Rifaximin

1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of XIFAXAN and other antibacterial drugs, XIFAXAN when used to treat infection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. XIFAXAN is a rifamycin antibacterial indicated for: • Treatment of travelers’ diarrhea (TD) caused by noninvasive strains of Escherichia coli in adult and pediatric patients 12 years of age and older. ( 1.1 ) • Reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults. ( 1.2 ) • Treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. ( 1.3 ) Limitations of Use TD: Should not use in patients with diarrhea complicated by fever or blood in the stool or diarrhea due to pathogens other than Escherichia coli. ( 1.1, 5.1 ) 1.1 Travelers’ Diarrhea XIFAXAN is indicated for the treatment of travelers’ diarrhea (TD) caused by noninvasive strains of Escherichia coli in adults and pediatric patients 12 years of age and older. Limitations of Use 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 [see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.4 ), Clinical Studies ( 14.1 )]. 1.2 Hepatic Encephalopathy XIFAXAN is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults. In the placebo-controlled trial of XIFAXAN for HE, 91% of the patients were using lactulose concomitantly. Differences in the treatment effect of those patients not using lactulose concomitantly could not be assessed. XIFAXAN has not been studied in patients with MELD (Model for End-Stage Liver Disease) scores >25, and only 8.6% of patients in the placebo-controlled trial had MELD scores over 19. There is increased systemic exposure in patients with more severe hepatic dysfunction [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. 1.3 Irritable Bowel Syndrome with Diarrhea XIFAXAN is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.

2 DOSAGE AND ADMINISTRATION Condition Recommended Oral Dosage TD ( 2.1 ) 200 mg 3 times a day for 3 days HE ( 2.2 ) 550 mg 2 times a day IBS-D ( 2.3 ) 550 mg 3 times a day for 14 days. Patients who experience recurrence can be retreated up to 2 times with the same regimen. XIFAXAN can be taken with or without food. ( 2.4 ) 2.1 Dosage for Travelers’ Diarrhea The recommended dosage of XIFAXAN is 200 mg taken orally three times a day for 3 days. 2.2 Dosage for Hepatic Encephalopathy The recommended dosage of XIFAXAN is 550 mg taken orally two times a day. 2.3 Dosage for Irritable Bowel Syndrome with Diarrhea The recommended dosage of XIFAXAN is 550 mg taken orally three times a day for 14 days. Patients who experience a recurrence of symptoms can be retreated up to two times with the same dosage regimen. 2.4 Administration XIFAXAN can be taken with or without food [see Clinical Pharmacology ( 12.3 )].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Clostridium difficile -associated diarrhea [see Warnings and Precautions ( 5.2 )] Most common adverse reactions: • TD (≥2%): Headache ( 6.1 ) • HE (≥10%): Peripheral edema, nausea, constipation, dizziness, fatigue, urinary tract infection, insomnia, anemia, pruritus, and ascites ( 6.1 ) • IBS-D (≥2%): ALT increased, nausea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Travelers’ Diarrhea The safety of XIFAXAN 200 mg taken three times a day was evaluated in patients with travelers’ diarrhea consisting of 320 patients in two placebo-controlled clinical trials with 95% of patients receiving three or four days of treatment with XIFAXAN. The population studied had a mean age of 31.3 (18-79) years of which approximately 3% were ≥65 years old, 53% were male and 84% were White, 11% were Hispanic. Discontinuations due to adverse reactions occurred in 0.4% of patients. The adverse reactions leading to discontinuation were taste loss, dysentery, weight decrease, anorexia, nausea and nasal passage irritation. The adverse reaction that occurred at a frequency ≥2% in XIFAXAN-treated patients (n=320) at a higher rate than placebo (n=228) in the two placebo-controlled trials of TD was: • headache (10% XIFAXAN, 9% placebo) Hepatic Encephalopathy Trial 1 The data described in Table 1 reflect exposure to XIFAXAN in 348 patients, including 265 exposed for 6 months and 202 exposed for more than a year (mean exposure was 364 days). The safety of XIFAXAN 550 mg taken two times a day for reducing the risk of overt HE recurrence in adult patients was evaluated in a 6-month placebo-controlled clinical trial (n=140) and in a long-term follow-up study (n=280) [see Clinical Studies ( 14.2 )] . The population studied had a mean age of 56 (range: 21 to 82) years; approximately 20% of the patients were ≥65 years old, 61% were male, 86% were White, and 4% were Black. Ninety-one percent of patients in the trial were taking lactulose concomitantly. The most common adverse reactions that occurred at an incidence ≥5% and at a higher incidence in XIFAXAN-treated subjects than in the placebo group in the 6-month trial are provided in Table 1. Table 1: Common Adverse Reactions*from a Clinical Study of XIFAXAN in Adult Patients with Hepatic Encephalopathy (Trial 1) Adverse Reaction XIFAXAN Tablets 550 mg TWICE DAILY (N=140) n (%) Placebo (N=159) n (%) 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%) Pruritus 13 (9%) 10 (6%) Abdominal pain 12 (9%) 13 (8%) Anemia 11 (8%) 6 (4%) Depression 10 (7%) 8 (5%) Nasopharyngitis 10 (7%) 10 (6%) Abdominal pain upper 9 (6%) 8 (5%) Arthralgia 9 (6%) 4 (3%) Dyspnea 9 (6%) 7 (4%) Pyrexia 9 (6%) 5 (3%) Rash 7 (5%) 1. (4%) *Adverse reactions that occurred in ≥5% of XIFAXAN-treated patients and greater than in patients who received placebo Trial 2 The data described in Table 2 reflect exposure to XIFAXAN in 221 of 222 randomized subjects, exposed for a median duration of 169 days, with 113 exposed to XIFAXAN monotherapy and 108 exposed to XIFAXAN added onto lactulose in a six-month active-controlled trial [see Clinical Studies ( 14.2 )]. The population studied had a mean age of 58; approximately 63% of subjects were male. The most common adverse reactions that occurred at an incidence ≥5% are provided in Table 2. Table 2: Common Adverse Reactions*from a Clinical Study of XIFAXAN + Lactulose Compared to XIFAXAN Monotherapy in Adult Patients with Hepatic Encephalopathy (Trial 2) Adverse Reaction XIFAXAN Tablets 550 mg TWICE DAILY + Lactulose (N=108) n (%) XIFAXAN Tablets 550 mg TWICE DAILY (N=113) n (%) Peripheral edema 15 (14%) 19 (17%) Insomnia 15 (14%) 13 (12%) Ascites 14 (13%) 8 (7%) Diarrhea 13 (12%) 6 (5%) Nausea 11 (10%) 17 (15%) Muscle spasms 11 (10%) 9 (8%) Dyspnea 10 (9%) 8 (7%) Anxiety 10 (9%) 6 (5%) Constipation 9 (8%) 18 (16%) Fatigue 9 (8%) 16 (14%) Urinary tract infection 9 (8%) 13 (12%) Abdominal pain 8 (7%) 8 (7%) Pruritus 6 (6%) 11 (10%) Decreased appetite 5 (5%) 8 (7%) Headache 5 (5%) 8 (7%) Cough 5 (5%) 6 (6%) Renal failure acute 5 (5%) 7 (6%) Vomiting 6 (5%) 6 (6%) Anemia 3 (3%) 11 (10%) * Adverse reactions that occurred in ≥5% of patients receiving XIFAXAN in either treatment group Irritable Bowel Syndrome with Diarrhea The safety of XIFAXAN for the treatment of IBS-D was evaluated in 3 placebo-controlled studies in which 952 patients were randomized to XIFAXAN 550 mg three times a day for 14 days. Across the 3 studies, 96% of patients received at least 14 days of treatment with XIFAXAN. In Trials 1 and 2, 624 patients received only one 14-day treatment. Trial 3 evaluated the safety of XIFAXAN in 328 patients who received 1 open-label treatment and 2 double-blind repeat treatments of 14 days each over a period of up to 46 weeks. The combined population studied had a mean age of 47 (range: 18 to 88) years of whom approximately 11% of the patients were ≥ 65 years old, 72% were female, 88% were White, 9% were Black, and 12% were Hispanic. The adverse reaction that occurred at a frequency ≥2% in XIFAXAN-treated patients at a higher rate than placebo in Trials 1 and 2 for IBS-D was: • nausea (3% XIFAXAN, 2% placebo) The adverse reactions that occurred at a frequency ≥2% in XIFAXAN-treated patients (n=328) at a higher rate than placebo (n=308) in Trial 3 for IBS-D during the double-blind treatment phase were: • ALT increased (XIFAXAN 2%, placebo 1%) • nausea (XIFAXAN 2%, placebo 1%) Less Common Adverse Reactions The following adverse reactions, presented by body system, were reported in less than 2% of patients in clinical trials of TD and IBS-D and in less than 5% of patients in clinical trials of HE: Hepatobiliary disorders: Clostridium colitis Investigations: Increased blood creatine phosphokinase Musculoskeletal and connective tissue disorders: Myalgia 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of XIFAXAN. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to XIFAXAN. Infections and Infestations Cases of C. difficile- associated colitis have been reported [see Warnings and Precautions ( 5.2 )]. Hypersensitivity Reactions Exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration. Musculoskeletal and Connective Tissue Disorders Cases of rhabdomyolysis have been reported in patients with cirrhosis, with and without concomitant statin use. Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with the use of rifaximin in patients with cirrhosis. Discontinue rifaximin at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and conduct a clinical evaluation.

12.3 Pharmacokinetics Absorption In healthy subjects, the mean time to reach peak rifaximin plasma concentrations was about an hour and the mean Cmax ranged 2.4 to 4 ng/mL after a single dose and multiple doses of XIFAXAN 550 mg. Travelers’ Diarrhea Systemic absorption of XIFAXAN (200 mg three times daily) was evaluated in 13 subjects challenged with shigellosis on Days 1 and 3 of a three-day course of treatment. Rifaximin plasma concentrations and exposures were low and variable. There was no evidence of accumulation of rifaximin following repeated administration for 3 days (9 doses). Peak plasma rifaximin concentrations after 3 and 9 consecutive doses ranged from 0.81 to 3.4 ng/mL on Day 1 and 0.68 to 2.26 ng/mL on Day 3. Similarly, AUC0-last estimates were 6.95 ± 5.15 ng•h/mL on Day 1 and 7.83 ± 4.94 ng•h/mL on Day 3. XIFAXAN is not suitable for treating systemic bacterial infections because of limited systemic exposure after oral administration [see Warnings and Precautions ( 5.1 )] . Hepatic Encephalopathy Mean rifaximin exposure (AUCτ) in patients with a history of HE was approximately 12-fold higher than that observed in healthy subjects. Among patients with a history of HE, the mean AUC in patients with Child-Pugh Class C hepatic impairment was 2-fold higher than in patients with Child-Pugh Class A hepatic impairment [see Warnings and Precautions ( 5.4 ), Use in Specific Populations (8.7 )]. Irritable Bowel Syndrome with Diarrhea In patients with irritable bowel syndrome with diarrhea (IBS-D) treated with XIFAXAN 550 mg three times a day for 14 days, the median Tmax was 1 hour and mean Cmax and AUC were generally comparable with those in healthy subjects. After multiple doses, AUCtau was 1.65-fold higher than that on Day 1 in IBS-D patients (see Table 3). Table 1. Mean (± SD) Pharmacokinetic Parameters of Rifaximin Following XIFAXAN 550 mg Three Times a Day in IBS-D Patients and Healthy Subjects Healthy Subjects IBS-D Patients Single- Dose (Day 1) n=12 Multiple- Dose (Day 14) n=14 Single- Dose (Day 1) n=24 Multiple- Dose (Day 14) n=24 C max (ng/mL) 4.04 (1.51) 2.39 (1.28) 3.49 (1.36) 4.22 (2.66) T max (h)ª 0.75 (0.5-2.1) 1.00 (0.5-2.0) 0.78 (0-2) 1.00 (0.5-2) AUC tau (ng•h/mL) 10.4 (3.47) 9.30 (2.7) 9.69 (4.16) 16.0 (9.59) Half-life (h) 1.83 (1.38) 5.63 (5.27) 3.14 (1.71) 6.08 (1.68) ª Median (range) Food Effect in Healthy Subjects A high-fat meal consumed 30 minutes prior to XIFAXAN dosing in healthy subjects delayed the mean time to peak plasma concentration from 0.75 to 1.5 hours and increased the systemic exposure (AUC) of rifaximin by 2-fold but did not significantly affect C max . Dose-Proportionality After oral administration of XIFAXAN 200 mg, 400 mg, or 600 mg, rifaximin systemic exposures increased dose- dependently by approximately 2-fold for both AUClast and Cmax from 200 mg to 400 mg, but with a less than dose- proportional increase of 1.3-fold for both AUClast and Cmax from 400 mg to 600 mg administration. Distribution Rifaximin is moderately bound to human plasma proteins. In vivo , the mean protein binding ratio was 67.5% in healthy subjects and 62% in patients with hepatic impairment when XIFAXAN was administered. Elimination The mean half-life of rifaximin in healthy subjects at steady-state was 5.6 hours and was 6 hours in IBS-D patients. Metabolism In an in vitro study, rifaximin was metabolized mainly by CYP3A4. Rifaximin accounted for 18% of radioactivity in plasma suggesting that the absorbed rifaximin undergoes extensive metabolism. Excretion In a mass balance study, after administration of 400 mg 14 C-rifaximin orally to healthy volunteers, of the 96.94% total recovery, 96.62% of the administered radioactivity was recovered in feces mostly as the unchanged drug and 0.32% was recovered in urine mostly as metabolites with 0.03% as the unchanged drug. Biliary excretion of rifaximin was suggested by a separate study in which rifaximin was detected in the bile after cholecystectomy in patients with intact gastrointestinal mucosa. Specific Populations Hepatic Impairment The systemic exposure of rifaximin was markedly elevated in patients with hepatic impairment compared to healthy subjects. The pharmacokinetics of rifaximin in patients with a history of HE was evaluated after administration of XIFAXAN 550 mg twice a day. The pharmacokinetic parameters were associated with a high variability and mean rifaximin exposure (AUC τ ) in patients with a history of HE was higher compared to those in healthy subjects. The mean AUC τ in patients with hepatic impairment of Child-Pugh Class A, B, and C was 10-, 14-, and 21-fold higher, respectively, compared to that in healthy subjects (see Table 4). Table 2. Mean (± SD) Pharmacokinetic Parameters of Rifaximin at Steady-State in Patients with a History of Hepatic Encephalopathy by Child-Pugh Class Cross-study comparison with pharmacokinetic parameters in healthy subjects Healthy Subjects (n=14) Child-Pugh Class A (n=18) B (n=15) C (n=6) AUC tau (ng•h/mL) 12.3 ± 4.8 118 ± 67.8 169 ± 55.7 257 ± 100.2 C max (ng/mL) 3.4 ± 1.6 19.5 ± 11.4 25.4 ± 11.9 39.7 ± 13.4 T max (h) 0.8 (0.5, 4.0) 1 (0.9, 10) 1 (1.0, 4.2) • 1 (0, 2) Renal Impairment The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied. Drug Interaction Studies An in vitro study suggests that rifaximin is a substrate of CYP3A4. In vitro rifaximin is a substrate of P-glycoprotein, OATP1A2, OATP1B1, and OATP1B3. Rifaximin is not a substrate of OATP2B1. Cyclosporine In vitro in the presence of P-glycoprotein inhibitor, verapamil, the efflux ratio of rifaximin was reduced greater than 50%. In a clinical drug interaction study, mean Cmax for rifaximin was increased 83-fold, from 0.48 to 40.0 ng/mL; mean AUC∞ was increased 124-fold, from 2.54 to 314 ng●h/mL following co-administration of a single dose of XIFAXAN 550 mg with a single 600 mg dose of cyclosporine, an inhibitor of P-glycoprotein [see Drug Interactions ( 7.1 )] . Cyclosporine is also an inhibitor of OATP, breast cancer resistance protein (BCRP) and a weak inhibitor of CYP3A4. The relative contribution of inhibition of each transporter by cyclosporine to the increase in rifaximin exposure is unknown. Effect of rifaximin on other drugs In in vitro drug interaction studies, the IC 50 values for rifaximin was >50 micromolar (~60 mcg) for CYP isoforms 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, and 2E1. In vitro IC 50 value of rifaximin for CYP3A4 was 25 micromolar. Based on in vitro studies, clinically significant drug interaction via inhibition of 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 by rifaximin is not expected. The inhibitory effect of rifaximin on P-glycoprotein transport was observed in an in vitro study. The effect of rifaximin on P-gp transporter was not evaluated in vivo . In in vitro studies, rifaximin at 3 micromolar inhibited the uptake of estradiol glucuronide via OATP1B1 by 64% and via OATP1B3 by 70% while the uptake of estrone sulfate via OATP1A2 was inhibited by 40%. The inhibitory potential of rifaximin on these transporters at the clinically relevant concentrations is unknown. Midazolam In an in vitro study, rifaximin was shown to induce CYP3A4 at the concentration of 0.2 micromolar. No significant induction of CYP3A4 enzyme using midazolam as a substrate was observed when rifaximin was administered three times a day for 7 days at 200 mg and 550 mg doses in two clinical drug interaction studies in healthy subjects. The effect of XIFAXAN 200 mg administered orally every 8 hours for 3 days and for 7 days on the pharmacokinetics of a single dose of either 2 mg intravenous midazolam or 6 mg oral midazolam was evaluated in healthy subjects. No significant difference was observed in the systemic exposure or elimination of intravenous or oral midazolam or its major metabolite, 1’-hydroxymidazolam, between midazolam alone or together with XIFAXAN. Therefore, XIFAXAN was not shown to significantly affect intestinal or hepatic CYP3A4 activity for the 200 mg three times a day dosing regimen. When a single dose of 2 mg midazolam was orally administered after administration of XIFAXAN 550 mg three times a day for 7 days and 14 days to healthy subjects, the mean AUC of midazolam was 3.8% and 8.8% lower, respectively, than when midazolam was administered alone. The mean C max of midazolam was lower by 4 to 5% when XIFAXAN was administered for 7-14 days prior to midazolam administration. This degree of interaction is not considered clinically meaningful. Oral Contraceptives Containing Ethinyl Estradiol and Norgestimate The oral contraceptive study utilized an open-label, crossover design in 28 healthy female subjects to determine if XIFAXAN 200 mg orally administered three times a day for 3 days (the dosing regimen for travelers’ diarrhea) altered the pharmacokinetics of a single dose of an oral contraceptive containing 0.07 mg ethinyl estradiol and 0.5 mg norgestimate. Results showed that the pharmacokinetics of single doses of ethinyl estradiol and norgestimate were not altered by XIFAXAN. An open-label oral contraceptive study was conducted in 39 healthy female subjects to determine if XIFAXAN 550 mg orally administered three times a day for 7 days altered the pharmacokinetics of a single dose of an oral contraceptive containing 0.025 mg of ethinyl estradiol (EE) and 0.25 mg norgestimate (NGM). Mean C max of EE and NGM was lower by 25% and 13%, after the 7-day XIFAXAN regimen than when the oral contraceptive was given alone. The mean AUC values of NGM active metabolites were lower by 7% to approximately 11%, while AUC of EE was not altered in presence of rifaximin. The clinical relevance of the C max and AUC reductions in the presence of rifaximin is not known.