The University Hospitals and Clinics The University of Mississippi Medical Center Jackson, Mississippi

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1 The University Hospitals and Clinics The University of Mississippi Medical Center Jackson, Mississippi Pharmacy and Therapeutics Committee Drug Evaluation (Xifaxan ) June 2012 Generic Name Brand Name Xifaxan (Salix Pharmaceuticals) (Raleigh, North Carolina) Synonyms: none Therapeutic Class: Antibacterial agent of the rifamycin class Similar Drugs: Lactulose Formulary Neomycin Formulary Available Formulations: Oral Tablets: 550mg FDA Approved Indications: For reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients 18 years of age Unapproved Indications: Irritable bowel syndrome (IBS) without constipation Pharmacology: Nonaminoglycoside, semisynthetic antibacterial derived from rifamycin Binds to the betasubunit of bacterial DNAdependent RNA polymerase resulting in inhibition of bacterial RNA synthesis Structural analog of rifamycin Thought to have an effect of the gastrointestinal flora in patients with HE Pharmacokinetics: Absorption: Oral bioavailability is approximately < 0.4% Time to peak plasma concentrations (T max ) is ~1h after a single dose or multiple doses High fat meals 30 minutes prior to administration can delay the mean T max to ~1.5h and increase the AUC by ~2fold

2 Page 2 of 8 Contraindications: Distribution: 8090% of an administered dose remains in the gut Moderately bound to plasma proteins (~6267.5%) Metabolism/Excretion: Mostly eliminated in the unchanged drug form in the feces (~90%). The small portion of systemically absorbed rifaximin is metabolized to metabolites and excreted as metabolites and unchanged drug in the urine. has also been detected in the bile following cholecystectomy in patient with intact gastrointestinal mucosa, suggesting biliary excretion of rifaximin. In vitro, rifaximin has shown to induce CYP3A4 in hepatocytes. Hypersensitivity to rifaximin, any of the rifamycin antibiotics, or any of the components of rifaximin Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis Black Box Warning: None Warnings / Precautions: Clostridium difficileassociated diarrhea (CDAD): CDAD has been reported with the use rifaximin, and may range in severity from mild diarrhea to fatal colitis. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Development of drug resistant bacteria can occur with antibiotic administration. Severe (ChildPugh C) hepatic impairment: There is an increased systemic exposure in patients with severe hepatic impairment. The clinical trials were limited to patients with a model for endstage liver disease (MELD) score of <25. Therefore, caution should be exercised when administering rifaximin to patients with severe hepatic impairment.

3 Page 3 of 8 Table 1 Adverse effects occurring in 5% of patients receiving rifaximin (XIFAXAN ) and at a higher incidence than placebo rifaximin 550 mg BID N=140 placebo N=159 Peripheral edema 21 (15%) 13 (8%) Nausea 20 (14%) 21 (13%) Dizziness 18 (13%) 13 (8%) Fatigue 17 (12%) 18 (11%) Ascites 16 (11%) 15 (9%) Muscle spasms 13 (9%) 11 (7%) Pruritis 13 (9%) 10 (6%) Abdominal pain 12 (9%) 13 (8%) Abdominal distension 11 (8%) 12 (8%) Anemia 11 (8%) 6 (4%) Cough 10 (7%) 11 (7%) Depression 10 (7%) 8 (5%) Nasopharyngitis 10 (7%) 10 (6%) Abdominal pain upper 9 (6%) 8 (5%) Arthralgia 9 (6%) 4 (5%) Dyspnea 9 (6%) 11 (4%) Pyrexia 9 (6%) 5 (3%) Rash 7 (5%) 6 (4%) Bass NM, et al. N Engl J Med Mar;362(12): Drug Interactions: Minimal CYP 3A4 interactions (induction) are possible due to the drug class may be a Pglycoprotein substrate Studies have shown no inhibition of CYP P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4 Use in Children and Other Special Populations: Pediatric Use: <18 years has not been studied Geriatric Use: In clinical trials 19.4% of subjects were 65 y/o and 2.3% were 75 y/o. No overall difference in safety or efficacy was noted. Hepatic Impairment: Elevation of AUC 1020fold has been noted in patients with hepatic impairment (ChildPugh A, B, C), but no dosage adjustment is necessary. Renal Impairment: Has not been studied. Pregnancy/Lactation: Pregnancy Category C Nursing Mothers: It is not known whether rifaximin is excreted in human milk. Dosing/Administration: Recommended Dose: Hepatic encephalitis: 550 mg orally BID with or without food Irritable bowel syndrome: 550 mg orally q8h for 14 days Medication Error Potential Xifaxan : Reprexain : rifamycin

4 Page 4 of 8 Bass N.M. Table 2: Clinical Results; 550mg PO BID use for HE March 2010 N= 299 US (N=205) Canada (N=14) Russia (N=80) Randomized, placebocontrolled, doubleblind comparison of rifaximin vs. placebo on time to first breakthrough HE episode and HErelated hospitalization Inclusion criteria: 18 y/o 2 episodes of overt HE (Conn 2) associated with cirrhosis during previous 6 months In remission (Conn 01) upon enrollment MELD score 25 Exclusion criteria: Expected liver transplant in 1 mo. Presence of conditions that precipitate HE within 3 months before screening* Chronic renal insufficiency (Cr >2) Respiratory insufficiency Anemia (Hb <8) Intercurrent infection Spontaneous bacterial peritonitis Serum Na <125mEq/L Serum K <3.5mEq/L Serum Ca >10mg/dL Procedures: 550mg PO BID OR PO BID Treatment period: 6 months or until patients discontinue because of breakthrough HE or another reason Concomitant lactulose use was allowed. Outcome measures: The time to the first breakthrough episode of HE The time to the first hospitalization involving HE Number of patients with breakthrough episodes of HE (%) Number of patients with hospitalizations involving HE (%) Number of patients reporting adverse events (%) (N=140) (N=159) Hazard Ratio (95% CI) 41 (22.1) 73 (45.9) 0.42 ( ) P< (13.6) 36 (22.6) 0.50 ( ) P<0.01 Adverse Effects (See previous Table 1) Relative Risk Reduction 58% 50% (N=140) (N=159) Difference Significance 112 (80) 127 (79.9) P>0.05 for all comparisons Patients treated with rifaximin for 6 months showed a decreased risk for the development of an HE episode when compared to placebo. The reduction in risk of HE episode development was seen across most subgroups.** therapy also reduced the risk of a patient being hospitalized for an HE episode, supporting the clinical significance of this study. The adverse effect profiles for the two study drugs were not significantly different reflecting rifaximin s safety profile as a nonabsorbable antibiotic. There was no significant difference in daily lactulose use between the rifaximin and placebo treatment groups (3.14 cups/day vs cups/day, respectively) Deaths thought to be caused by disease progression 9 11 None * gastrointestinal hemorrhage, placement of portosystemic shunt, or transjugular intrahepatic portosystemic shunt ** geographic location, sex, age, race/ethnicity, baseline MELD score, baseline Conn score, diabetes, duration of current remission, number of episodes of HE within past 6 months, lactulose use at baseline, and placement of transjugular intrahepatic portosystemic shunt

5 Page 5 of 8 Sanyal A. October 2011 N=219 Randomized, placebocontrolled, doubleblind comparison of rifaximin vs. placebo on healthrelated quality of life (HRQL) scores Subgroup analysis of Bass N.M excluding Russian subjects because CLDQ is not validated in Russia Inclusion criteria: Same as previous study Exclusion criteria: Same as previous study Procedures: 550mg PO BID OR PO BID Treatment period: 6 months or until patients discontinue because of breakthrough HE or another reason Concomitant lactulose use was allowed. Outcome measures: vs. placebo treatment effects on chronic liver disease questionnaire (CLDQ) results Figure 1: Comparison of CDLQ overall and domain scores of rifaximin (N=118) vs. placebo (N=101) This study provides evidence that treating complications of cirrhosis, such as HE, improves HRQL. The effects of rifaximin treatment for HE demonstrated significant differences in overall and individual domain scores of HRQL compared to the results of treatment with placebo. Although it s not a measure of HRQL, it is highly likely that the reduction of risk of hospitalization with rifaximin treatment had a positive impact on the HRQL for these patients. There was no significant difference in daily lactulose use between the rifaximin and placebo treatment groups (3.14 cups/day vs cups/day, respectively)

6 Page 6 of 8 Bajaj J.S. Driving Simulator Outcomes Compared with Baseline February 2011 N= 42 Randomized, doubleblind, placebocontrolled trail comparing rifaximin vs. placebo on driving performance in patients with minimal HE (MHE)* Inclusion criteria: Patients with cirrhosis and cognitive dysfunction** No prior episode of overt HE No prior therapy for HE No psychotherapy drugs except stable doses of SSRIs Current car drivers Exclusion criteria: History of overt HE Alcohol and/or illicit drug abuse with the past 6 months Noncurrent car drivers MMSE < 25 Concomitant antibiotic use Allergy to rifampin, rifamycin, rifaximin Procedures: Treatment period: 8 weeks Outcome measures: vs. placebo treatment effects on driving performance in a simulated driving test vs. placebo treatments effects on cognitive function, QOL (SIP), and blood markers baseline end Pvalue for rifaximin group baseline end Pvalue for placebo group Total errors 10.3 ± ± ± ± Speeding tickets 4.4 ± ± ± ± Illegal turns 2.6 ± ± ± ± Collisions 3.2 ± ± ± ± Change in Simulator Outcomes by Group group group Pvalue Reduced total driving errors 16 (76%) 7 (33%) Reduced speeding tickets 17 (81%) 7 (33%) Reduced illegal turns 13 (62%) 4 (19%) Reduced collisions 9 (43%) 7 (33%) Cognitive tests Mean total cognitive battery Significant Changes in Cognitive Function withingroup comparison NCTA NCTB DST BDT ICT withingroup comparison NCTA NCTB DST BDT ICT % improved rifaximin % improved placebo There were no significant changes in QOL from baseline to endpoint or between rifaximin vs placebo treatment groups. The results showed that patients randomized to rifaximin have a higher rate of improvement in total driving errors, specifically speeding tickets and navigation of illegal turns on a simulated driving experience compared to patients randomized to placebo. No treatment group patients developed overt HE, infections, required antibiotics, or were hospitalized during the trial. There was no significant difference in the MELD score, ALT/AST level, and serum ammonia levels between the treatment groups at endpoint. Treatment adverse effects were similar between the groups, with the most common complaints being nausea, vomiting, HA, and abdominal pain. The only serum marker that significantly changed from baseline to endpoint in either group was IL10 in the rifaximin group. * MHE deficits in attention, reaction time, and working memory as a result of neurocognitive impairment in patients with hepatic cirrhosis ** Cognitive dysfunction Zscore of < 2 on 2 of the following tests: number connection test A and B (NCT A/B), digit symbol test (DST), block design test (BDT), and inhibitory control test (ICT) The difference of the total driving errors between treatment groups (# of speeding tickets, # of collisions, and # of illegal turns) SIP Sickness Impact Questionnaire; Blood markers: markers for inflammation (TNFa, IL2, IL6, IL10), markers for endothelial function (endotoxin, VCAM, asymmetric dimethyl arginine, soluble intracellular adhesion molecule), and markers for neuroglial injury (nonspecific enolase [NSE], s100b protein)

7 Page 7 of 8 Cost Comparison / Potential Budget Impact: Table 3: Drug Single Dose Cost/dose ($) Daily dose Cost/day ($) Xifaxan 550 mg mg Lactulose (10 g/15ml) 3045 ml (TID 8X/day) ml Neomycin 500 mg g Potential Advantages: Potential Disadvantages: Twice daily dosing with or without food Fewer GI issues (flatulence, bloating) than lactulose Minimal oral bioavailability No dosage adjustment for elderly, renal or hepatic impairment Cost Potential for antibiotic resistance Potential for antibiotic associated C. difficile infection Formulary Eligibility Criteria: Established efficacy superior to formulary agents? Established safety superior to formulary options? Significant cost/budget advantage versus formulary options? No Yes No Summary Recommendations: (Xifaxan ) is a nonabsorbable antibiotic of the rifamycin class of antibiotics. It works by inhibiting RNA synthesis in bacteria of the GI tract which is thought to decrease the production of ammonia by the GI flora. As a result, decreased circulating ammonia levels in the blood may benefit patients with an acute HE exacerbation, prevent an overt HE occurrence, and/or prevent a hospitalization due to a HE breakthrough event. at a dose of 1100 mg/day has not been proven superior to comparators (lactulose, neomycin). However, it has been shown to be effective and safe with or without lactulose in patients with HE. However, rifaximin provides a means of dosing that is much easier to adhere to when compared to lactulose, as lactulose is dosed to the desired effect. Adverse effects due to lactulose therapy, such as flatulence and bloating, are notably less in patients receiving rifaximin only. There is no potential cost savings for using rifaximin in the place of lactulose for HE as rifaximin cost more per day to administer. The Department of Pharmacy recommends not adding rifaximin 550 mg to formulary. Patients receiving rifaximin prior to admission will be honored per pharmacy s nonformulary policy (PS/D009).

8 Page 8 of 8 References: 1. Bass NM, Mullen KD, Sanyal A, et al. treatment in hepatic encephalopathy. N Engl J Med [Internet].2010 Mar25 [cited 2012 Apr 28];362(12): Available from: 2. Sanyal A, Younossi AM, Bass NM, et al. Randomised clinical trial: rifaximin improves healthrelated quality of life in cirrhotic patients with hepatic encephalopathy a doubleblind placebocontrolled study. Aliment Pharmacol Ther [Internet] Oct [cited 2012 Apr 28];34(8): Available from: 3. Bajaj JS, Heuman DM, Wade JB, et al. improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology [Internet] Feb [cited 2012 Apr 28];140(2): Available from: 4. [package insert] [cited 2012 Apr 25].