Positive Results from Salix Pivotal Phase III Study of Rifaximin for the Prevention and Maintenance of Remission of Hepatic Encephalopathy (HE) Presented at Digestive Disease Week (DDW)
Data Shows Rifaximin Provided Significant Protective Effect in Preventing HE Breakthrough and HE–Related Hospitalization
CHICAGO AND RALEIGH, June 1, 2009 – Salix Pharmaceuticals, Ltd. (NASDAQ:SLXP) today announced
the presentation of new data from its Phase III pivotal
clinical trial evaluating the efficacy, safety and tolerability of rifaximin – a non–absorbed (<0.4%), gut selective antibiotic –
in adult patients with hepatic encephalopathy (HE). These data, presented during two oral sessions at the annual meeting of Digestive Disease Week (DDW) being held this week in Chicago (May 30–June 4, 2009), demonstrated that rifaximin significantly reduced the risk of HE–related
hospitalizations in patients with previous episodes of HE and showed a highly significant reduction in the risk of breakthrough HE during the six month
study.
The new data come from two additional analyses of the pivotal Phase III, multinational, randomized, double–blind, placebo–controlled study of 299 patients with a history of HE. The data showed that patients who received rifaximin (1100 mg / day, dosed at 550 mg twice daily) for six months
experienced a highly statistically significant reduction in the risk of breakthrough HE compared to those who received placebo (58% risk reduction,
p<0.0001) in the intent to treat (ITT) population. One analysis presented today showed that rifaximin significantly reduced the risk of HE–related
hospitalizations compared to placebo (50% risk reduction, p=0.01) during the six month treatment period. The other data analysis presented showed that rifaximin treatment after adjusting for significant prognostic factors (such as geographic location, age, sex, race, model for end–stage
liver disease [MELD], and Conn score – that can contribute to breakthrough HE) resulted in a 60% risk reduction demonstrating a highly significant
protective effect (p<0.0001) in preventing HE breakthrough.
"The findings in this study that rifaximin use decreases the hospitalization rate by 50 percent for those with frequent episodes of HE within only six months is quite impressive," said Samuel H. Sigal, MD, Assistant Professor of Medicine, Weill Cornell Medical College, New York. "This represents a major
advance for a condition that until now had limited options."
The 299 patients were randomized to either rifaximin (n=140) 550 mg / bid, or placebo (n=159). Patients with cirrhosis who had ≥2 episodes of HE (defined
as Conn score ≥2) within six months prior to screening and were currently in remission (defined as a Conn score = 0 or 1) were enrolled in the study.
The primary endpoint was time to first breakthrough HE episode (increase of Conn score to ≥2; or a Conn score and asterixis grade increase of
1 each, if baseline Conn score = 0).
O144. The Effect of Prognostic Factors on the Maintenance of Remission in Hepatic Encephalopathy Patients Treated with Rifaximin
(Oral Presentation, Sunday, May 31, 2009, 10:30 – 10:45 AM CT, # 144)
In an oral presentation, Dr. Sigal and colleagues presented the results of an additional analysis of the Phase III study that demonstrated rifaximin significantly
reduced the risk of breakthrough HE by 60% versus placebo (HR, 0.403; 95% confidence interval (CI), 0.264–0.617; p<0.0001) during the six month treatment period. The most influential prognostic factors for maintenance of remission in this covariate analysis were age (p=0.03) and MELD score (p=0.0003).
O66. Rifaximin Reduces Hospitalizations in Patients with Previous Episodes of Hepatic Encephalopathy: Results from a Phase 3 Placebo–Controlled Trial
(Oral Presentation: Sunday, May 31, 2009, 9:30 – 9:45 AM CT, #66)
In another oral presentation earlier today, Dr. Neff and colleagues presented the results of an additional analysis that showed rifaximin provided significant
reduction in the risk of HE–related hospitalizations by 50% compared to placebo (hazard ratio=0.500; 95% CI, 0.287–0.873; p=0.01).
The data also indicated on average that for every nine patients treated with rifaximin one fewer patient was hospitalized due to HE.
"This new data solidly supports the clinical efficacy of rifaximin in reducing the risk of HE–related hospitalization," said Guy Neff, MD, MBA, Medical
Director of Transplant and Associate Professor of Clinical Medicine, Hepatology and Transplant at the University of Cincinnati, College of Medicine.
"As demonstrated in previously published pharmacoeconomic data, reducing recurrent HE events may reduce the need for HE–related hospitalization,
thereby potentially decreasing the costs of care."
Other Rifaximin Presentations at DDW
In addition to the presentations by Dr. Sigal and Dr. Neff, the DDW program includes the following rifaximin presentations:
- Poster # M1197: DuPont, et al. The Role of Travelers' Diarrhea in the Development and Worsening of PI–IBS. Monday June 1, 2009, 8:00 AM –
5:00 PM CT.
Embargoed until Monday, June 1, 2009, 8:00 AM CT.
- Poster # T2052: DuPont, et al. In Vitro Assessment of Susceptibility of 359 Clostridium Difficile Isolates to Rifaximin. Tuesday, June 2, 2009, 8:00 AM – 5:00 PM CT.
Embargoed until Tuesday, June 2, 2009, 8:00 AM CT.
-
Poster # T2048: Rayapudi, et al. Rifaximin Salvage Therapy for Metronidazole–Resistant Clostridium Difficile Infection–a Prospective Pilot
Trial. Tuesday, June 2, 2009, 8:00 AM – 5:00 PM CT.
Embargoed until Tuesday, June 2, 2009, 8:00 AM CT.
-
Poster # W1644: Pimentel, et al. Histological Changes of the Small Intestine Are Seen in the Acute Phase of Infection with Campylobacter Jejuni in a New Rat Model of Post–Infectious IBS. Wednesday, June 3, 2009, 8:00 AM – 5:00 PM CT.
Embargoed until Wednesday, June 3, 2009, 8:00 AM CT.
About Hepatic Encephalopathy
Hepatic encephalopathy (HE) is a neurological disorder caused by chronic liver failure resulting in cognitive, psychiatric, and motor impairments1. The
condition encompasses a wide spectrum of often reversible neuropsychiatric abnormalities caused by the inability of the liver to remove toxic products
in the gut, most notably ammonia producing bacteria.2 When toxins reach the central nervous system, this condition can result in symptoms ranging
in severity from mild cerebral function deficits to coma and characterized by: disruption in sleep patterns, changes in personality and intellectual
capacity, high blood ammonia levels, altered neuromuscular activity and electroencephalogram (EEG) abnormalities.2,3
There are reported to be more than 100,000 patients in the United States (U.S.) with overt HE4 with the majority of cases caused by increased nitrogen load
(GI bleeding, excess dietary protein, Azotemia), electrolyte imbalance and drug use (narcotics, tranquilizers and sedatives).5 HE occurs frequently
in alcoholics with cirrhosis,1 a leading cause of death in the U.S.6 The number of cases of liver disease in the U.S. and around the world is rapidly
increasing with more than 7 million people in the U.S. being diagnosed with chronic liver disease.7
About XIFAXAN® (rifaximin)
Rifaximin, which Salix markets in the United States under the trade name XIFAXAN® (rifaximin), currently is approved for the treatment of
patients, 12 years of age or older, with travelers' diarrhea caused by non–invasive strains of Escherichia coli. XIFAXAN (rifaximin) is a gut–selective antibiotic with negligible systemic absorption (<0.4%) and broad–spectrum activity in vitro against both gram–positive
and gram–negative pathogens. Rifaximin has a similar tolerability profile to that of placebo and has activity against the most common TD
pathogens. XIFAXAN should not be used in patients with diarrhea complicated by fever or blood in the stool or diarrhea due to pathogens other than Escherichia coli. XIFAXAN should be discontinued if diarrhea symptoms get worse or persist more than 24–48 hours and alternative antibiotic
therapy should be considered. In clinical trials, XIFAXAN was generally well tolerated. The most common side effects (vs. placebo) were flatulence
11.3% (versus 19.7%), headache 9.7% (versus 9.2%), abdominal pain 7.2% (versus 10.1 %) and rectal tenesmus 7.2% (versus 8.8%).
Rifaximin (550 mg) is currently in late stage development for the prevention of hepatic encephalopathy breakthrough and maintenance of remission of overt
hepatic encephalopathy. Rifaximin has been granted orphan drug designation for the treatment of hepatic encephalopathy by the U. S. Food and Drug
Administration. Additionally, rifaximin (550 mg) is under investigation in the United States as a treatment for irritable bowel syndrome.
Rifaximin has been used in Italy for 24 years and is approved in 33 countries. Salix acquired rights to market rifaximin in North America from Alfa Wassermann
S.p.A. in Bologna, Italy. Alfa Wassermann markets rifaximin in Italy under the trade name Normix®.
About DDW
DDW is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal
surgery. Jointly sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association (AGA)
Institute, the American Society for Gastrointestinal Endoscopy and the Society for Surgery of the Alimentary Tract, DDW takes place May 30 –
June 4, 2009, at McCormick Place, Chicago. The meeting showcases approximately 5,000 abstracts and hundreds of lectures on the latest advances in
GI research, medicine and technology. For more information, visit http://www.ddw.org.
About Salix Pharmaceuticals
Salix Pharmaceuticals, Ltd., headquartered in Morrisville, NC, develops and markets prescription pharmaceutical products for the treatment of gastrointestinal
diseases. Salix's strategy is to in–license late–stage or marketed proprietary therapeutic drugs, complete with any required development
and regulatory submission of these products, and market them through the Company's gastroenterology specialty sales and marketing team.
Salix also markets OSMOPREP® (sodium phosphate monobasic monohydrate, USP and sodium phosphate dibasic anhydrous, USP) Tablets, MOVIPREP®
(PEG 3350, Sodium Sulfate, Sodium Chloride, Potassium Chloride, Sodium Ascorbate and Ascorbic Acid for Oral Solution), VISICOL®
(sodium phosphate monobasic monohydrate, USP, and sodium phosphate dibasic anhydrous, USP) Tablets, APRISO™ (mesalamine)
extended–release capsules 0.375 g., PEPCID® (famotidine) for Oral Suspension, Oral Suspension DIURIL® (Chlorothiazide),
AZASAN® Azathioprine Tablets, USP, 75/100 mg, ANUSOL–HC® 2.5% (Hydrocortisone Cream, USP), ANUSOL–HC®
25 mg Suppository (Hydrocortisone Acetate), PROCTOCORT® Cream (Hydrocortisone Cream, USP) 1% and PROCTOCORT®
Suppository (Hydrocortisone Acetate Rectal Suppositories) 30 mg. METOZOLVTM ODT (metoclopramide), vapreotide acetate, crofelemer and rifaximin
for additional indications are under development.
1National Institute on Alcoholism and Alcohol Abuse of the National Institutes of Health. Hepatic Encephalopathy. September 29, 2004. Available at:
http://pubs.niaaa.nih.gov/publications/arh27-3/240-246.htm.
2Blei AT, Co'rdoba J and The Practice Parameters Committee of the American College of Gastroenterology. Hepatic Encephalopathy. Practice Guidelines. Vol.
96, No. 7, 2001.
3Abou–Assi S. Vlahcevic ZR. Hepatic encephalopathy. Metabolic consequence of cirrhosis often is reversible. Postgraduate Medicine. 109(2):52–4,
57–60, 63–5 passim, 2001 Feb.
4Poordad FF. Review Article: The Burden of Hepatic Encephalopathy. Alimentary Pharmacology & Therapeutics. 25 Supplement 1:3–9, February 2007.
5Worobetz, L.J. Hepatic Encephalopathy. First Principles of Gastroenterology. 2005. Accessed April 21, 2009. Available at: http://www.gastroresource.com/gitextbook/en/chapter14/14-13.htm.
6Miniño AM, Heron MP, Murphy SL, Kochanek KD. Deaths: Final data for 2004. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/nchs/data/nvsr/nvsr55/nvsr55_19.pdf.
Updated October 10, 2007. Accessed January 20, 2008.
7Everhart JE, editor. The burden of digestive diseases in the United States. US Department of Health and Human Services, Public Health Service, National
Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Washington, DC: US Government Printing Office, 2008; NIH
Publication No. 09–6443 [pp. 111–114]
For full prescribing information on Salix products, please visit www.salix.com or
contact the Company at 919–862–1000.
Salix trades on the NASDAQ Global Select Market under the ticker symbol "SLXP".
For more information please visit our web site at www.salix.com or contact the Company at 919–862–1000. Information on our web site is not incorporated
in our SEC filings.
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APRISO™ is a locally-acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older.
APRISO is contraindicated in patients with hypersensitivity to salicylates, aminosalicylates, or to any of the components of APRISO capsules.
The recommended dose of APRISO is four 0.375 g capsules once daily in the morning (1.5 g/day) with or without food. Because dissolution of the coating of APRISO
granules depends on pH, APRISO should not be coadministered with antacids. Patients with phenylketonuria should be aware that APRISO contains aspartame,
equivalent to 0.56 mg of phenylalanine. In two well-controlled clinical trials, the most common treatment-related adverse events occurring in at least 3%
of adult patients taking 1.5 g/day of APRISO were headache (11% vs. 8% for placebo), diarrhea (8% vs. 7% for placebo), upper abdominal pain (5% vs 3% for placebo),
nausea (4% vs 3% for placebo), nasopharyngitis (4% vs 3% for placebo), influenza and influenza-like illness (4% vs 4% for placebo) and sinusitis (3% vs 3% for placebo).
For complete Prescribing Information, please click here.
MOVIPREP® (PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution) is indicated for cleansing of the
colon as a preparation for colonoscopy in adults 18 years of age or older. MOVIPREP is contraindicated in patients who have had a severe hypersensitivity reaction
to any of its components. MOVIPREP should be used with caution in patients using concomitant medications that increase the risk of electrolyte abnormalities, in patients with known or suspected hyponatremia,
severe ulcerative colitis, ileus, gastrointestinal obstruction or perforation, gastric retention, toxic colitis, toxic megacolon, or glucose-6-phosphate dehydrogenase deficiency. In clinical trials, abdominal
distention, anal discomfort, thirst, nausea, and abdominal pain were the most common adverse reactions to MOVIPREP administration. MOVIPREP contains a maximum of 2.33 mg of phenylalanine per treatment.
Consult with your physician to see if this product is right for you.
For complete Prescribing Information, please click here.
Important Safety Information about OSMOPREP
There have been rare, but serious reports of acute phosphate nephropathy in patients who received oral sodium phosphate products for colon cleansing prior
to colonoscopy. Some cases have resulted in permanent impairment of renal function and some patients required long–term dialysis. While some
cases have occurred in patients without identifiable risk factors, patients at increased risk of acute phosphate nephropathy may include those with
increased age, hypovolemia, increased bowel transit time (such as bowel obstruction), active colitis, or baseline kidney disease, and those using
medicines that affect renal perfusion or function (such as diuretics, angiotensin converting enzyme [ACE] inhibitors, angiotensin receptor blockers
[ARBs], and possibly nonsteroidal anti–inflammatory drugs [NSAIDs]).
It is important to use the dose and dosing regimen as recommended (PM/AM split dose).
OSMOPREP® (sodium phosphate monobasic monohydrate, USP, and sodium phosphate dibasic anhydrous, USP) Tablets are indicated for cleansing
of the colon as a preparation for colonoscopy in adults 18 years of age or older. Considerable caution should be advised before OSMOPREP is used in
patients with severe renal insufficiency, congestive heart failure, ascites, unstable angina, gastric retention, ileus, severe chronic constipation,
bowel perforation, toxic megacolon, gastric bypass or stapling surgery, or hypomotility syndrome. Use with caution in patients with impaired renal
function, patients with a history of seizures or at higher risk of seizure, patients with higher risk of cardiac arrhythmias, known or suspected electrolyte
disturbances (such as dehydration), or people taking drugs that affect electrolyte levels. Patients with electrolyte abnormalities such as
hypernatremia, hyperphosphatemia, hypokalemia, or hypocalcemia should have their electrolytes corrected before treatment with OSMOPREP.
OSMOPREP is contraindicated in patients with a known allergy or hypersensitivity to sodium phosphate salts or any of its ingredients, and in patients with
biopsy–proven acute phosphate nephropathy. In clinical trials, the most commonly reported adverse reactions (reporting frequency >3%) were
abdominal bloating, nausea, abdominal pain, and vomiting. It is recommended that patients receiving OSMOPREP be advised to adequately hydrate before,
during, and after the use of OsmoPrep.
For complete Prescribing Information for OSMOPREP including BOXED WARNING, please click here.
Important Safety Information about XIFAXAN 550 mg
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%).
For complete Prescribing Information, please click here.
Important Safety Information about METOZOLV ODT
Treatment with metoclopramide can cause tardive dyskinesia, a serious movement disorder that is often irreversible.
The risk of developing tardive dyskinesia increases with the duration of treatment and the total cumulative dose.
Metoclopramide therapy should be discontinued in patients who develop signs or symptoms of tardive dyskinesia.
There is no known treatment for tardive dyskinesia. In some patients, symptoms may lessen or resolve after metoclopramide treatment is stopped.
Treatment with metoclopramide for longer than 12 weeks should be avoided in all but rare cases where therapeutic benefit is thought to outweigh the risk of developing tardive dyskinesia.
METOZOLV® ODT
(metoclopramide HCl) is indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic, documented gastroesophageal
reflux disease (GERD) who fail to respond to conventional therapy and for the relief of symptoms associated with acute and
recurrent diabetic gastroparesis (diabetic gastric stasis) in adults. Therapy should not exceed 12 weeks in duration. Take on
an empty stomach up to four times daily, at least 30 minutes before eating and at bedtime.
METOZOLV ODT is contraindicated in patients with intestinal obstruction, hemorrhage, or perforation; pheochromocytoma;
known sensitivity or intolerance to metoclopramide; epilepsy; or are receiving concomitant medications with extrapyramidal reactions.
Extrapyramidal symptoms (EPS), manifested primarily as acute dystonic reactions, occur in approximately 1 in 500 patients treated with the
usual adult dosages of 30 to 40 mg/day of metoclopramide. These usually are seen during the first 24 to 48 hours of treatment with metoclopramide,
occur more frequently in pediatric patients and adult patients less than 30 years of age and are even more frequent at higher doses.
Drug-induced Parkinsonism can occur during metoclopramide therapy, more commonly within the first 6 months after beginning treatment,
but also after longer periods. Patients with a history of Parkinson’s disease should be given metoclopramide cautiously, if at all,
since such patients can experience exacerbation of Parkinsonian symptoms when taking metoclopramide.
There have been rare reports of an uncommon but potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) associated
with metoclopramide. Clinical manifestations of NMS include hyperthermia, muscle rigidity, altered consciousness, and evidence of autonomic instability.
The management of NMS should include immediate discontinuation of metoclopramide and other drugs not essential to concurrent therapy.
Depression associated with metoclopramide use has occurred in patients with and without a history of depression.
For those patients with a prior history of depression, metoclopramide should only be given if the expected benefits outweigh the potential risks.
In one study in hypertensive patients, intravenously administered metoclopramide was shown to release catecholamines; hence, caution should be exercised
when metoclopramide is used in patients with hypertension. Any rapid rise in blood pressure associated with METOZOLV ODT use should result in immediate
cessation of metoclopramide use in those patients.
Since metoclopramide produces a transient increase in plasma aldosterone, patients with cirrhosis or congestive heart failure may be at risk of developing
fluid retention and volume overload. If these side effects occur at any time in any patients during metoclopramide therapy, the drug should be discontinued.
Adverse reactions, especially those involving the nervous system, may occur after stopping the use of METOZOLV ODT.
In clinical studies, the most frequently reported adverse events (≥2% occurrence) were headache, nausea, fatigue, somnolence, and vomiting.
Full Prescribing Information for METOZOLV ODT, including BOXED WARNING.