common problem,” said Dr. Cohen. “I don’t think that the Analpram Advanced® Kit is going to help that much with the prolapse, but that is why I like using it in combination. All the bleeding stopped, and the prolapse is better. The question is: Before the Kit would this have gotten better just with the rubber bands? I don’t know. I think the bleeding gets better a lot quicker with this. And I think the patients are much happier with it. Patients are eager to help in the management of their disease. They do not like suppositories and they love the idea of a pill to help shrink down their swollen tissue.”

14

REPORT

Clinical Scenario:

Medical Management After Surgery

P

atients may benefit from a continuation of medical therapy after office procedures or surgery to help manage their recovery. “We should not view surgery as necessarily a failure of medical management or as a reason not to use it again,” said Dr. Parker. The following case illustrates how the Analpram Advanced® Kit can be used after surgery.

Case 5 Glenn Parker, MD, FACS, FASCRS Introduction A 52-year-old woman presented from another institution 3 months post-elective conventional closed Ferguson hemorrhoidectomy with severe circumferential mucosal prolapse, pain, discharge, and discomfort. Her perianal area was severely inflamed, externally and internally. Her incision sites were together, but not perfectly healed.

There was no sign of infection or abscess. The overall appearance was similar to what would be expected 1 week after surgery.

Diagnosis, Treatment, and Outcome The patient was diagnosed with persistent rectal mucosal prolapse post-hemorrhoidectomy. She had a history of 13 pregnancies and 13 children, so there may have been an element of prolapse syndrome that was not adjusted with surgery. She was prescribed a 2-month course of the Analpram Advanced® Kit, increased water intake, sitz baths, stool softeners, and ibuprofen. Swelling was resolved at 2 months. Symptoms improved dramatically with no plan for additional surgery. Prolapse diminished as well as pain and discomfort.

Discussion According to Dr. Parker, “She was just in agony, but I did not want to re-operate on her. She wasn’t drinking enough liquids. I don’t use a lot of fiber with my patients post-hemorrhoidectomy. I just find that if they take a lot of pain medication and a lot of fiber without drinking enough liquids they can get impacted. She required 2 months of therapy with the Analpram Advanced® Kit and she was not 100% because the pathology was so severe initially, but I would say she was 80% better. It did help me avoid taking her back to the operating room.

It did make her symptoms 80% better, so I think in this particular case it was a great help. I recommended in follow-up that she maintain high fluids, make sure she’s on a stool softener, continue her sitz baths, and reevaluate at 4 to 6 months.”

Conclusion Medical management including flavonoids should be viewed as the cornerstone of a comprehensive management program for hemorrhoidal disease because it is the only approach that can address the underlying causes of the condition. As Dr. Parker noted, “You have to correct the underlying cause, that’s why medical management is the foundation.” This approach places medical therapy at the core of a management plan, with procedural or surgical treatments added as needed depending on the type and severity of hemorrhoidal disease. Medical therapy including the Analpram Advanced® Kit, which provides a flavonoid, can be an important component of management plans in a wide range of clinical scenarios. It can be used alone or in combination with any procedural treatments and may be continued after those procedures. “Medical management is the hallmark of therapy, because most patients are going to respond to it,” said Dr. Siemons.

15

REPORT

References 1.

Ravadeneira D, Steele S, Ternent C, Chalasani S, Buie D, Rafferty J. Practice parameters for the management of hemorrhoids (revised 2010). Dis Colon Rectum. 2011;54(9): 1059-1064.

2.

Haas PA, Fox TA, Haas GP. The pathogenesis of hemorrhoids.

Dis Colon Rectum. 1984;27(7):442-450.

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Kaidar-Person O, Person B, Wexner SD. Hemorrhoidal disease: a comprehensive review. J Am Coll Surg. 2007;204(1):102-117.

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Lyseng-Williamson KA, Perry CM. Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers, and haemorrhoids. Drugs. 2003;65(1):71-100.

TM

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Vasculera MI; 2010.

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Serdula MK, Gillespie C, Kettel-Khan L, Farris R, Seymour J, Denny C. Trends in fruit and vegetable consumption among adults in the United States: behavioral risk factor surveillance system, 1994-2000. Am J Public Health. 2004;94(6):1014-1018.

[package insert]. Ferndale Laboratories: Ferndale,

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Beecher GR. Overview of dietary flavonoids: nomenclature, occurrence and intake. J Nutr. 2003;133(10):3248S-3254S.

8.

Sampson L, Rimm E, Hollman PC, de Vries JH, Katan MB. Flavonol and flavone intakes in US health professionals.

J Am Diet Assoc. 2002;102(10):1414-1420.

9.

Scarborough H, Bacharach AL. Vitamins and hormones.

New York, NY: Academic Press, 1949;1-55.

10. Garg A, Garg S, Zaneveld LJD, Singla AK. Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytother Res. 2001;15(8):655-669.

11. Scarborough H. Observations on the nature of vitamin P and the vitamin P potency of certain foodstuffs. Biochem J. 1945;39(3):271-278.

14. Data on file. Ferndale Healthcare, Inc.: Ferndale, MI. 15. Smith PD. Neutrophil activation and mediators of inflammation in chronic venous insufficiency. J Vasc Res. 1999;36(suppl 1): 24-36.

16. Vasculera [product information]. Primus Pharmaceuticals, Inc. Scottsdale, AZ; 2010.

17. Cova D, De Angelis L, Giavarini F, Palladini G, Perego R. Pharmacokinetics and metabolism of oral diosmin in healthy volunteers. Int J Clin Pharmacol Ther Toxicol. 1992;309(1):29–33.

18. Serra H, Mendes T, Bronze MR, Simplício AL. Prediction of intestinal absorption and metabolism of pharmacologically active flavones and flavanones. Bioorg Med Chem. 2008;16(7):4009-4018.

19. Kanaze FI, Bounartzi MI, Niopas I. A validated HPLC determination of the flavone aglycone diosmetin in human plasma. Biomed Chromatogr.

2004;18(10):800-804.

20. Amiel M, Barbe R. Study of the pharmacodynamic activity of daflon 500 mg. Ann Cardiol Angeiol (Paris). 1998;47(3):185-188.

21. Labrid C. Pharmacologic properties of Daflon 500 mg. Angiology.

1994;45(6 Pt 2):524-530.

22. The pharmacological, pharmacodynamic and clinical properties of a new vasoactive agent: a meeting on Dalfon 500 mg. Int Angiol.

1988;7(2 suppl):1-43.

23. Monograph. Diosmin. Alt Med Rev. 2004;9(3):301-311.

24. Araujo D, Viana F, Osswald W. Diosmin therapy alters the in vitro metabolism of noradrenaline by the varicose human saphenous vein. Pharmacol Res. 1991;24(3):253-256.

25. Jean T, Bodinier MC. Mediators involved in inflammation: effects of Daflon 500 mg on their release. Angiology. 1994;45(6 pt 2):554-559.

AK027 01/12

12. Cospite M. Double-blind, placebo-controlled evaluation of clinical activity and safety of Dalflon 500 mg in the treatment of acute hemorrhoids. Angiology. 1994;45(6 suppl 2):566-573.

13. Godeberge P. Daflon 500 mg in the treatment of hemorrhoidal disease: a demonstrated efficacy in comparison with placebo.

Angiology. 1994;45(6 suppl 2):574-578.

Copyright © 2012, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

16

SR125

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Ferndale Healthcare, Inc., and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

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GastroenteroloGy & endoscopy news • april 2012

From the Literature

Colonoscopy Versus FIT: Similar Rates of Cancer Detection, but Compliance an Issue New Study Finds Polyp Detection Better With Colonoscopy, but Patients Prefer FIT

By Monica J. Smith Fecal immunochemical testing (FIT) and colonoscopy screening for colorectal cancer (CrC) appear to have similar rates of cancer detection; but differences exist in polyp detection and subject preference, according to the preliminary findings of a long-term prospective, randomized controlled trial (Quintero E et al. N Engl J Med 2012;366:697-706).

compliance and the other to lesion yield.”

In the study, researchers randomized asymptomatic adults between the ages of 50 and 69 years to receive one-time colonoscopy (n=26,703) or FIT every two years (n=26,599), with a primary outcome of death from CrC at 10 years.

Participation was 24.6% for those in the colonoscopy arm and 34.2% in the FIT

‘There are two central lessons to be learned, one related to compliance and the other to lesion yield.’

—David A. Ahlquist, MD

‘There is probably a slight advantage to colonoscopy in terms of cancer prevention, but in terms of mortality outcomes, I’m not sure there will be a difference.’

—Theodore Levin, MD

“This was a big orchestration, and the investigators are to be commended for taking it on,” said David A. Ahlquist, MD, consultant in the Division of Gastroenterology and Hepatology, and professor of medicine at the College of Medicine, Mayo Clinic, in rochester, Minn. “Even at this early stage, there are two central lessons to be learned, one related to

arm (P<0.001). Findings of CrC were similar: 30 cases in the colonoscopy group (0.1%) compared with 33 cases in the FIT group (0.1%; odds ratio [or], 0.99; 95% confidence interval [CI], 0.61-1.64; P=0.99). However, adenoma detection was higher in the colonoscopy group—514 advanced and 1,109 non-advanced adenomas were found

via colonoscopy compared with 231 advanced and 119 non-advanced adenomas via FIT (or, 2.30; 95% CI, 1.972.69; P<0.001 for advanced adenomas; or, 9.80; 95% CI, 8.10-11.85; P<0.001 for non-advanced adenomas).

“FIT was at a bit of a disadvantage in this report because it was a one-time application, and the way it will be used in this program is every two years over a 10-year period,” said Theodore Levin, MD, physician site leader, associate chief of gastroenterology, Kaiser Permanente Medical Center, in Walnut Creek, Calif. “Some of the polyps that weren’t detected in this first round of FIT would likely be detected on subsequent rounds of screening. There is probably a slight advantage to colonoscopy in terms of cancer prevention, but in terms of mortality outcomes, I’m not sure there will be a difference.”

Polyp Yield and Complication Rates Although there was no statistically significant difference between the number of cancers detected in each arm of the study, overall lesion yield was much higher in the colonoscopy arm.

“For adenomas, one might expect this.

About twice as many were advanced adenomas, and roughly 10-fold more non-advanced adenomas were found in the colonoscopy group than in the FIT group,” Dr. Ahlquist said.

The dark side of the equation was in the difference between complication rates: 24 major complications occurred in the colonoscopy arm versus 10 in the FIT arm, which were primarily related to follow-up colonoscopies. “How that washes out over the whole study will be important,” Dr. Ahlquist said.

A potential oversight of the research is the lack of attention to serrated polyps, which may drive about 30% of CrC. “That’s a conspicuous absence in this paper,” Dr. Ahlquist noted. “They do mention a group of polyps that were non-neoplastic, but they say nothing else about that subset in the tables or in any further comment.

“It may be that the results between the two arms would be most discrepant for this important subset,” he continued. “It would have been nice to see the data; perhaps they are there and just need to be mined. I hope that will be part of this study going forward.”

At this point, it is difficult to predict

the primary outcome of the study, CrC mortality.

“There are potential benefits for either arm. It will be interesting to see how this all plays out,” Dr. Ahlquist said.

Participation and Compliance A major advantage of the less invasive test appears to be the rate of participation in the study. Although the majority of subjects were unwilling to be screened with either method, compliance was higher in the FIT arm, in which about one-third of patients underwent testing compared with about one-fourth of those in the colonoscopy arm.

Even more telling, perhaps, was that of 7,368 subjects who agreed to participate in the study and who were randomized to the colonoscopy group, 1,706 asked to cross over to the FIT group. In contrast, of 9,512 subjects who were randomized to the FIT group, only 117 asked to switch to the colonoscopy group.

“There was a 14-fold greater crossover toward FIT than colonoscopy,” Dr. Ahlquist said. “I think there is a real opportunity here to learn what drives participation, and we could glean some insights from further evaluation.”

Screening rates certainly can be raised through public outreach and education.

Since 2005, the proportion of Kaiser Permanente members eligible for CrC screening has gone from about 35% to about 80%.

“A lot of this is being driven through mailed outreach with FIT and from patientelected provider referral for colonoscopy,” Dr. Levin said. “you have to give people an option. About 40% to 50% of the U.S. population is not getting screened, and the only way we’re going to reach nationwide screening goals is by having something in addition to colonoscopy to offer patients.”

However, effective screening using FIT requires attention, perseverance and a solid infrastructure. “you need to be able to know who is due for screening, to deliver it to them in an easy and convenient way, and to make sure patients get a colonoscopy if their test is positive,” Dr. Levin said.

Dr� Ahlquist has licensed intellectual property to and is a minor equity investor in Exact Sciences; he also is a scientific adviser and research collaborator with Exact Sciences and is an inventor of licensed technology�

28

GastroenteroloGy & endoscopy news • april 2012

From the Literature

Recession Drives Down Screening Colonoscopy Use, Even Among Insured

By George Ochoa

Between December 2007 and June 2009, the use of screening colonoscopy among insured patients was lower than the two years before the recession began, according to a recent study by researchers at the University of north Carolina (UnC), Chapel Hill (Dorn SD et al. Clin Gastroenterol Hepatol 2012;10:278-284). out-of-pocket costs, such as copayments and coinsurance, were inversely related to screening use at all time points, but especially during the recession, the longest and most severe since World War II. Lead author Spencer Dorn, MD, MPH, assistant professor of medicine at UnC, said he was surprised that “continuously insured Americans reduced their use of this cost-effective, highly recommended preventive service.”

Prior to the study, it was unclear whether those who were continuously insured cut back on their use of health services and whether the services they cut back on were superfluous or necessary, Dr. Dorn said.

“We found that during the difficult economic times of the recession, insured Americans cut back on screening colonoscopy. Cutbacks were more pronounced among those with higher out-of-pocket costs ($300 or more vs. $50 or less), and were not met by a commensurate increase in the use of other screening modalities, such as fecal occult blood test or sigmoidoscopy.”

The study examined administrative data from 106 health plans to determine the monthly rates of screening colonoscopies performed in patients aged 50 to 64 years from 2005 to 2009. Dr. Dorn and his team found that screening colonoscopy rates diminished by 68.9 colonoscopies per 1 million individuals per month during the recession. They estimated that, in the United States as a whole, there were 500,000 fewer screening colonoscopies among commercially insured patients aged 50 to 64 years during the recession.

Durado Brooks, MD, MPH, director of Prostate and Colorectal Cancers at the American Cancer Society, in Atlanta, called the study “very important and useful” and “very well thought out.” one reason the paper is significant, Dr. Brooks said, is that it does not concern an uninsured population.

“This is an insured population—they have insurance, but copayments and deductibles serve as a financial barrier.”

Dr. Brooks also pointed out that the study is important in light of a loophole in the Patient Protection and Affordable Care Act regarding screening colonoscopy:

If, during the course of the procedure, a polyp is found and the procedure is reclassified as a therapeutic procedure, a Medicare patient can face unexpected costs. A bill introduced by rep. Charlie Dent (r-Pa.) and now in the House (Hr 4120) attempts to close the loophole by waiving, as the bill states, “coinsurance under Medicare for colorectal cancer screening tests, regardless of whether therapeutic intervention is required during the screening.”

Dr. Brooks also noted that the study was published around the same time as a survey from the national Center for Health Statistics, which reported in the first six months of 2011, one in three persons was in a family experiencing the financial burden of medical care.

“If we as a society value colonoscopy and other preventive services, we need to limit barriers,” he said. “Finances are a significant barrier.”

Dr. Dorn and colleagues called for

consideration of “policies to reduce patient cost sharing for colonoscopy and other recommended, cost-effective preventive services.”

Asked for an area of investigation that he would suggest as a follow-up, Dr. Dorn said, “the effect of waiving copayments and deductible requirements on colonoscopy utilization.”

Drs� Brooks and Dorn reported no relevant financial disclosures�

Inadequate Bowel Preps: A Problem With Potentially Serious Consequences

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

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GastroenteroloGy & endoscopy news • april 2012

Drug Shortage continued from page 1

diazepam and IV lorazepam and have directed providers ... to use IV midazolam. However, we’re not counting on receiving any more shipments of any IV products until at least next week and maybe not until mid-February and do expect this shortage to be long-term,” wrote Curtis Haas, PharmD, director of pharmacy at the hospital in an email to staff clinicians.

Dr. Haas said he knew the switch to

midazolam, although helpful, would only be a temporary solution; he anticipated there would be a domino effect causing midazolam to become scarce. He thus urged his colleagues to use oral benzodiazepines whenever possible “even in our intubated patients if the gut works,” and to choose propofol for hemodynamically stable intubated patients with gastrointestinal function. For hemodynamically unstable patients, he recommended “trying to use a fentanyl infusion along with intermittent or even ATC [aroundthe-clock] oral [benzodiazepines],” and

to use IV midazolam “as our preferred intermittent-dose benzodiazepine for anxiety and agitation if an oral route is not an option.”

Dr. Haas ended the email with an optimistic plea: “We ask that you pass this along to the appropriate providers and encourage judicious use of the IV products. Hopefully, if we all conserve as much as we can we’ll be able to squeeze by until our next shipment.”

Unfortunately, as soon as one shortage of sedatives or anesthesic agents is dealt with, another one crops up, Dr. Haas

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 with difficulty of colonoscopy (% of patients)6

50

Low*

49.1

Intermediate*

40 30 20

33.1

High*

34.2

20.0 15.4

10 0

Easy†

12.4

Difficult†

* Cleansing quality was determined by endoscopist grading using a 5-point scale. High = completely clean (score 5); 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. ©2011 Braintree Laboratories, Inc.

SU-12873

October, 2011

Brought to you as an educational service by

said in an interview.

“Just last week [late February], a shortage of preservative-free morphine for neuroaxial anesthesia hit us hard.

Whether it’s Astramorph or Duramorph and other equivalents, they’re simply unavailable. We hear there may be some new shipments coming in early March, but there’s no guarantees; we have maybe enough drug to last another seven to 10 days.”

In the meantime, Dr. Haas noted, his colleagues are looking at possible alternatives, such as fentanyl.

“It’s not preferred, but at least it’s an option,” he said. Preservative-free hydromorphone or bipuvicaine are other options for neuroaxial anesthesia, “but bipuvicaine has been in short supply as well. So this is very much still a moving target.”

Nationwide Problem Rochester is far from alone in feeling the pinch on key sedatives and anesthetics. Hospitals across the country are facing similar shortfalls in the supply of these and other important drugs, including certain treatments for cancer. One major facility in the Midwest listed no fewer than eight “new or high-priority” shortages during the second week of January. On the list: etomidate, heparin, ketorolac, morphine, ropivacaine and alfentanil. Those drugs joined a roster of nearly two dozen other agents, from diazepam and midazolam to lorazepam and rocuronium, in the “ongoing” category.

Reasons for the low supply are unclear, but involve production issues, indefinite plant shutdowns and drugmakers exiting the market.

When they are able, hospitals and clinics adapt by using substitute drugs or stretching their stocks to the limit.

When no alternative is possible, many facilities are turning to the so-called “gray market” for pharmaceuticals, a poorly regulated network of suppliers who charge several times the usual rate for the medications.

Keith Candiotti, MD, director of clinical research and chief of perioperative medicine at the University of Miami Leonard M. Miller School of Medicine, said his facility recently had been forced to pay as much as 20 times the regular rate for some anesthetic agents. Miami is having trouble finding fentanyl, sufentanil and even midazolam, Dr. Candiotti said, as well as diazepam and lorazepam.

“If you are willing to pay a premium you can find drug right now, but the supply is clearly reduced,” he said.

Gastroenterologists Feel the Pain Although some clinicians may have

see Drug Shortage, page 30

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GastroenteroloGy & endoscopy news • april 2012

Shortage continued from page 29

workarounds, others who depend heavily on benzodiazAn FDA representative contacted by Gastroenterology epines have been even harder hit by the shortages. Gas- & Endoscopy News said Dr. Hamburg would “carefully troenterologists, who rely on the drugs in combination review the letter and respond directly to the American with opioids for endoscopic procedures, are among them, College of Gastroenterology in a timely manner.” said Lawrence Cohen, MD, of Mount Sinai School of Medicine, in New York City.

‘We, like many other groups “We, like many other groups throughout the counthroughout the country, have been try, have been affected by the affected by the shortage of certain shortage of certain sedatives sedatives and opioid drugs.’ and opioid drugs,” Dr. Cohen said. “Currently, there are —Lawrence Cohen, MD shortages of fentanyl, midazolam and meperidine— the last one created by the unavailability of fentanyl, which has led to increased use and hoarding of meperidine.”

The fallout from the sedative shortage could range from limiting the number of endoscopic procedures to a shift in sedation methods, Dr. Cohen continued.

In early February, the American College of Gastroenterology wrote to FDA commissioner Margaret Hamburg, MD, to express its “deep concern” regarding the shortage of sedatives.

“Members across the United States are experiencing tremendous difficulty in accessing certain sedative and FDA To Address Shortages On Jan. 18, an FDA interim final rule took effect, narcotic agents that are used routinely during endoscopic procedures such as colonoscopy,” the letter stated. “We broadening the circumstances under which the sole urge FDA to use its full authority under current law manufacturer of certain critical drugs must report to to help resolve these shortages as supplies continue to the FDA about stopping production. No longer will a company that interrupts, but does not permanently dwindle.”

The letter, which cited shortages of fentanyl, meperi- cease, the manufacture of a critical drug be exempt from dine and midazolam, noted that the cost of endoscopy the requirement to give the FDA a six-month advance might rise if gastroenterologists turned to propofol and notice. According to the U.S. Department of Health required the presence of an anesthesiologist to perform and Human Services, the intent of the presidential executive order that led to the rule was “to take action monitored anesthesia care.

to help reduce and prevent drug shortages, protect consumers, and prevent stockpiling and exorbitant pricing of drugs in shortage.”

The rule does not set monetary penalties for failure to provide the required advance notice. Senate bill 296 and House bill 2245 do specify such fines; both bills await committee action.

Joseph M. Hill, director of federal legislative affairs for the American Society of Health-System Pharmacists, said there is a “downstream hope” that with more information, the FDA may be able to work behind the scenes to help stop shortages. Mr. Hill said 2011 was a recordsetting year for drug shortages, with 267 reported. At the time this article went to press, the FDA had at least 115 drugs on its list of current shortages, with the latest addition being IV zinc sulfate caused by “manufacturing delays.”

Drug shortages create more than logistic headaches for hospitals and clinics— they also pose ethical dilemmas. In a recent editorial in the American Journal of Health-System Pharmacy, Michael Manolakis, PharmD, PhD, assistant dean at the Wingate University School of Pharmacy, in Wingate, N.C., wrote of three such ethical problems: rationing, hoarding and gray market buying. To the last problem, he wrote: “Despite assurances of pedigree, a purchase from a secondary market represents a disruption in the integrity of the drug supply chain, and it places a patient at risk. Until every hospital refuses to pay the marked-up prices for short-supply products, the problem will persist.” n

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ASCO GI 2012

GastroenteroloGy & endoscopy news • april 2012

PAM4–cA19-9 Assay enhances Pancreatic cancer detection

By Caroline Helwick San Francisco—A serum-based enzyme immunoassay employing the PAM4 antibody combined with the serum marker CA19-9 detected stage I pancreatic cancer in nearly two-thirds of patients analyzed and it did so with high discriminatory power with respect to benign pancreatitis. The data were presented at the 2012 American Society of

Clinical Oncology Gastrointestinal Cancers Symposium (abstract 151).

“The PAM4-based assay to quantitate antigen in patient sera shows high sensitivity and specificity for the detection of pancreatic ductal adenocarcinoma [PDAC],” said David V. Gold, PhD, director of laboratory research at the Garden State Cancer Center in Morris Plains, N.J. “The results provide a basis for future studies of a combined PAM4 plus CA19-9 biomarker analysis for surveillance of

patients at high risk for the development of PDAC, which makes up approximately 90% of all pancreatic cancers and is highly lethal,” Dr. Gold added.

The study was conducted in collaboration with the University Medical Center in Gottingen, Germany, Johns Hopkins Medical Center and New York University Medical Center.

The assay was evaluated in more than 600 blood specimens, including 234 samples from patients with PDAC. The

analysis showed that combining analysis of PAM4 and CA19-9 led to greater sensitivity, while maintaining a high level of specificity. When used individually, PAM4 detected 74% of PDAC cases and CA19-9 detected 77%; combined, 84% of cases were detected, a significant improvement over the single tests (P<0.0001), Dr. Gold reported.

“The combined use of PAM4 and CA19-9 biomarkers gave enhanced detection of PDAC, versus either biomarker alone, and importantly, achieved this with high specificity,” Dr. Gold said.

For patients at high risk for PDAC, long-term follow-up using the PAM4

Fluorescent Laparoscopy Could Improve Staging, Treatment for Pancreatic Cancer

By Christina Frangou A new laparoscopic technique that uses fluorescent antibody markers and an LED light source has the potential to improve pancreatic staging and treatment, according to a report presented at the 2011 Clinical Congress of the American College of Surgeons. researchers took two antibodies commonly expressed by pancreatic

The LED light improves visualization of both the tumor and surrounding anatomy in the abdominal cavity.

ASCO GI 2012

GastroenteroloGy & endoscopy news • april 2012

immunoassay might help detect early PDAC, he added.

The specificity of the PAM4 assay was significantly greater than that of CA19-9, which gave positive results with more than twice as many patients having benign conditions, such as chronic pancreatitis. But although the PAM4 assay yielded positive results in approximately 20% of patients diagnosed with benign disease, these patients may not represent “false-positives,” Dr. Gold said. His team examined 32 specimens from patients with chronic pancreatitis and identified 10 neoplastic lesions. PAM4 reacted with these lesions, but not the completely benign, non-neoplastic tissues.

“Our results indicate that PAM4 is

‘It meets a need that doesn’t exist now with any of the diagnostic tests that we currently have.’

—Tushar Patel, MD not reactive with inflamed pancreatic tissue, but rather with neoplastic tissue that develops within the inflamed chronic pancreatitis parenchyma,” Dr. Gold explained. “We speculate that chronic pancreatitis patients, and perhaps others having disease that places them at high risk for the development of PDAC, who

are PAM4-positive, may harbor occult PDAC or have significant numbers of neoplastic precursor lesions producing the PAM4 biomarker.”

Tushar Patel, MD, professor of medicine at Mayo Clinic, Jacksonville, Fla., who moderated the session where the results were presented, said the assay

“looks extremely promising.”

“It meets a need that doesn’t exist now with any of the diagnostic tests that we currently have, but it needs to be validated in clinical practice and in different sets of patients,” he said.

“We also need to know if it offers long-term benefits in the identification of patients with early pancreatic cancer.

There are still critical issues that need to be worked out,” he concluded. n Drs. Gold and Patel reported no conflicts of interest.

MoviPrep® cancer and tagged them with a fluorescent marker, making the cancer cells light up in bright green or red. The researchers then administered the fluorescent antibodies into mice and studied the mice under LED light and during traditional laparoscopy.

Analysis showed that the LED light vividly identified the primary and metastatic tumors, with a sensitivity of 96% compared with 40% for traditional laparoscopy. Fluorescent laparoscopy rendered fewer false-positives than traditional laparoscopy and was sensitive enough to illuminate metastatic lesions smaller than 1 mm, which are not visible with a standard laparoscope.

The combination of fluorescent markers and LED light potentially could sharpen how physicians detect and treat pancreatic cancer in human patients, said investigators Michael Bouvet, MD, and robert M. Hoffman, PhD, both professors of surgery at the University of California, San Diego (UCSD).

The LED light improves visualization of both the tumor and the surrounding anatomy in the abdominal cavity of the mice. “you can see both the normal background of the anatomy plus the fluorescent tumor signal at the same time,” said Dr. Bouvet.

The technology also could be used to target tumor cells for treatment with drugs, but the work is still in early stages.

The surgeons plan to join forces with industry to secure FDA approval for clinical trials of the fluorescent antibodies in humans.

This research was funded by a five-year grant to UCSD and AntiCancer, Inc� from the National Cancer Institute� The UCSD team worked with AntiCancer Inc�, on the mouse model and with laparoscopic technicians at Stryker Corporation�

#1 prescribed branded purgative in the United States1

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 5%) are malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing (incidence 5%) 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

35

www.MoviPrep.com

36

ASCO GI 2012

GastroenteroloGy & endoscopy news • april 2012

BE Biomarkers continued from page 1

sometimes intestinal metaplasia from a patient with high-grade dysplasia [HGD] looks normal under a traditional microscope,” explained Randall Brand, MD, of the University of Pittsburgh, who presented the findings at the 2012 American Society of Clinical Oncology’s Gastrointestinal Cancers Symposium.

“We hypothesized that our approach could distinguish patients with BE

alone, without any dysplastic changes, from those who have early adenocarcinoma or high-grade dysplasia,” he continued. “It is based on the concept of field effect, which involves a genetic change distal from the neoplastic lesion, or cells that are abnormal but not normally picked up.”

The approach aims to detect HGD or esophageal adenocarcinoma through the analysis of nondysplastic intestinal

metaplasia, thus identifying a highrisk BE population. In other words, the strategy aims to risk-stratify patients, so that high-risk patients can be referred for further work-up, Dr. Brand said.

To do so, investigators used spatial-domain low-coherence quantitative phase microscopy (SL-QPM).

They found at least three new features that are based on light reflectance to detect abnormalities in cells that can

‘The problem with traditional monitoring is that sometimes MoviPrep

®

(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.

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.

USE IN SPECIFIC POPULATIONS 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.

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.

intestinal metaplasia from a patient with highgrade dysplasia looks normal under a traditional microscope.’

—Randall Brand, MD

Geriatric Use: Of the 413 patients in clinical studies receiving MoviPrep, 91 (22%) patients were aged 65 or older, while 25 (6%) patients were over 75 years of age. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients, and other reported clinical experience has not identified differences in responses between geriatric patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

OVERDOSAGE There have been no reported cases of overdose with MoviPrep. Purposeful or gross accidental ingestion of more than the recommended dose of MoviPrep might be expected to lead to severe electrolyte disturbances, including hyponatremia and/or hypokalemia, as well as dehydration and hypovolemia, with signs and symptoms of these disturbances. The patient who has taken an overdose should be monitored carefully, and treated symptomatically for complications.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Long-term studies in animals to evaluate the carcinogenic potential have not been performed with MoviPrep. Studies to evaluate potential for impairment of fertility or mutagenic potential have not been performed with MoviPrep.

STORAGE Store carton/container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

When reconstituted, store upright and keep solution refrigerated. Use within 24 hours.

PATIENT COUNSELING INFORMATION s Advise patients to read the Medication Guide included in the full prescribing information. s Advise patients who require a diet low in phenylalanine that MoviPrep contains phenylalanine. s Ask patients to inform you if they have trouble swallowing or are prone to regurgitation or aspiration. s Instruct patients that each pouch needs to be diluted in water before ingestion and that they need to drink additional clear liquid (e.g., water, clear soup, fruit juice without pulp, soft drinks, tea and/or coffee without milk) according to instructions. s Inform patients that oral medications may not be absorbed properly if they are taken within one hour of starting each dose of MoviPrep. s Tell patients not to take other laxatives while they are taking MoviPrep. s Tell patients that MoviPrep produces a watery stool (diarrhea) which cleanses the colon before colonoscopy. Advise patients receiving MoviPrep to adequately hydrate before, during, and after the use of MoviPrep. Patients may have clear soup and/or plain yogurt for dinner, finishing the evening meal at least one hour prior to the start of MoviPrep treatment. No solid food should be taken from the start of MoviPrep treatment until after the colonoscopy. s Tell patients that the first bowel movement may occur approximately 1 hour after the start of MoviPrep administration. Abdominal bloating and distention may occur before the first bowel movement. If severe abdominal discomfort or distention occurs, stop drinking MoviPrep temporarily or drink each portion at longer intervals until these symptoms diminish. If severe symptoms persist, notify your health provider.

Rx only Manufactured by: Norgine B.V. Hogehilweg 7 1101 CA Amsterdam Zuidoost Netherlands For: Salix Pharmaceuticals, Inc. Raleigh, NC 27615 © 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.

distinguish BE patients without cancer from those with HGD or cancer. These features include: • Average optical path length of the cell nucleus, or density of the nucleus • Intra-nuclear entropy, or the random structure of the cell nucleus • Intra-nuclear uniformity, or the texture uniformity of the cell nucleus Using these biomarkers, Dr. Bland and colleagues developed a prediction model, which they applied retrospectively to archived tissue from 60 patients with BE. Of these, 33 were known to have only intestinal metaplasia, whereas 27 had HGD or cancer.

The investigators found that the test had an overall accuracy rate of 87%. Sensitivity was 89% and specificity was 76% in distinguishing BE patients with HGD or adenocarcinoma from patients without dysplasia.

The authors believe this approach could help monitor patients with BE to identify a subset of those at high risk who need more intensive surveillance or who might be candidates for treatment.

For example, if a standard pathologic examination identifies any form of dysplasia, the patient would immediately undergo treatment and not undergo this special imaging test. But this test would be useful in the majority of patients whose pathology examination shows

ASCO GI 2012

GastroenteroloGy & endoscopy news • april 2012

37

‘We are hoping this technique will provide a way to simplify BE surveillance by identifying a subset [of patients who] warrant more intensive surveillance, and by eliminating the need to biopsy several areas of the esophagus.’

al. N Engl J Med 2011;365:1375-1383) showed the absolute risk for cancer to be 0.12%—much lower than the previously assumed risk of 0.5%—which called into question the rationale for current guidelines for surveillance of patients with BE without dysplasia. However, we do know that Barrett’s is a risk factor, because some patients do go on to develop dysplasia and cancer,” Dr. Bhutani said.

“As Dr. Brand and colleagues have

pointed out, intestinal metaplasia and high-grade dysplasia can look the same on endoscopy, creating issues with sampling error. What we really need are other predictors to tell us who would be more likely among patients with BE to have dysplasia or to develop cancer so we can be more aggressive with surveillance and follow-up in those patients—especially now that we have an opportunity to intervene at the dysplasia level by

ablation, to potentially prevent progression to cancer. The optical biomarkers being proposed by Brand et al, if validated, could play an important role in reaching this elusive goal. I encourage the investigators to validate their results n in further trials.”

Dr. Brand has received research funding from SomaLogic, Inc. Dr. Bhutani has no conflicts of interest.

—Randall Brand, MD

nondysplastic intestinal metaplasia or is ambiguous for dysplasia.

The researchers plan to expand the study population and test additional optical biomarkers, as well as improve on the current sensitivity and specificity of the test. If the test continues to look promising, they hope to validate the benefit of the test in a multicenter trial.

“Our technology works on biopsies that are acquired and can be done anywhere in the community with formalinfixed tissue,” Dr. Brand said. “We are hoping this technique will provide a way to simplify BE surveillance by identifying a subset [of patients who] warrant more intensive surveillance, and by eliminating the need to biopsy several areas of the esophagus.”

Manoop S. Bhutani, MD, professor of medicine and experimental diagnostic imaging, and director of endoscopic research and development at University of Texas MD Anderson Cancer Center, Houston, commented on the findings.

“Barrett’s esophagus is considered to be a strong risk factor for esophageal adenocarcinoma. The problem we have in following and surveying these patients is that the majority of patients with Barrett’s esophagus will never develop cancer while others will progress to dysplasia and cancer,” he said.

“A recent study (Hvid-Jensen F et

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GastroenteroloGy & endoscopy news • april 2012

Brush Biopsy increases Accuracy of Barrett’s diagnosis

By Rosemary Frei, MSc With one stroke of the brush, gastroenterologists can identify more patients who have dysplastic Barrett’s esophagus (BE).

Using computer-assisted brush biopsies can significantly increase the accuracy of screening for BE and dysplasia.

“There is no reason not to do this test.

It increases detection by about 40% and takes less than a minute, unless a longer

segment of Barrett’s esophagus is being examined, in which case it will take a little longer,” said Mark Rutenberg, founder and CEO, CDx Diagnostics, manufacturer of the test, called EndoCDx. “We anticipate that doctors will continue to do targeted forceps biopsies and supplement that with the computerassisted brush biopsy to test areas that otherwise would not be biopsied,” Mr. Rutenberg added. He also noted that only one more bottle of biopsy sample

per patient is required, and that the cost of the computer analysis, which is performed at CDx’s headquarters, is covered by medical insurance.

Seth A. Gross, MD, director of Advanced Endoscopy, Norwalk Hospital, in Conn., said that he has recently introduced the brush biopsy system to his hospital and finds it inexpensive and useful, particularly compared with the many high-end technologies that have not yet proven their worth in the clinic.

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“These are exciting results that have the potential to improve the diagnostic utility of what we do during upper endoscopy,” said Dr. Gross. “What’s unique about it is the computer analysis that’s behind it, which can sort through hundreds of thousands of cells to identify those with dysplasia.”

Data on brush biopsy, including two papers published in Digestive Diseases and Sciences last year, support the adoption of its use. One multicenter, community-based trial, conducted from 2004 to 2005, indicated that adding computer-assisted brush biopsies to forceps biopsy increased the BE detection rate by 39.8% ( Johanson JF et al. Dig Dis Sci 2011;56:767-772). Of 1,266 patients recruited in the community-based trial, 363 were diagnosed with BE by forceps

From the Literature

Tobacco Smoking Doubles Cancer Risk In Patients With Barrett’s Esophagus

By George Ochoa Smoking tobacco increases the risk for progression of Barrett’s esophagus (BE) to high-grade dysplasia (HGD) or cancer by twofold compared with never smoking. This risk was found in a study by Coleman et al, published in the February issue of Gastroenterology (2012;142:233-240).

Lead study author Helen Coleman, PhD, a postdoctoral research fellow at the Centre for Public Health, Queen’s University Belfast, in northern Ireland, told Gastroenterology & Endoscopy News, “It has previously been known that smoking was a risk factor for esophageal adenocarcinoma, but what wasn’t known was the stage at which carcinogens in tobacco smoke act.”

Historically, it was not clear whether smoking promoted the conversion of healthy tissue to inflamed tissue, inflamed tissue to BE, or BE to HGD or cancer.

“This study has shown for the first time that smoking is a major reason for progression from BE to high-grade dysplasia/cancer,” Dr. Coleman said.

For their study, Dr. Coleman and colleagues analyzed data from the population-based northern Ireland BE register, which includes all adults diagnosed with columnar-lined epithelium of the esophagus between 1993 and 2005 in

39

Photo courtesy of CDx Diagnostics

GastroenteroloGy & endoscopy news • april 2012

identify one more case of BE. Furthermore, the study revealed that in a subset of 848 patients with gastroesophageal reflux disease and no history of BE, the addition of brush biopsy to forceps biopsy pinpointed an additional 105 patients with BE (a 70.5% increase in BE detection). Dysplasia was diagnosed in 16

patients by forceps biopsy alone, with an additional 14 cases detected with brush biopsy; adding brush biopsy increased the detection of dysplasia by 87.5%.

The other study, which focused on a high-risk surveillance population at four large academic institutions, revealed that the addition of brush biopsy to forceps biopsy increased the yield of dysplasia by 42% (Anandasabapathy S et al. Dig Dis Sci 2011;56:761-766). This trial included 151 patients with BE (124 men, 27 women; mean age, 65 years); 117 of these patients had forceps and brush biopsy

specimens adequate for interpretation.

The overall yield of dysplasia with forceps biopsy alone was 25.2% (38 of 151 cases). Brush biopsy detected another 16 cases of dysplasia, increasing the dysplasia detection by 42%. The number needed to test to detect one more case of dysplasia in this trial was 9.4. The results were no different whether using standard or jumbo forceps, or when a forceps biopsy was taken every 1 or 2 cm. n Dr. Gross serves on the medical advisory board for EndoCDx.

EndoCDx from CDx Diagnostics

biopsy alone (28.7%) and another 146 cases (11.5%) when brush biopsy also was performed. Adding brush biopsy to forceps biopsy increased the overall detection of BE by 39.8% and resulted in a number needed to test of 8.7 to

northern Ireland. The researchers identified 3,167 patients who had ever been diagnosed with specialized intestinal metaplasia, and they collected data on lifestyle and clinical and demographic characteristics from hospital case notes.

Linking the northern Ireland BE register to the northern Ireland Cancer registry, the researchers identified which of these patients later developed esophageal HGD or adenocarcinomas of the esophagus or gastric cardia.

By Dec. 31, 2008, a total of 117 patients with BE had developed esophageal HGD or adenocarcinomas of the esophagus or gastric cardia. Using Cox proportional hazard models, the researchers determined that current tobacco smoking was significantly associated with increased risk for progression compared with never smoking, across all strata of smoking intensity (hazard ratio, 2.03; 95% confidence interval, 1.29-3.17).

Additionally, the researchers found that risk for progression of BE was not related to alcohol consumption. Body mass index was not associated with risk for neoplastic progression, although caution in interpretation was advised because of inconsistent collection of data on height and weight.

The researchers recommended that smoking cessation strategies be considered in patients with BE. Previously, there was no “evidence base to specifically target these patients with dedicated smoking cessation programs,” Dr. Coleman said. “Therefore, this would be a change of practice.”

Dr� Coleman reported no relevant financial disclosures�

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GastroenteroloGy & endoscopy news • april 2012

fdA Warns of risk for C. difficile–Associated diarrhea With PPis

By George Ochoa In a safety alert dated Feb. 8, the FDA warned that proton pump inhibitors (PPIs) may be associated with an increased risk for Clostridium difficile– associated diarrhea (CDAD). Evidence of a potential association between PPI use and risk for CDAD has been accumulating for some time.

“The FDA reacted to a string of

Get recognized for promoting Quality and Safety in your endoscopy unit

publications showing that PPI therapy is associated with C. difficile and C. difficile colitis,” said Ronnie Fass, MD, professor of medicine, University of Arizona College of Medicine, and director, GI Motility Laboratory, University of Arizona Health Sciences Center, both in Tucson. “It makes sense to me, and I think it is timely.”

Despite the warning, the FDA cautioned that patients should not stop taking prescription PPIs without first consulting

their health care providers. Patients taking over-the-counter PPIs should pay careful attention to the directions for use in the package inserts of those drugs, the FDA advised. The agency says it is working with manufacturers of PPIs to expand drug labels to include information about the increased risk for CDAD with PPI use.

“PPIs are a therapeutic class of drugs which have known efficacy and safety profiles, having a therapeutic benefit for many patients with the labeled

ASGE Endoscopy Unit Recognition Program ASGE’s Endoscopy Unit Recognition Program honors endoscopy units committed to the highest standards of quality and safety. It is the only national program recognizing quality and safety in the practice of endoscopy. > Gain recognition among healthcare professionals, public and private regulatory bodies, and patients as a unit dedicated to quality care > Prepare to meet the changing expectation of public and private regulatory bodies > Promote improvement and create uniformity in your practice > Other marketing tools for promoting your recognition Certain eligibility criteria apply, including completion of the ASGE Quality Course, “Improving Quality and Safety in your Endoscopy Unit,” by a representative of your unit within one year of program application. In 2012, ASGE will offer the course as follows: • March 9 – Scottsdale, AZ • July 14 – Dallas/Ft. Worth, TX • September 13 – Washington, DC Receive the ASGE Certificate of Recognition to proudly display in your endoscopy unit’s office

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Tips for Treating With PPIs By ronnie Fass, MD

• reassess if patients truly need PPI treatment.

• Ensure that patients receive the lowest dose possible, and avoid prescribing more than once-daily dosing.

• Consider switching to a different PPI. As an example, for cases of gastroesophageal reflux disease, instead of doubling the PPI dose, consider switching to a different PPI, or a PPI in combination with another anti-reflux therapy.

• Consider alternative approaches to chronic PPI treatment. For example, think about on-demand or intermittent dosing.

• Discuss long-term PPI use and adverse events with patients.

• If patients taking PPIs have diarrhea that is not self-limiting, consider a diagnosis of C� difficile infection.

indications,” stated Karen R. Mahoney, an FDA representative, in an email to Gastroenterology & Endoscopy News. “Recommendations to avoid PPIs as a therapeutic class are unwarranted,” she said.

“Since there are many causes of diarrhea, FDA is recommending that PPI users with diarrhea that does not improve should contact their health care professional to be evaluated for the possibility that their symptoms could represent CDAD,” she said.

The agency also advises that patients taking PPIs seek immediate medical care if they develop watery stool that does not resolve, abdominal pain and fever. PPI therapy should be limited to the lowest dose and the shortest duration appropriate for the condition being treated, according to the FDA. Mark Reid, MD, a hospitalist at Denver Health Medical Center, and associate professor of medicine, University of Colorado Health Sciences Center, both in Denver, noted that the FDA alert is “worded very gently. It’s a notification of a possibility of increased risk,” he said. “The wording fits the level of information we have.”

Dr. Reid added that “it’s reasonable to

41

GastroenteroloGy & endoscopy news • april 2012

From the Literature

Most C. difficile Infections Linked to Health Care Settings

Researchers Call for More Collaborative Efforts To Promote Infection Prevention

By George Ochoa overall, 94% of Clostridium difficile infections (CDIs) are related to health care exposures, according to a recent report from researchers at the Centers for Disease Control and Prevention (CDC; McDonald LC et al. MMWR Morb Mortal Wkly Rep 2012;61:157-162). Despite the known association between CDI and hospitals, the researchers found that 75% of these infections began among patients not currently hospitalized, including recently discharged patients, outpatients and nursing home residents.

Fifty-two percent of CDIs treated in hospitals were present on admission.

Some cases occurred in patients who were exposed to multiple health care settings, the investigators noted. For example, 20% of hospital-onset CDIs occurred in recent residents of nursing homes. Also, 67% of infections that had their onset in nursing homes occurred in patients who were recently discharged from an acute care hospital.

Also of note was a 20% decline over approximately 21 months in the pooled CDI rate among 71 hospitals that participated in CDI prevention programs in three states (Illinois, Massachusetts and new york). The prevention programs focused primarily on infection control, although the Massachusetts program included an antibiotic stewardship component as well.

Infection control strategies included early reliable detection of cases, isolation of infected patients and enhanced environmental cleaning. Antibiotic stewardship comprised administering the correct antibiotic, at the right dosage, at the right time

suspect, with the information we have now, that a patient on PPIs may be more likely to get C. difficile infection than a patient who is not on these medications.

It’s a good time for clinicians to start looking at their own practice, to scrutinize their use of these medicines.”

Dr. Fass speculated that the FDA alert was not more specific because more studies need to be done. For example, age, high dosing and duration of PPI therapy also are suspected risk factors, he said, but there is “no sufficient evidence to state that clearly.

“This warning will be the impetus for further research,” he predicted. n Drs. Fass and Reid reported no relevant financial disclosures.

and for the right duration.

Data for the MMWR paper were generated using population-based surveillance from the CDC’s Emerging Infections Program in 2010, in which 10,342 CDIs were identified. The researchers also used data from the CDC’s national Healthcare Safety network, an Internet-based surveillance system, and from the three

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state-led prevention programs.

According to the authors of the study, CDI incidence rates, mortality rates and medical care costs have reached historic highs, despite the fact that many of the infections can be prevented. They called for more to be done to prevent CDIs and suggested that infection control programs and antibiotic stewardship be

extended to non-hospital settings.

“State health departments and partner organizations have shown leadership in preventing CDIs in hospitals and can prevent more CDIs by extending their programs to cover other health care settings,” the authors concluded. “Clinicians and other health care providers, as well as inpatient and outpatient health care facilities, [and] state and federal public health officials … could benefit from increased collaboration in preventing CDIs.”

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42

Opinion

GastroenteroloGy & endoscopy news • april 2012

The Proliferation of Gowns and Gloves The other day while making rounds on a patient who was in her fourth postoperative day after a colectomy for diverticular disease, I was struck by a new collection of gowns and gloves on her door, along with multiple other signs indicating an infection control issue. As I looked up and down the hall, I noticed that almost every door on the surgical unit had the same collection of yellow gowns and blue gloves with signage indicating some form of isolation. Although I didn’t know anything about the other patients on the unit, I did know that my own patient had no particular bacterial issues when admitted and there were certainly no intra- or postoperative infection control stigmata that would warrant new signage and the proliferation of gowns and gloves.

I asked a nursing student who was in the throes of putting on a gown and gloves in front of my patient’s door if she knew anything about the infection control issue. She mentioned that there was a reference somewhere in the electronic medical record that in 2008 my patient “may have had” a culture of methicillin-resistant Staphylococcus aureus (MRSA). I then proceeded to go into my patient’s room, donning all of the appropriate accoutrements of the infection control guidelines, and asked my patient whether she had any recollection of any infectious issues.

She assured me that she had never had any involvement with MRSA and said she was rather surprised that the gowns and gloves all of a sudden appeared on her fourth postoperative day.

I use this little scenario to highlight a potential problem that seems to be proliferating throughout my hospital and perhaps yours as well. Although I am certainly not against appropriate infection control measures and have always supported the guidelines as to when these measures should be deployed, I feel that we are seeing an increase in patient isolation that may be inappropriate and that may actually foster poor infection control because of the ubiquitous nature of these protective measures. I think

this is representative of Frederick L. Greene, MD the “boy who cried wolf ” Chairman, Department of syndrome. If we employ General Surgery this process too freCarolinas Medical Center quently and potentially Charlotte, north Carolina indiscriminately, then appropriate infection control measures may be ignored.

It amazes me to see the number of doors in the inpatient unit covered with signs indicating a variety of infection control measures and I wonder whether these types of measures are well founded or potentially placed at the whim of a well-meaning ID [infectious disease] nurse without appropriate information to justify these actions.

Again, before any readers accuse me of not wanting to disclosure to the patient or without gaining additional follow appropriate guidelines, I feel that we are now in information that might be helpful in avoiding an indissome ways overusing these measures with the resultant criminate application. unintended consequences.

My plea is that if infection control is being used, we The overall cost of having multiple gowns, gloves, need to have a solid reason for employing it. The global masks and other infection control methods instituted utilization and proliferation of gowns, gloves and masks without appropriate indicators to warrant their use also may not accomplish our goal. Like universal precautions must be eschewed. I cringe sometimes to see how much in the operating room, we may get to the point where waste is collected each day as a consequence of using these everyone has the obligate box of gloves and gowns and expensive disposable items, and I believe that in our cul- other paraphernalia hanging on their door. I certainly ture we tend to give little thought to the waste that is hope this does not come to pass and would urge that generated and the overall cost that is engendered. good science and common sense be employed in all of Another possible byproduct of indiscriminate use of our infection control guidelines. infection control guidelines is worse patient care: Health Take a look at your own hospital corridors and your care workers may avoid entering a patient’s room because patients’ doors. Are you satisfied that there are good reaof the need to gown and glove and perhaps because of sons for isolation and the donning of gowns and gloves? their own fear of picking up some ethereal organism. Perhaps all of us should be willing to ask the appropriate We also must ensure that caregivers discuss fully with questions and to inquire as to why these measures have the patient the need to launch infection control guide- been instituted. Also, make sure that you are familiar with lines. The sudden appearance of gowns and gloves hang- the actions that are needed (nasal swab, etc) at your instiing on the door and signs indicating isolation guidelines tution to have a patient removed from questionable isolamight stress out even the most stalwart patient and his tion. Good infectious disease practices are important, but n or her family. Many times these events occur without full they can be detrimental if used indiscriminately.

Government to Industry: Improve Patient Follow-up After Hospital Discharge Government Sponsors IT Competition, Hopes To Find Innovative Solutions

By George Ochoa The federal government has issued a challenge to software developers: Create an easy-to-use, Web-based tool that will improve the scheduling of follow-up appointments after hospital discharge. The winning entry in the competition, which will close on April 30, will streamline scheduling; enhance sharing among providers, patients and caregivers; and include a plan for adoption at the community level.

The Discharge Follow-Up Appointment Challenge, as the competition is called (www.health2challenge.org/2012/discharge-follow-up-appointment-challenge), is offered by the office of the national Coordinator for Health Information Technology (onC) in collaboration with the Partnership for Patients (http://partnershippledge.healthcare.gov)—a collaboration of the government, hospitals, provider groups, employers and patient advocates.

The second in a series of projected health care–related challenges, this has the goal

of supporting information technology (IT) that will improve health care transitions and avoid unnecessary hospital readmissions. “We’re very excited about improving the care transition,” said Wil yu, special assistant at onC. According to Mr. yu, the competition judges have no particular end product in mind.

“The onC believes in open innovations. We encourage a wide variety of interpretations,” he said.

The winning entry could be an application for a mobile phone or tablet computer, a Web site or a software program incorporated into existing hospital technology.

The product might be integrated with electronic medical records, have messaging capability and be able to track “no shows” and cancellations. “We’re hoping for fantastic possibilities,” Mr. yu said.

Patricia A. rutherford, rn, MS, vice president of the Institute for Healthcare Improvement, and co-principal investigator for the STAAr (STate Action on

Avoidable rehospitalizations) Initiative, in Cambridge, Mass., noted that at least four projects already are under way to improve the hospital-to-home transition: STAAr, Project BooST (Better outcomes for older adults through Safe Transitions), Project rED (re-Engineered Discharge) and H2H (Hospital to Home).

“All four projects strongly recommend making follow-up appointments prior to discharge,” Ms. rutherford said. “IT solutions could help. There could be better IT solutions to assist clinicians within the community to share relevant clinical information about patients in their care.”

A Web-based solution would be “ideal,” but is “far from being a practical reality,” she added, because many practices are small and lack the necessary IT interfaces.

Brian Jack, MD, principal investigator for Project rED, and vice chair of family medicine at Boston University School of Medicine, said a recent increase in IT solutions that follow up with patients after discharge is a significant improvement over

the conventional post–hospital discharge telephone call.

“The area of hospital transitions is morphing into care of the complex patient over time. A variety of Web-based platforms are being developed to help monitor patients over time and that allow better communication among providers, family, pharmacists and community-based caregivers.”

First prize in the Discharge Follow-Up Appointment Challenge “aligns those who win the challenge with a test bed, a community where technology can be tested,” said Mr. yu. It also includes up to $5,000 to support a visit to the pilot community.

Second and third prizes involve a showcase and learning session with innovative communities and pilot programs focused on improved care transitions.

Mr� Yu, Ms� Rutherford and Ms� Reilly reported no relevant financial disclosures� Dr� Jack is working with a company, Engineered Care, on a software tool to teach patients about the post-discharge period�

WITH LOWER DOSE

1

EFFICACY YOU EXPECT1

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

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

Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reďŹ&#x201A;ex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use.

Please see brief summary of Prescribing Information on adjacent page.

44

FDA Update & Product News

GastroenteroloGy & endoscopy news • april 2012

Boceprevir in combination With ritonavir-boosted hiV Protease inhibitors May reduce efficacy of Both, fdA Warns

By George Ochoa A February safety alert from the FDA warned that drug interactions between the hepatitis C virus (HCV) protease inhibitor (PI) boceprevir (Victrelis, Merck & Co., Inc.) and certain ritonavir-boosted HIV PIs may reduce the effectiveness of

these medications when used together.

The HIV PIs specified are atazanavir (Reyataz, Bristol-Myers Squibb), lopinavir (Kaletra, Abbott Laboratories) and darunavir (Prezista, Janssen Therapeutics).

According to the FDA, a drug interaction study showed that taking boceprevir in combination with one of these drugs reduced blood levels of the HIV

medications and boceprevir in the body.

The boceprevir label will be updated to reflect these drug interactions. Another HCV PI, telaprevir (Incivek, Vertex Pharmaceuticals Inc.), already carries warnings about drug interactions with HIV PIs. “There has been considerable concern about the off-label use of these drugs

EFFICACY YOU EXPECT1

WITH LOWER DOSE1

• Lowest volume phosphate-free lavage1,2 • No oral sodium phosphate

and how they are used in patients with retroviral infections,” said Andrew Talal, MD, MPH, associate professor of medicine and associate medical director, Center for the Study of Hepatitis C, Weill Cornell Medical College, New York City. “I am pleased by the release of these data.”

Data presented on March 6 at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) from researchers at Merck (Hulskotte E et al, paper 771LB) support the FDA action.

Statin Labels Updated HCV Protease Inhibitor Contraindication Highlighted References: 1. HalfLytely® and Bisacodyl Tablet Bowel Prep Kit [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2010. 2. See package inserts: GoLYTELY®(PEG-3350 and Electrolytes for Oral Solution), 2001; NuLYTELY® (PEG-3350, Sodium Chloride, Sodium Bicarbonate and Potassium Chloride for Oral Solution), 2008. Braintree, MA: Braintree Laboratories, Inc.; MoviPrep® (PEG-3350, Sodium Sulfate, Sodium Chloride, Potassium Chloride, Sodium Ascorbate and Ascorbic Acid for Oral Solution), 2006; Morrisville, NC: Salix Pharmaceuticals, Inc.

Brief Summary: Before prescribing, please see full Prescribing Information and Medication Guide for HalfLytely and Bisacodyl Tablet Bowel Prep Kit. INDICATIONS 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 ©2011 Braintree Laboratories, Inc.

HL-12437T

January, 2011

By George Ochoa The product labels on statins are changing to reflect new information deemed important by the FDA. The FDA announced the changes in late February as part of an overhaul of statin prescribing information. one of the changes regards interactions between certain statins and hepatitis C virus (HCV) and HIV protease inhibitors. Taken together, statins and protease inhibitors may raise the blood levels of statins and increase the risk for muscle injury. one statin in particular, lovastatin, has been updated with new contraindications and dose limitations when it is taken with certain other drugs that can increase the risk for myopathy and rhabdomyolysis, including the HCV protease inhibitors boceprevir and telaprevir.

The FDA also approved labeling changes regarding the potential for statins to increase levels of blood sugar and glycosylated hemoglobin, signs of incipient type 2 diabetes. This decision was based on accumulating studies linking statins with the development of type 2 diabetes, the agency said.

These included the Justification for the Use of Statins in Primary Prevention: an

FDA Update & Product News

GastroenteroloGy & endoscopy news • april 2012

Investigators evaluated drug interactions between boceprevir and ritonavir-boosted HIV PIs in 39 healthy adults. Blood samples were analyzed for pharmacokinetic characteristics of HIV PIs, ritonavir and boceprevir. The researchers found that boceprevir in combination with ritonavir-boosted atazanavir, darunavir and lopinavir resulted in reduced steadystate exposures of the HIV medications. Darunavir and lopinavir, but not atazanavir, lowered boceprevir exposure.

However, another study, presented on the same day at CROI (Sulkowski M et al, oral abstract Q-175), came to a different conclusion. This study evaluated the efficacy of boceprevir in patients coinfected with HIV and HCV genotype 1 who were previously untreated for HCV. Patients were treated with HIV PIs and also received boceprevir in combination with peginterferon alfa-2b/ribavirin (B/PR; n=64) or peginterferon alfa-2b/ ribavirin (PR; n=34) alone. In an interim analysis, sustained virologic response at week 12 was achieved in 61% of patients in the B/PR group compared with 27% of patients in the PR group. The rates of HIV breakthrough (defined as HIV RNA >50 copies/mL at two consecutive visits) Intervention Trial Evaluating rosuvastatin trial, which reported a 27% increase in investigator-reported diabetes in patients who received rosuvastatin compared with those who took a placebo (ridker PM et al. N Engl J Med 2008;359:21952207); the Pravastatin or Atorvastatin Evaluation and Infection Therapy— Thrombolysis In Myocardial Infarction 22 substudy, which found an association between high-dose atorvastatin and worsening glycemic control (Sabatine MS et al. Circulation 2004;110:S834); and meta-analyses such as one by Sattar et al (Lancet 2010;375:735-742), which found that statin therapy was associated with a 9% increased risk for incident diabetes.

The potential for cognitive side effects, such as memory loss and confusion, in patients taking statins also was noted by the FDA. These side effects are generally reversible and not serious. The FDA stressed that “the cardiovascular benefits of statins outweigh these small increased risks.”

Additionally, statin labels have been revised to eliminate the need for routine periodic monitoring of liver enzymes in patients taking these drugs. Instead, statin labels now recommend the use of liver enzyme tests before starting the drugs and as clinically indicated afterward. Serious liver injury with statins is rare and unpredictable, according to the FDA, and routine periodic monitoring does not seem effective in detecting or preventing the problem.

were 4.7% (three of 64) for patients who received boceprevir and 11.8% (four of 34) for those who did not.

“Although this study included a small number of patients, it did not demonstrate an increased rate of HIV breakthrough in patients receiving boceprevir plus HIV protease inhibitors compared with subjects receiving protease inhibitors alone,” said Kristen Marks, MD, assistant professor of medicine, Division of Infectious Diseases, Weill Cornell Medical College, New York City, and investigator, Cornell Clinical Trials, who

was not involved in the study. “However, further study is needed to determine if HCV and HIV protease inhibitors can be safely used together.”

Dr. Talal said he would hold off initiating combination therapy with boceprevir and ritonavir-boosted HIV PIs in a patient with HCV–HIV co-infection who had not already been started on such therapy. As for patients who have already been started on the combination, the FDA alert recommends they should be closely monitored for HCV treatment response and potential HCV and HIV

45

virologic rebound.

Dr. Marks said that she would make decisions about whether to continue treatment with boceprevir and a ritonavirboosted HIV PI on a case-by-case basis.

“For example, if a patient has been on combination therapy for half a year and is doing well with respect to both HIV and HCV, I would leave them on it,” she said. n Dr. Talal has received research and consulting fees from Merck. Dr. Marks reported no relevant conflicts of interest.

46

FDA Update & Product News

GastroenteroloGy & endoscopy news • april 2012

New EUS Aspiration Needle Launched To Help Improve Diagnostic Capabilities Flex needle allows for access to challenging anatomy and sampling of solid and cystic lesions where traditional needles of this size can’t be used,” said Shyam Varadarajulu, MD, chief of endoscopy at the University of Alabama at Birmingham, in a press release from Boston Scientific.

The Expect 19 Flex needle is made of nitinol to improve flexibility and resistance to deformation compared with traditional stainless steel needles. The new needle

also has a large diameter that allows expanded diagnostic capabilities and an echogenic pattern that provides excellent visibility and precise needle guidance within an organ. With these features, physicians may be able to more easily and accurately obtain tissue samples, according to the manufacturer.

“The Expect 19 Flex needle provides physicians with a clinically differentiated product designed to help improve patient

Think of Enterography as a GPS for Crohn’s disease.

Photo courtesy of Boston Scientific

on Feb. 6, Boston Scientific announced the global launch of the Expect 19 Flex Endoscopic Ultrasound Aspiration needle. The Expect 19 Flex needle was designed to advance existing endoscopic ultrasound-guided fine needle aspiration (EUS-FnA) devices by enhancing physicians’ ability to acquire tissue samples for cancer diagnosis in organs next to the gastrointestinal tract.

“The improved design of the Expect 19

the expect 19 flex endoscopic ultrasound Aspiration Needle is made of nitinol to improve flexibility, and its echogenic pattern provides excellent visibility and precise needle guidance. care,” said David Pierce, president of Boston Scientific’s Endoscopy Division.

For more information on EUS-FnA procedures, visit the Boston Scientific Endoscopy Channel at www.youtube. com/bostonscientificendo.

—Based on a press release from Boston Scientific

Image shows not only thickening of the bowel wall, but also the increased attenuation of the mucosa compatible with active Crohn’s disease.*

Olympus Introduces New Single-Use Aspiration Needles For Endoscopic Ultrasound

Photo courtesy of olympus America Inc.

olympus America Inc., recently introduced a collection of Ez Shot 2 single-use aspiration needles for endoscopic ultrasound

Enterography gives you a highly effective diagnostic tool for evaluating and managing treatment of small bowel disorders like Crohn’s disease.1 By producing abdominal images that provide clear visualization of the small bowel wall and lumen,2 enterography shows the degree, extent and location of Crohn’s disease3 and is quickly becoming a first-line exam in leading IBD Centers for the evaluation of small bowel disorders.2 For more information about the benefits of enterography for small bowel diagnostics, please contact Bracco Professional Services at 1-800-257-5181, option 1. * Representational image, individual results may vary. Image courtesy of Alec Megibow, MD, NYU REFERENCES: 1. Bruining DH, Siddiki HA, Fletcher JG, et al. Benefit of computed tomography enterography in Crohn’s disease: Effects on patient management and physician level of confidence. Inflamm Bowel Dis. 2012;18(2):219-225. 2. Fletcher JG. CT enterography technique: theme and variations. Abdom Imaging. 2009;34(3):283-288. 3. MDCT and 3D imaging of the small bowel and mesentery.

Mahmoud M. Al-Hawary, MD, Ravi K. Kaza, MD, and Joel F. Platt, MD, University of Michigan Health System, Ann Arbor, MI. Applied Radiology. 2011 Nov;40(11). ©2012 Bracco Diagnostics Inc. All Rights Reserved.

Olympus’ EZ Shot 2 single-use aspiration needles are designed with echogenic dimples to ensure visibility of the needles during eus procedures.

FDA Update & Product News

GastroenteroloGy & endoscopy news • april 2012

47

on Feb. 7, US Endoscopy announced the release of its Torrent irrigation tubing.

The Torrent tubing is a two-part system, which consists of a disposable, 24-hour irrigation tubing and a single-use endoscope connector.

The irrigation tubing is used along with an electric water pump and endoscope to provide irrigation during gastrointestinal (GI) endoscopic procedures. The disposable Torrent tubing and single-use scope connector protects patients from cross-contamination.

With concerns about infection control

growing in the GI market, “the Torrent irrigation tubing helps support infection control efforts while saving time and costs associated with reprocessing reusable tubing,” Gulam Khan, US Endoscopy CEo, president and co-chairman, said in a statement.

For more information about Torrent, visit www.usendoscopy.com.

—Based on press releases from US Endoscopy

The Torrent single-use endoscope connector

Spring Issue Coming Soon

GI FELLOW

ADVISOR

An educational newsletter for physicians in training The Torrent irrigation tubing system features 24-hour use irrigation tubing that can be used for a day, then thrown away.

(EUS) procedures. The four unique needles offer excellent puncture capability along with an adjustable sheath designed to help physicians more accurately approach the targeted site, olympus said in a press release. Available in a variety of sizes and styles, the surface of the Ez Shot 2 needle is designed with echogenic dimples to ensure it is visible during EUS procedures.

“These new needles provide olympus’ customers with an unprecedented offering in the EUS suite,” said Patrick MacCarthy, vice president of marketing for the Endoscopy Division of olympus America.

For more information about olympus’ fine-needle aspiration product line and the Ez Shot 2 needles, visit www.olympusamerica.com/msg_section/msg_eus_ fineneedle.asp.

—Based on a press release from Olympus America Inc�

www.GIFellowAdvisor.com Sponsored by:

Photos courtesy of US Endoscopy

New Disposable Endoscope Irrigation Tubing Helps Protect Against Cross-Contamination

Spotlight On Our Very Best As 2011 drew to a close, the McMahon Group bestowed honors on several employees within its talented workforce. Throughout the year, McMahon’s portfolio of clinical news magazines maintained readership numbers that solidified their best-read status, and sales revenues increased despite a challenging economic climate. The diverse talents and collaborations among McMahon’s staff allowed the company to maintain its position as a trusted source of news and educational initiatives. McMahon’s publishing success was on display both in print and on the Web sites of its publications and custom media platforms.

2011

Here is a look at those recognized for their unique contributions during 2011.

SUPPORT/PRODUCTION/IT/FINANCE PERSON OF THE YEAR:

SUPPORT/PRODUCTION/IT/FINANCE PERSON OF THE YEAR:

GRAPHIC DESIGNER OF THE YEAR:

Employees were asked to select the two most outstanding members from these departments. The first winner was JOHN CABA, software developer, for his tireless devotion toward improving the company’s digital platforms.

The second winner was ROSA DIMICCO, accounting associate, for diligently ensuring that freelance writers and key opinion leaders are paid in a timely manner for their exceptional work.

JEANETTE MOONEY won the award in recognition of her creative talents as art director for Pain Medicine News, along with her superb layout designs for a host of Special Reports and custom newsletters.

MOST IMPROVED SALESPERSON OF THE YEAR:

SPECIAL PROJECTS EDITOR OF THE YEAR:

NEWSMAGAZINE EDITOR OF THE YEAR:

Each member of the sales staff seeks to improve throughout the year; however, one inevitably displays accelerated growth. DAVID NATHANSON, account manager, managed to do just that across several publications in 2011.

SETH KANDEL was voted best projects editor for his exemplary work on numerous custom media programs for medical industry clients as well as his management of the editorial in Infectious Disease Special Edition.

DONALD PIZZI, managing editor of Pain Medicine News, was recognized for the excellence of his news coverage throughout 2011. Under Don’s discerning eye, the magazine offers a comprehensive resource for clinicians involved in the management of pain.

SALES ACHIEVEMENT AWARD:

SALESPERSON OF THE YEAR:

DAVE KAPLAN, publication director of Pharmacy Practice News, was the 2011 winner in this category. Dave has proven himself to be an innovator among his peers by championing exciting new platforms and marketing opportunities for his many clients.

Whereas the other awards are decided by a jury of one’s peers, this honor is bestowed on the one salesperson who brings in the most revenue. For a record-breaking sixth year in a row, the winner was RICHARD TUORTO, senior group publication director for Anesthesiology News and Pain Medicine News. Richard’s dedication to his clients’ marketing needs and intimate knowledge of their products enable him to reach the zenith of sales proficiency year after year.

PERSON OF THE YEAR

PARTNERS AWARD

PERSON OF THE YEAR 2011:

PARTNERS SPECIAL RECOGNITION AWARD 2011:

This award recognizes the cream of the crop, and MARY LOU CAMPANELLA, chief financial officer, was the 2011 Person of the Year. Mary Lou has been able to streamline the company’s finances by thwarting inefficiencies and highlighting excess expenditures. Her constant professionalism, hard work and keen eye for detail have proven to be invaluable commodities that are greatly appreciated by her peers.

The partners of McMahon Publishing occasionally present an award to someone who has contributed to the success of the company over many years of service. This year’s winner was URBAN S. MULVEHILL, who has provided legal services to the company since 1983. He became a partner at his law firm, O’Neill DiManno and Kelly, in 1980 after having served as a trial lawyer for several years at the U.S. Department of Justice. Urban’s relaxed demeanor and sage advice over the past three decades have been greatly appreciated.

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Acing the GI Board Exam: The Ultimate Crunch-Time Resource

Brennan Spiegel; Hetal Karsan Slack Incorporated, August 11, 2011 This book presents time-tested and high-yield information in a rational, useful, and contextually appealing format.

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2

Atlas of Clinical Gastrointestinal Endoscopy: Expert Consult—Online and Print: Third Edition

C. Mel Wilcox Elsevier/Saunders, April 2, 2012 This atlas provides more high-quality images than any other to help you accurately interpret endoscopic images and diagnose gastrointestinal disorders. This edition covers new radiographic imaging and endoscopic evaluation methods and features an expanded image collection that includes more pathology and radiology images.

3

Atlas of Endoscopic Ultrasonography Frank G. Gress; Thomas J. Savides

John Wiley/Blackwell Publishing, October 18, 2011 This atlas provides a large collection of excellent images obtained from both diagnostic and therapeutic procedures to give readers a preview of practice. It includes a CD-ROM with video clips and searchable database of images.

4

CURRENT Diagnosis & Treatment Gastroenterology, Hepatology, & Endoscopy, Second Edition

Norton Greenberger; Richard Blumberg; Robert Burakoff McGraw-Hill, 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 and the content is delivered in an easy-access, find-it-now presentation.

5

ERCP: Expert Consult—Online and Print

Todd H. Baron, MD; Richard Kozarek, MD; David Leslie Carr-Locke, MD, FACG, FRCP Elsevier/Saunders, October 25, 2007 This comprehensive and user-friendly book combines an in-depth review of ERCP with easily accessible, detailed and authoritative instructions on how to safely gain access to the biliary and pancreatic ducts and deliver effective therapy. The intricacies of the procedures are shown using beautifully drawn step-by-step illustrations.

6

Gastroenterology Coding Manual, Third Edition

AGA Institute and the Professional Association of Healthcare Coding Specialists AGA Institute, May 1, 2011 Published jointly by the AGA Institute and PAHCS, this manual presents the essential elements of gastroenterology coding in a two-part, easyto-use format designed for both the experienced coder and the novice.

7

Oxford Handbook of Gastroenterology and Hepatology

Stuart Bloom; George Webster; Daniel Marks Oxford University Press, January 15, 2012 Fully revised and updated for the new edition, the Oxford Handbook of Gastroenterology and Hepatology comprises a unique A-Z compendium of the specialty and a dedicated section detailing 30 of the most common problems in GI medicine, which can be used as a quick reference.

8

Year Book of Gastroenterology 2011

Nicholas J. Talley Elsevier/Mosby, December 1, 2011 The Year Book of Gastroenterology brings you abstracts of the articles that reported the year’s breakthrough developments in gastroenterology, carefully selected from more than 500 journals worldwide. Expert commentaries evaluate the clinical importance of each article and discuss its application to your practice. There’s no faster or easier way to stay informed! Abstracts from the year’s most important articles from hundreds of journals are included in chapters on motility disorders, inflammatory bowel disease, liver disease, and more.

GEN0412

FDA Update & Product News

FDA Approves Two New Pancreatic Enzyme Products

GastroenteroloGy & endoscopy news • april 2012

www.CMEZone.com Photo courtesy of Aptalis Pharma

50

Ultresa (pancrelipase) and Viokace (pancrelipase), two pancreatic enzyme products marketed by Aptalis Pharma U.S. Inc., were approved on March 1 by the FDA. The products, intended to aid food digestion, are the fourth and fifth pancreatic enzyme products approved by the FDA, and, according to the agency, will help ensure adequate supply of the medications.

Ultresa is a delayed-release capsule used to treat children and adults with cystic fibrosis or other conditions that prevent patients from digesting food normally because of exocrine pancreatic insufficiency. Viokace, taken in combination with a proton pump inhibitor, is used to treat adults who cannot digest food normally, including those with chronic pancreatitis or those who have had a pancreatectomy.

Viokace’s safety and efficacy in children has not been established.

“The approvals of Ultresa and Viokace, along with the other approved pancreatic enzyme products, allow health care providers to prescribe the product that is most appropriate for the estimated 200,000 patients in the United States who have pancreatic insufficiency,” Julie Beitz, MD, director of the office of Drug Evaluation III in FDA’s Center for Drug Evaluation and research, Beltsville, Md., said in a statement.

Unapproved pancreatic enzyme products had been available for decades; however, as of April 28, 2010, the manufacture and distribution of unapproved pancreatic enzyme products was no longer permitted by the FDA. Besides Ultresa and Viokace, Creon (Abbott Laboratories), Pancreaze (Janssen Pharmaceuticals, Inc.) and zenpep (Eurand Pharmaceuticals, Inc.) are also approved by the FDA. —Based on a press release from the FDA

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51

GastroenteroloGy & endoscopy news • april 2012

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Anorectal pain can change people’s lives … for the worse! It can, and usually does, manage to interfere with almost everything one does, from something as simple as sitting on a bus to enjoying a meal out with friends.

To help address this problem— which affects millions of Americans, especially between the ages of 20 and 50 years—Ferndale Healthcare® has launched RectiCare™ (Lidocaine 5%) Anorectal Cream, an over-the-counter topical, local anesthetic that contains the highest nonprescription strength of lidocaine available.

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FDA Approves First H. pylori Breath Test For Children on Feb. 22, the FDA approved the BreathTek UBT breath test for use in children aged 3 to 17 years to detect Helicobacter pylori bacterial infection.

The test, manufactured by otsuka America Pharmaceutical, is a noninvasive urea breath test to diagnose and monitor H� pylori infection, and was approved by the FDA for adults in 1996. “results from this test, when considered with a physician’s assessment of the patient’s history, other risk factors and professional guidelines, can quickly indicate infection, which allows a physician to initiate appropriate health measures in a timely manner,” Alberto Gutierrez, PhD, director of the office of In Vitro Diagnostic Device Evaluation and Safety in FDA’s Center for Devices and radiological Health, said in a statement.

The FDA based its approval of the breath test on a multicenter study of 176 children, which showed the method had 95.8% sensitivity and 99.2% specificity when compared with a composite reference. In a follow-up study performed one to six months after therapy, researchers demonstrated the test’s efficacy in monitoring patients after treatment; the test achieved 88.3% sensitivity and 100% specificity.

—Based on a press release from the FDA

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* HE RE

Xifaxan550 IS

*

Efficacy and tolerability for control of overt hepatic encephalopathy (HE) recurrence in adults Xifaxan 550 mg offers:

58

%

50

%

proven reduction in the risk of breakthrough HE over a 6-month period 1 †

†

P<0.0001 vs placebo.

proven reduction in the risk of HE-related hospitalizations over a 6-month period 1‡§ ‡

P=0.0129 vs placebo.

Safety and tolerability comparable to placebo when used as directed1 HE-related hospitalization defined as hospitalization directly caused by HE or a hospitalization during which an HE event occurred.

§

Reference: 1. Xifaxan [prescribing information]. Morrisville, NC: Salix Pharmaceuticals, Inc; 2010.

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 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 brief summary of Prescribing Information on following page.

Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIF 10/34-2

www.Xifaxan550.com