ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions in travelers diarrhea (>= 5%): Flatulence, headache, abdominal pain, rectal tenesmus, defecation urgency and nausea (6.1)Most common adverse reactions in HE (>= 10%): Peripheral edema, nausea, dizziness, fatigue, ascites, flatulence, and headache (6.1)To report suspected adverse reactions, contact Salix Pharmaceuticals at 1-800-508-0024 and www.Salix.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most common adverse reactions in travelers diarrhea (>= 5%): Flatulence, headache, abdominal pain, rectal tenesmus, defecation urgency and nausea (6.1). Most common adverse reactions in HE (>= 10%): Peripheral edema, nausea, dizziness, fatigue, ascites, flatulence, and headache (6.1). 6.1 Clinical Studies Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 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. All adverse reactions for XIFAXAN 200 mg three times daily that occurred at frequency >= 2% in the two placebo-controlled trials combined are provided in Table 1. (These include adverse reactions that may be attributable to the underlying disease.)Table 1. All Adverse Reactions With an Incidence >=2% Among Patients Receiving XIFAXAN Tablets, 200 mg Three Times Daily, in Placebo-Controlled StudiesMedDRA Preferred TermNumber (%) of Patients XIFAXANTablets, 600 mg/day(N 320)PlaceboN 228 NOS: Not otherwise specified Flatulence 36 (11%) 45 (20%) Headache 31 (10%) 21 (9%) Abdominal Pain NOS 23 (7%) 23 (10%) Rectal Tenesmus 23 (7%) 20 (9%) Defecation Urgency 19 (6%) 21 (9%) Nausea 17 (5%) 19 (8%) Constipation 12 (4%) (4%) Pyrexia 10 (3%) 10 (4%) Vomiting NOS (2%) (2%) The following adverse reactions, presented by body system, have also been reported in <2% of patients taking XIFAXAN in the two placebo-controlled clinical trials where the 200 mg tablet was taken three times day for travelers diarrhea. The following includes adverse reactions regardless of causal relationship to drug exposure. Blood and Lymphatic System Disorders: Lymphocytosis, monocytosis, neutropenia Ear and Labyrinth Disorders: Ear pain, motion sickness, tinnitus Gastrointestinal Disorders: Abdominal distension, diarrhea NOS, dry throat, fecal abnormality NOS, gingival disorder NOS, inguinal hernia NOS, dry lips, stomach discomfort General Disorders and Administration Site Conditions: Chest pain, fatigue, malaise, pain NOS, weakness Infections and Infestations: Dysentery NOS, respiratory tract infection NOS, upper respiratory tract infection NOS Injury and Poisoning: Sunburn Investigations: Aspartate aminotransferase increased, blood in stool, blood in urine, weight decreased Metabolic and Nutritional Disorders: Anorexia, dehydration Musculoskeletal, Connective Tissue, and Bone Disorders: Arthralgia, muscle spasms, myalgia, neck pain Nervous System Disorders: Abnormal dreams, dizziness, migraine NOS, syncope, loss of taste Psychiatric Disorders: Insomnia Renal and Urinary Disorders: Choluria, dysuria, hematuria, polyuria, proteinuria, urinary frequency Respiratory, Thoracic, and Mediastinal Disorders: Dyspnea NOS, nasal passage irritation, nasopharyngitis, pharyngitis, pharyngolaryngeal pain, rhinitis NOS, rhinorrhea Skin and Subcutaneous Tissue Disorders: Clamminess, rash NOS, sweating increased Vascular Disorders: Hot flashes NOS Hepatic Encephalopathy The data described below reflect exposure to XIFAXAN 550 mg in 348 patients, including 265 exposed for months and 202 exposed for more than year (mean exposure was 364 days). The safety of XIFAXAN 550 mg taken two times day for reducing the risk of overt hepatic encephalopathy recurrence in adult patients was evaluated in 6-month placebo-controlled clinical trial (n 140) and in long term follow-up study (n 280). The population studied had mean age of 56.26 (range: 21-82) 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. All adverse reactions that occurred at an incidence >= 5% and at higher incidence in XIFAXAN 550 mg-treated subjects than in the placebo group in the 6-month trial are provided in Table 2. (These include adverse events that may be attributable to the underlying disease).Table 2: Adverse Reactions Occurring in >= 5% of Patients Receiving XIFAXAN and at Higher Incidence Than Placebo Number (%) of Patients MedDRA Preferred Term XIFAXAN Tablets 550 mg TWICEDAILY = 140PlaceboN 159 Edema peripheral 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%) Abdominal distension 11 (8%) 12 (8%) Anemia 11 (8%) (4%) Cough 10 (7%) 11 (7%) Depression 10 (7%) (5%) Insomnia 10 (7%) 11 (7%) Nasopharyngitis 10 (7%) 10 (6%) Abdominal pain upper (6%) (5%) Arthralgia (6%) (3%) Back pain (6%) 10 (6%) Constipation (6%) 10 (6%) Dyspnea (6%) (4%) Pyrexia (6%) (3%) Rash (5%) (4%) The following adverse reactions, presented by body system, have also been reported in the placebo-controlled clinical trial in greater than 2% but less than 5% of patients taking XIFAXAN 550 mg taken orally two times day for hepatic encephalopathy. The following includes adverse events occurring at greater incidence than placebo, regardless of causal relationship to drug exposure. Ear and Labyrinth Disorders: Vertigo Gastrointestinal Disorders: Abdominal pain lower, abdominal tenderness, dry mouth, esophageal variceal bleed, stomach discomfort General Disorders and Administration Site Conditions: Chest pain, generalized edema, influenza like illness, pain NOS Infections and Infestations: Cellulitis, pneumonia, rhinitis, upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications: Contusion, fall, procedural pain Investigations: Weight increased Metabolic and Nutritional Disorders: Anorexia, dehydration, hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia Musculoskeletal, Connective Tissue, and Bone Disorders: Myalgia, pain in extremity Nervous System Disorders: Amnesia, disturbance in attention, hypoesthesia, memory impairment, tremor Psychiatric Disorders: Confusional state Respiratory, Thoracic, and Mediastinal Disorders: Epistaxis Vascular Disorders: Hypotension. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of XIFAXAN. Because these reactions are reported voluntarily from 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)]. General Hypersensitivity reactions, including 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.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Oral administration of rifaximin for 3-6 months produced hepatic proliferation of connective tissue in rats (50 mg/kg/day) and fatty degeneration of liver in dogs (100 mg/kg/day). However, plasma drug levels were not measured in these studies. Subsequently, rifaximin was studied at doses as high as 300 mg/kg/day in rats for months and 1000 mg/kg/day in dogs for months, and no signs of hepatotoxicity were observed. The maximum plasma AUC 0-8 hr values from the month rat and month dog toxicity studies (range: 42-127 ngoh/mL) was lower than the maximum plasma AUC 0-8 hr values in cirrhotic patients (range: 19-306 ngoh/mL).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Malignant schwannomas in the heart were significantly increased in male Crl:CD(R) (SD) rats that received rifaximin by oral gavage for two years at 150 to 250 mg/kg/day (doses equivalent to 2.4 to times the recommended dose of 200 mg three times daily for travelers diarrhea, and equivalent to 1.3 to 2.2 times the recommended dose of 550 mg twice daily for hepatic encephalopathy, based on relative body surface area comparisons). There was no increase in tumors in Tg.rasH2 mice dosed orally with rifaximin for 26 weeks at 150 to 2000 mg/kg/day (doses equivalent to 1.2 to 16 times the recommended daily dose for travelers diarrhea and equivalent to 0.7 to times the recommended daily dose for hepatic encephalopathy, based on relative body surface area comparisons). Rifaximin was not genotoxic in the bacterial reverse mutation assay, chromosomal aberration assay, rat bone marrow micronucleus assay, rat hepatocyte unscheduled DNA synthesis assay, or the CHO/HGPRT mutation assay. There was no effect on fertility in male or female rats following the administration of rifaximin at doses up to 300 mg/kg (approximately times the clinical dose of 600 mg/day, and approximately 2.6 times the clinical dose of 1100 mg/day, adjusted for body surface area).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Rifaximin is an antibacterial drug [see Clinical Pharmacology (12.4)].. 12.3 Pharmacokinetics. Absorption Travelers Diarrhea Systemic absorption of rifaximin (200 mg three times daily) was evaluated in 13 subjects challenged with shigellosis on Days and of 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 days (9 doses). Peak plasma rifaximin concentrations after and consecutive doses ranged from 0.81 to 3.4 ng/mL on Day and 0.68 to 2.26 ng/mL on Day 3. Similarly, AUC0-last estimates were 6.95 +- 5.15 ngoh/mL on Day and 7.83 +- 4.94 ngoh/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 After single dose and multiple doses of rifaximin 550 mg in healthy subjects, the mean time to reach peak plasma concentrations was about an hour. The pharmacokinetic (PK) parameters were highly variable and the accumulation ratio based on AUC was 1.37. The PK of rifaximin in patients with history of HE was evaluated after administration of XIFAXAN, 550 mg two times day. The PK parameters were associated with high variability and mean rifaximin exposure (AUC) in patients with history of HE (147 ngoh/mL) was approximately 12-fold higher than that observed in healthy subjects following the same dosing regimen (12.3 ngoh/mL). When PK parameters were analyzed based on Child-Pugh Class A, B, and C, the mean AUC was 10-, 13-, and 20-fold higher, respectively, compared to that in healthy subjects (Table 3).Table 3. Mean (+- SD) Pharmacokinetic Parameters of Rifaximin at Steady-State in Patients with History of Hepatic Encephalopathy by Child-Pugh Class1 Healthy Subjects(n 14)Child-Pugh ClassA (n 18)B (n 7)C (n 4) 1Cross-study comparison with PK parameters in healthy subjects 2Median (range) AUCtau (ngoh/mL) 12.3 +- 4.8 118 +- 67.8 161 +- 101 246 +- 120 Cmax (ng/mL) 3.4 +- 1.6 19.5 +- 11.4 25.1 +- 12.6 35.5 +- 12.5 Tmax (h) 0.8 (0.5, 4.0) (0.9, 10) (0.97, 1) (0, 2) Food Effect in Healthy Subjects 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 (Table 4).Table 4. Mean (+- SD) Pharmacokinetic Parameters After Single-Dose Administration of XIFAXAN Tablets 550 mg in Healthy Subjects Under Fasting and Fed Conditions (N 12) ParameterFastingFed Median (range) Cmax (ng/mL) 4.1 +- 1.5 4.8 +- 4.3 Tmax1 (h) 0.8 (0.5, 2.1) 1.5 (0.5, 4.1) Half-Life (h) 1.8 +- 1.4 4.8 +- 1.3 AUC (ngoh/mL) 11.1 +- 4.2 22.5 +- 12 XIFAXAN can be administered with or without food [see Dosage and Administration (2.1 and 2.2)]. 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 550 mg was administered. Metabolism and Excretion In mass balance study, after administration of 400 mg 14C-rifaximin orally to healthy volunteers, of the 96.94% total recovery, 96.62% of the administered radioactivity was recovered in feces almost exclusively as the unchanged drug and 0.32% was recovered in urine mostly as metabolites with 0.03% as the unchanged drug. Rifaximin accounted for 18% of radioactivity in plasma. This suggests that the absorbed rifaximin undergoes metabolism with minimal renal excretion of the unchanged drug. The enzymes responsible for metabolizing rifaximin are unknown. In separate study, rifaximin was detected in the bile after cholecystectomy in patients with intact gastrointestinal mucosa, suggesting biliary excretion of rifaximin. Specific Populations Hepatic Impairment The systemic exposure of rifaximin was markedly elevated in patients with hepatic impairment compared to healthy subjects. The mean AUC in patients with Child-Pugh Class hepatic impairment was 2-fold higher than in patients with Child-Pugh Class hepatic impairment (see Table 3), [see Warnings and Precautions (5.4) and Use in Specific Populations (8.7)]. Renal Impairment The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied. Drug Interactions In vitro drug interaction studies have shown that rifaximin, at concentrations ranging from to 200 ng/mL, did not inhibit human hepatic cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4. In an in vitro study, rifaximin was shown to induce CYP3A4 at the concentration of 0.2 uM. An in vitro study suggests that rifaximin is substrate of P-glycoprotein. In the presence of P-glycoprotein inhibitor verapamil, the efflux ratio of rifaximin was reduced greater than 50% in vitro. The effect of P-glycoprotein inhibition on rifaximin was not evaluated in vivo. The inhibitory effect of rifaximin on P-gp transporter was observed in an in vitro study. The effect of rifaximin on P-gp transporter was not evaluated in vivo. Midazolam The effect of rifaximin 200 mg administered orally every hours for days and for days on the pharmacokinetics of single dose of either midazolam mg intravenous or midazolam mg orally was evaluated in healthy subjects. No significant difference was observed in the metrics of systemic exposure or elimination of intravenous or oral midazolam or its major metabolite, 1-hydroxymidazolam, between midazolam alone or together with rifaximin. Therefore, rifaximin was not shown to significantly affect intestinal or hepatic CYP3A4 activity for the 200 mg three times day dosing regimen. After XIFAXAN 550 mg was administered three times day for days and 14 days to healthy subjects, the mean AUC of single midazolam mg orally was 3.8% and 8.8% lower, respectively, than when midazolam was administered alone. The mean Cmax of midazolam was also decreased by 4-5% when XIFAXAN was administered for 7-14 days prior to midazolam administration. This degree of interaction is not considered clinically meaningful. The effect of rifaximin on CYP3A4 in patients with impaired liver function who have elevated systemic exposure is not known. Oral Contraceptives Containing 0.07 mg Ethinyl Estradiol and 0.5 mg Norgestimate The oral contraceptive study utilized an open-label, crossover design in 28 healthy female subjects to determine if rifaximin 200 mg orally administered three times day for days (the dosing regimen for travelers diarrhea) altered the pharmacokinetics of 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 rifaximin [see Drug Interactions (7)]. Effect of rifaximin on oral contraceptives was not studied for XIFAXAN 550 mg twice day, the dosing regimen for hepatic encephalopathy. 12.4 Microbiology. Mechanism of Action Rifaximin is non-aminoglycoside semi-synthetic antibacterial derived from rifamycin SV. Rifaximin acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase resulting in inhibition of bacterial RNA synthesis. Escherichia coli has been shown to develop resistance to rifaximin in vitro. However, the clinical significance of such an effect has not been studied. Rifaximin is structural analog of rifampin. Organisms with high rifaximin minimum inhibitory concentration (MIC) values also have elevated MIC values against rifampin. Cross-resistance between rifaximin and other classes of antimicrobials has not been studied. Rifaximin has been shown to be active against the following pathogen in clinical studies of infectious diarrhea as described in the Indications and Usage (1) section: Escherichia coli (enterotoxigenic and enteroaggregative strains). For HE, rifaximin is thought to have an effect on the gastrointestinal flora. Susceptibility Tests In vitro susceptibility testing was performed according to the National Committee for Clinical Laboratory Standards (NCCLS) agar dilution method M7-A6 [see References (15)]. However, the correlation between susceptibility testing and clinical outcome has not been determined.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Travelers Diarrhea. The efficacy of XIFAXAN given as 200 mg orally taken three times day for days was evaluated in randomized, multi-center, double-blind, placebo-controlled studies in adult subjects with travelers diarrhea. One study was conducted at clinical sites in Mexico, Guatemala, and Kenya (Study 1). The other study was conducted in Mexico, Guatemala, Peru, and India (Study 2). Stool specimens were collected before treatment and to days following the end of treatment to identify enteric pathogens. The predominant pathogen in both studies was Escherichia coli. The clinical efficacy of XIFAXAN was assessed by the time to return to normal, formed stools and resolution of symptoms. The primary efficacy endpoint was time to last unformed stool (TLUS) which was defined as the time to the last unformed stool passed, after which clinical cure was declared. Table displays the median TLUS and the number of patients who achieved clinical cure for the intent to treat (ITT) population of Study 1. The duration of diarrhea was significantly shorter in patients treated with XIFAXAN than in the placebo group. More patients treated with XIFAXAN were classified as clinical cures than were those in the placebo group.Table 5. Clinical Response in Study (ITT population) XIFAXAN (n=125) Placebo (n=129)Estimate (97.5% CI) P-Value Hazard Ratio Difference in rates Median TLUS (hours) 32.5 58.6 1.78a (1.26, 2.50) 0.0002 Clinical cure, (%) 99 (79.2) 78 (60.5) 18.7b (5.3, 32.1) 0.001 Microbiological eradication (defined as the absence of baseline pathogen in culture of stool after 72 hours of therapy) rates for Study are presented in Table for patients with any pathogen at baseline and for the subset of patients with Escherichia coli at baseline. Escherichia coli was the only pathogen with sufficient numbers to allow comparisons between treatment groups. Even though XIFAXAN had microbiologic activity similar to placebo, it demonstrated clinically significant reduction in duration of diarrhea and higher clinical cure rate than placebo. Therefore, patients should be managed based on clinical response to therapy rather than microbiologic response.Table 6. Microbiologic Eradication Rates in Study Subjects with Baseline Pathogen XIFAXAN Placebo Overall 48/70 (68.6) 41/61 (67.2) E. coli 38/53 (71.7) 40/54 (74.1) The results of Study supported the results presented for Study 1. In addition, this study provided evidence that subjects treated with XIFAXAN with fever and/or blood in the stool at baseline had prolonged TLUS. These subjects had lower clinical cure rates than those without fever or blood in the stool at baseline. Many of the patients with fever and/or blood in the stool (dysentery-like diarrheal syndromes) had invasive pathogens, primarily Campylobacter jejuni, isolated in the baseline stool. Also in this study, the majority of the subjects treated with XIFAXAN who had Campylobacter jejuni isolated as sole pathogen at baseline failed treatment and the resulting clinical cure rate for these patients was 23.5% (4/17). In addition to not being different from placebo, the microbiologic eradication rates for subjects with Campylobacter jejuni isolated at baseline were much lower than the eradication rates seen for Escherichia coli. In an unrelated open-label, pharmacokinetic study of oral XIFAXAN 200 mg taken every hours for days, 15 adult subjects were challenged with Shigella flexneri 2a, of whom 13 developed diarrhea or dysentery and were treated with XIFAXAN. Although this open-label challenge trial was not adequate to assess the effectiveness of XIFAXAN in the treatment of shigellosis, the following observations were noted: eight subjects received rescue treatment with ciprofloxacin either because of lack of response to XIFAXAN treatment within 24 hours (2), or because they developed severe dysentery (5), or because of recurrence of Shigella flexneri in the stool (1); five of the 13 subjects received ciprofloxacin although they did not have evidence of severe disease or relapse.. 14.2 Hepatic Encephalopathy. The efficacy of XIFAXAN 550 mg taken orally two times day was evaluated in randomized, placebo-controlled, double-blind, multi-center 6-month trial of adult subjects from the U.S., Canada and Russia who were defined as being in remission (Conn score of or 1) from hepatic encephalopathy (HE). Eligible subjects had >= episodes of HE associated with chronic liver disease in the previous months. total of 299 subjects were randomized to receive either XIFAXAN (n=140) or placebo (n=159) in this study. Patients had mean age of 56 years (range, 21-82 years), 81% 65 years of age, 61% were male and 86% White. At baseline, 67% of patients had Conn score of and 68% had an asterixis grade of 0. Patients had MELD scores of either <= 10 (27%) or 11 to 18 (64%) at baseline. No patients were enrolled with MELD score of 25. Nine percent of the patients were Child-Pugh Class C. Lactulose was concomitantly used by 91% of the patients in each treatment arm of the study. Per the study protocol, patients were withdrawn from the study after experiencing breakthrough HE episode. Other reasons for early study discontinuation included: adverse reactions (XIFAXAN 6%; placebo 4%), patient request to withdraw (XIFAXAN 4%; placebo 6%) and other (XIFAXAN 7%; placebo 5%). The primary endpoint was the time to first breakthrough overt HE episode. breakthrough overt HE episode was defined as marked deterioration in neurological function and an increase of Conn score to Grade >= 2. In patients with baseline Conn score of 0, breakthrough overt HE episode was defined as an increase in Conn score of and asterixis grade of 1. Breakthrough overt HE episodes were experienced by 31 of 140 subjects (22%) in the XIFAXAN group and by 73 of 159 subjects (46%) in the placebo group during the 6-month treatment period. Comparison of Kaplan-Meier estimates of event-free curves showed XIFAXAN significantly reduced the risk of HE breakthrough by 58% during the 6-month treatment period. Presented below in Figure is the Kaplan-Meier event-free curve for all subjects (n 299) in the study.Figure 1: Kaplan-Meier Event-Free Curves1 in HE Study (Time to First Breakthrough-HE Episode up to Months of Treatment, Day 170) (ITT Population) Note: Open diamonds and open triangles represent censored subjects. Event-free refers to non-occurrence of breakthrough HE. When the results were evaluated by the following demographic and baseline characteristics, the treatment effect of XIFAXAN 550 mg in reducing the risk of breakthrough overt HE recurrence was consistent for: sex, baseline Conn score, duration of current remission and diabetes. The differences in treatment effect could not be assessed in the following subpopulations due to small sample size: non-White (n=42), baseline MELD 19 (n=26), Child-Pugh (n=31), and those without concomitant lactulose use (n=26). HE-related hospitalizations (hospitalizations directly resulting from HE, or hospitalizations complicated by HE) were reported for 19 of 140 subjects (14%) and 36 of 159 subjects (23%) in the XIFAXAN and placebo groups respectively. Comparison of Kaplan-Meier estimates of event-free curves showed XIFAXAN significantly reduced the risk of HE-related hospitalizations by 50% during the 6-month treatment period. Comparison of Kaplan-Meier estimates of event-free curves is shown in Figure 2.Figure 2: Kaplan-Meier Event-Free Curves1 in Pivotal HE Study (Time to First HE-Related Hospitalization in HE Study up to Months of Treatment, Day 170) (ITT Population) Note: Open diamonds and open triangles represent censored subjects. Event-free refers to non-occurrence of HE-related hospitalization. Kaplan-Meier Event-Free Curves Graph. Kaplan-Meier Event-Free CurvesPivotalHEStudy.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. History of hypersensitivity to rifaximin, rifamycin antimicrobial agents, or any of the components of XIFAXAN (4.1) 4.1 Hypersensitivity. XIFAXAN is contraindicated in patients with 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 [see Adverse Reactions 6.2 )].

DESCRIPTION SECTION.

11 DESCRIPTION. XIFAXAN tablets contain rifaximin, non-aminoglycoside semi-synthetic, nonsystemic antibiotic derived from rifamycin SV. Rifaximin is structural analog of rifampin. The chemical name for rifaximin is (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-a]-benzimidazole-1,15(2H)-dione,25-acetate. The empirical formula is C43H51N3O11 and its molecular weight is 785.9. The chemical structure is represented below: XIFAXAN Tablets for oral administration are film-coated and contain 200 mg or 550 mg of rifaximin. Inactive ingredients: Each 200 mg tablet contains colloidal silicon dioxide, disodium edetate, glycerol palmitostearate, hypromellose, microcrystalline cellulose, propylene glycol, red iron oxide, sodium starch glycolate, talc, and titanium dioxide.Each 550 mg tablet contains colloidal silicon dioxide, glycerol palmitostearate, microcrystalline cellulose, polyethylene glycol/macrogol, polyvinyl alcohol, red iron oxide, sodium starch glycolate, talc, and titanium dioxide.. Xifaxan Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Travelers diarrhea: One 200 mg tablet taken orally three times day for days, with or without food (2.1)Hepatic encephalopathy: One 550 mg tablet taken orally two times day, with or without food (2.2). Travelers diarrhea: One 200 mg tablet taken orally three times day for days, with or without food (2.1). Hepatic encephalopathy: One 550 mg tablet taken orally two times day, with or without food (2.2). 2.1 Dosage for Travelers Diarrhea. The recommended dose of XIFAXAN is one 200 mg tablet taken orally three times day for days. XIFAXAN can be administered orally, with or without food [see Clinical Pharmacology (12.3)].. 2.2 Dosage for Hepatic Encephalopathy. The recommended dose of XIFAXAN is one 550 mg tablet taken orally two times day, with or without food[see Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. XIFAXAN is pink-colored biconvex tablet and is available in the following strengths:200 mg a round tablet debossed with Sx on one side. 550 mg an oval tablet debossed with rfx on one side.. 200 mg a round tablet debossed with Sx on one side. 550 mg an oval tablet debossed with rfx on one side.. 200 mg and 550 mg tablets (3). 200 mg and 550 mg tablets (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. In vitro studies have shown that rifaximin did not inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 at concentrations ranging from to 200 ng/mL [see Clinical Pharmacology (12.3)]. Rifaximin is not expected to inhibit these enzymes in clinical use. An in vitro study has suggested that rifaximin induces CYP3A4 [see Clinical Pharmacology (12.3)]. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. An in vitro study suggested that rifaximin is substrate of P-glycoprotein. It is unknown whether concomitant drugs that inhibit P-glycoprotein can increase the systemic exposure of rifaximin [see Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies with rifaximin 200 mg for travelers diarrhea did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects. In the controlled trial with XIFAXAN 550 mg for hepatic encephalopathy, 19.4% were 65 and over, while 2.3% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 200 mg tablet is pink-colored, round, biconvex tablet with Sx debossed on one side. It is available in the following presentations: NDC 54868-5972-1, bottles of 03 tablets NDC 54868-5972-2, bottles of 09 tabletsNDC 54868-5972-0, bottles of 30 tablets The 550 mg tablet is pink-colored, oval, biconvex tablet with rfx debossed on one side. It is available in the following presentations:NDC 54868-6154-0, bottles of 02 tablets NDC 54868-6154-1, bottles of 09 tabletsNDC 54868-6154-2, bottles of 10 tabletsStorage Store XIFAXAN Tablets at 20-25C (68-77F); excursions permitted to 15-30C (59-86F). See USP Controlled Room Temperature.. NDC 54868-5972-1, bottles of 03 tablets NDC 54868-5972-2, bottles of 09 tablets. NDC 54868-5972-0, bottles of 30 tablets. NDC 54868-6154-0, bottles of 02 tablets NDC 54868-6154-1, bottles of 09 tablets. NDC 54868-6154-2, bottles of 10 tablets.

INDICATIONS & USAGE SECTION.

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 rifamycin antibacterial indicated for:The treatment of patients (>= 12 years of age) with travelers diarrhea (TD) caused by noninvasive strains of Escherichia coli (1.1)Reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients >= 18 years of age (1.2)Limitations of UseTD: Do 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). The treatment of patients (>= 12 years of age) with travelers diarrhea (TD) caused by noninvasive strains of Escherichia coli (1.1). Reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients >= 18 years of age (1.2). TD: Do 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). 1.1 Travelers Diarrhea. XIFAXAN 200 mg is indicated for the treatment of patients (>= 12 years of age) with travelers diarrhea caused by noninvasive strains of Escherichia coli see Warnings and Precautions (5), Clinical Pharmacology (12.4) and Clinical Studies (14.1)]. 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.. 1.2 Hepatic Encephalopathy. 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. 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 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)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 17.1 Persistent Diarrhea. For those patients being treated for travelers diarrhea, discontinue XIFAXAN if diarrhea persists more than 24-48 hours or worsens. Advise the patient to seek medical care for fever and/or blood in the stool [see Warnings and Precautions (5.1)].. 17.2 Clostridium difficile-Associated Diarrhea. 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 antibiotics alters the normal flora of the colon which may lead to C. difficile. Patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If diarrhea occurs after therapy or does not improve or worsens during therapy, advise patients to contact physician as soon as possible [see Warnings and Precautions (5.4)].. 17.3 Administration with Food. Inform patients that XIFAXAN may be taken with or without food.. 17.4 Antibacterial Resistance. Counsel patients that antibacterial drugs including XIFAXAN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When XIFAXAN is prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by XIFAXAN or other antibacterial drugs in the future.. 17.5 Severe Hepatic Impairment. Patients should be informed that in patients with severe hepatic impairment (Child-Pugh C) there is an increase in systemic exposure to XIFAXAN [see Warnings and Precautions (5.4)].Manufactured for:Salix Pharmaceuticals, Inc. Raleigh, NC 27615XIFAXAN(R) is trademark of Salix Pharmaceuticals, Inc., under license from Alfa Wassermann S.p.A.Copyright (C) Salix Pharmaceuticals, Inc.Rifaximin for Travelers Diarrhea and Hepatic encephalopathy is protected by US Patent Nos. 7,045,620; 7,612,199; 7,902,206 and 7,906,542. Rifaximin for Travelers Diarrhea is also protected by US Patent No. 7,928,115.Web site: www.Salix.com All rights reserved.VENART-156-2OCT 2011Relabeling and Repackaging by:Physicians Total Care, Inc. Tulsa, Oklahoma 74146. salix-logo.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Rifaximin is an antibacterial drug [see Clinical Pharmacology (12.4)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Malignant schwannomas in the heart were significantly increased in male Crl:CD(R) (SD) rats that received rifaximin by oral gavage for two years at 150 to 250 mg/kg/day (doses equivalent to 2.4 to times the recommended dose of 200 mg three times daily for travelers diarrhea, and equivalent to 1.3 to 2.2 times the recommended dose of 550 mg twice daily for hepatic encephalopathy, based on relative body surface area comparisons). There was no increase in tumors in Tg.rasH2 mice dosed orally with rifaximin for 26 weeks at 150 to 2000 mg/kg/day (doses equivalent to 1.2 to 16 times the recommended daily dose for travelers diarrhea and equivalent to 0.7 to times the recommended daily dose for hepatic encephalopathy, based on relative body surface area comparisons). Rifaximin was not genotoxic in the bacterial reverse mutation assay, chromosomal aberration assay, rat bone marrow micronucleus assay, rat hepatocyte unscheduled DNA synthesis assay, or the CHO/HGPRT mutation assay. There was no effect on fertility in male or female rats following the administration of rifaximin at doses up to 300 mg/kg (approximately times the clinical dose of 600 mg/day, and approximately 2.6 times the clinical dose of 1100 mg/day, adjusted for body surface area).. 13.2 Animal Toxicology and/or Pharmacology. Oral administration of rifaximin for 3-6 months produced hepatic proliferation of connective tissue in rats (50 mg/kg/day) and fatty degeneration of liver in dogs (100 mg/kg/day). However, plasma drug levels were not measured in these studies. Subsequently, rifaximin was studied at doses as high as 300 mg/kg/day in rats for months and 1000 mg/kg/day in dogs for months, and no signs of hepatotoxicity were observed. The maximum plasma AUC 0-8 hr values from the month rat and month dog toxicity studies (range: 42-127 ngoh/mL) was lower than the maximum plasma AUC 0-8 hr values in cirrhotic patients (range: 19-306 ngoh/mL).

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. It is not known whether rifaximin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from XIFAXAN, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

OVERDOSAGE SECTION.

10 OVERDOSAGE. No specific information is available on the treatment of overdosage with XIFAXAN. In clinical studies at doses higher than the recommended dose (> 600 mg/day for travelers diarrhea or 1100 mg/day for hepatic encephalopathy), adverse reactions were similar in subjects who received doses higher than the recommended dose and placebo. In the case of overdosage, discontinue XIFAXAN, treat symptomatically, and institute supportive measures as required.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY. PACKAGE LABEL PRINCIPAL DISPLAY XIFAXAN 200 mg Tablets Xifaxan(R) (rifaxamin) tablets 200 mg Rx only. XIFAXAN 200 mg Tablets Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of XIFAXAN 200 mg in pediatric patients with travelers diarrhea less than 12 years of age have not been established. The safety and effectiveness of XIFAXAN 550 mg for HE have not been established in patients 18 years of age.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption Travelers Diarrhea Systemic absorption of rifaximin (200 mg three times daily) was evaluated in 13 subjects challenged with shigellosis on Days and of 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 days (9 doses). Peak plasma rifaximin concentrations after and consecutive doses ranged from 0.81 to 3.4 ng/mL on Day and 0.68 to 2.26 ng/mL on Day 3. Similarly, AUC0-last estimates were 6.95 +- 5.15 ngoh/mL on Day and 7.83 +- 4.94 ngoh/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 After single dose and multiple doses of rifaximin 550 mg in healthy subjects, the mean time to reach peak plasma concentrations was about an hour. The pharmacokinetic (PK) parameters were highly variable and the accumulation ratio based on AUC was 1.37. The PK of rifaximin in patients with history of HE was evaluated after administration of XIFAXAN, 550 mg two times day. The PK parameters were associated with high variability and mean rifaximin exposure (AUC) in patients with history of HE (147 ngoh/mL) was approximately 12-fold higher than that observed in healthy subjects following the same dosing regimen (12.3 ngoh/mL). When PK parameters were analyzed based on Child-Pugh Class A, B, and C, the mean AUC was 10-, 13-, and 20-fold higher, respectively, compared to that in healthy subjects (Table 3).Table 3. Mean (+- SD) Pharmacokinetic Parameters of Rifaximin at Steady-State in Patients with History of Hepatic Encephalopathy by Child-Pugh Class1 Healthy Subjects(n 14)Child-Pugh ClassA (n 18)B (n 7)C (n 4) 1Cross-study comparison with PK parameters in healthy subjects 2Median (range) AUCtau (ngoh/mL) 12.3 +- 4.8 118 +- 67.8 161 +- 101 246 +- 120 Cmax (ng/mL) 3.4 +- 1.6 19.5 +- 11.4 25.1 +- 12.6 35.5 +- 12.5 Tmax (h) 0.8 (0.5, 4.0) (0.9, 10) (0.97, 1) (0, 2) Food Effect in Healthy Subjects 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 (Table 4).Table 4. Mean (+- SD) Pharmacokinetic Parameters After Single-Dose Administration of XIFAXAN Tablets 550 mg in Healthy Subjects Under Fasting and Fed Conditions (N 12) ParameterFastingFed Median (range) Cmax (ng/mL) 4.1 +- 1.5 4.8 +- 4.3 Tmax1 (h) 0.8 (0.5, 2.1) 1.5 (0.5, 4.1) Half-Life (h) 1.8 +- 1.4 4.8 +- 1.3 AUC (ngoh/mL) 11.1 +- 4.2 22.5 +- 12 XIFAXAN can be administered with or without food [see Dosage and Administration (2.1 and 2.2)]. 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 550 mg was administered. Metabolism and Excretion In mass balance study, after administration of 400 mg 14C-rifaximin orally to healthy volunteers, of the 96.94% total recovery, 96.62% of the administered radioactivity was recovered in feces almost exclusively as the unchanged drug and 0.32% was recovered in urine mostly as metabolites with 0.03% as the unchanged drug. Rifaximin accounted for 18% of radioactivity in plasma. This suggests that the absorbed rifaximin undergoes metabolism with minimal renal excretion of the unchanged drug. The enzymes responsible for metabolizing rifaximin are unknown. In separate study, rifaximin was detected in the bile after cholecystectomy in patients with intact gastrointestinal mucosa, suggesting biliary excretion of rifaximin. Specific Populations Hepatic Impairment The systemic exposure of rifaximin was markedly elevated in patients with hepatic impairment compared to healthy subjects. The mean AUC in patients with Child-Pugh Class hepatic impairment was 2-fold higher than in patients with Child-Pugh Class hepatic impairment (see Table 3), [see Warnings and Precautions (5.4) and Use in Specific Populations (8.7)]. Renal Impairment The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied. Drug Interactions In vitro drug interaction studies have shown that rifaximin, at concentrations ranging from to 200 ng/mL, did not inhibit human hepatic cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4. In an in vitro study, rifaximin was shown to induce CYP3A4 at the concentration of 0.2 uM. An in vitro study suggests that rifaximin is substrate of P-glycoprotein. In the presence of P-glycoprotein inhibitor verapamil, the efflux ratio of rifaximin was reduced greater than 50% in vitro. The effect of P-glycoprotein inhibition on rifaximin was not evaluated in vivo. The inhibitory effect of rifaximin on P-gp transporter was observed in an in vitro study. The effect of rifaximin on P-gp transporter was not evaluated in vivo. Midazolam The effect of rifaximin 200 mg administered orally every hours for days and for days on the pharmacokinetics of single dose of either midazolam mg intravenous or midazolam mg orally was evaluated in healthy subjects. No significant difference was observed in the metrics of systemic exposure or elimination of intravenous or oral midazolam or its major metabolite, 1-hydroxymidazolam, between midazolam alone or together with rifaximin. Therefore, rifaximin was not shown to significantly affect intestinal or hepatic CYP3A4 activity for the 200 mg three times day dosing regimen. After XIFAXAN 550 mg was administered three times day for days and 14 days to healthy subjects, the mean AUC of single midazolam mg orally was 3.8% and 8.8% lower, respectively, than when midazolam was administered alone. The mean Cmax of midazolam was also decreased by 4-5% when XIFAXAN was administered for 7-14 days prior to midazolam administration. This degree of interaction is not considered clinically meaningful. The effect of rifaximin on CYP3A4 in patients with impaired liver function who have elevated systemic exposure is not known. Oral Contraceptives Containing 0.07 mg Ethinyl Estradiol and 0.5 mg Norgestimate The oral contraceptive study utilized an open-label, crossover design in 28 healthy female subjects to determine if rifaximin 200 mg orally administered three times day for days (the dosing regimen for travelers diarrhea) altered the pharmacokinetics of 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 rifaximin [see Drug Interactions (7)]. Effect of rifaximin on oral contraceptives was not studied for XIFAXAN 550 mg twice day, the dosing regimen for hepatic encephalopathy.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. XIFAXAN tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Administration of rifaximin to pregnant rats and rabbits at dose levels that caused reduced body weight gain resulted in eye malformations in both rat and rabbit fetuses. Additional malformations were observed in fetal rabbits that included cleft palate, lumbar scoliosis, brachygnathia, interventricular septal defect, and large atrium.The fetal rat malformations were observed in study of pregnant rats administered high dose that resulted in 16 times the therapeutic dose to diarrheic patients or times the therapeutic dose to patients with hepatic encephalopathy (based upon plasma AUC comparisons). Fetal rabbit malformations were observed from pregnant rabbits administered mid and high doses that resulted in or times the therapeutic dose to diarrheic patients or less than 0.1 times the dose in patients with hepatic encephalopathy, based upon plasma AUC comparisons.Post-natal developmental effects were not observed in rat pups from pregnant/lactating female rats dosed during the period from gestation to Day 20 post-partum at the highest dose which resulted in approximately 16 times the human therapeutic dose for travelers diarrhea (based upon AUCs) or approximately times the AUCs derived from therapeutic doses to patients with hepatic encephalopathy.

REFERENCES SECTION.

15 REFERENCES. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. National Committee for Clinical Laboratory Standards, Sixth Edition, Wayne PA. Approved Standard NCCLS Document M7-A6 January 2003; 23 (2).

SPL UNCLASSIFIED SECTION.

17.1 Persistent Diarrhea. For those patients being treated for travelers diarrhea, discontinue XIFAXAN if diarrhea persists more than 24-48 hours or worsens. Advise the patient to seek medical care for fever and/or blood in the stool [see Warnings and Precautions (5.1)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm (8.1)Nursing Mothers: Discontinue nursing or drug, taking into account the importance of the drug to the mother (8.3). Pregnancy: Based on animal data, may cause fetal harm (8.1). Nursing Mothers: Discontinue nursing or drug, taking into account the importance of the drug to the mother (8.3). 8.1 Pregnancy. Pregnancy Category There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. XIFAXAN tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Administration of rifaximin to pregnant rats and rabbits at dose levels that caused reduced body weight gain resulted in eye malformations in both rat and rabbit fetuses. Additional malformations were observed in fetal rabbits that included cleft palate, lumbar scoliosis, brachygnathia, interventricular septal defect, and large atrium.The fetal rat malformations were observed in study of pregnant rats administered high dose that resulted in 16 times the therapeutic dose to diarrheic patients or times the therapeutic dose to patients with hepatic encephalopathy (based upon plasma AUC comparisons). Fetal rabbit malformations were observed from pregnant rabbits administered mid and high doses that resulted in or times the therapeutic dose to diarrheic patients or less than 0.1 times the dose in patients with hepatic encephalopathy, based upon plasma AUC comparisons.Post-natal developmental effects were not observed in rat pups from pregnant/lactating female rats dosed during the period from gestation to Day 20 post-partum at the highest dose which resulted in approximately 16 times the human therapeutic dose for travelers diarrhea (based upon AUCs) or approximately times the AUCs derived from therapeutic doses to patients with hepatic encephalopathy.. 8.3 Nursing Mothers. It is not known whether rifaximin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from XIFAXAN, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.. 8.4 Pediatric Use. The safety and effectiveness of XIFAXAN 200 mg in pediatric patients with travelers diarrhea less than 12 years of age have not been established. The safety and effectiveness of XIFAXAN 550 mg for HE have not been established in patients 18 years of age.. 8.5 Geriatric Use. Clinical studies with rifaximin 200 mg for travelers diarrhea did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects. In the controlled trial with XIFAXAN 550 mg for hepatic encephalopathy, 19.4% were 65 and over, while 2.3% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.. 8.6 Renal Impairment. The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.. 8.7 Hepatic Impairment. Following administration of XIFAXAN 550 mg twice daily to patients with history of hepatic encephalopathy, the systemic exposure (i.e., AUC) of rifaximin was about 10-, 13-, and 20-fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively, compared to that in healthy volunteers. No dosage adjustment is recommended because rifaximin is presumably acting locally. Nonetheless, caution should be exercised when XIFAXAN is administered to patients with severe hepatic impairment[see Warnings and Precautions (5.4), Clinical Pharmacology (12.3), Nonclinical Toxicology (13.2), and Clinical Studies (14.2)].

WARNINGS AND PRECAUTIONS SECTION.

2.2 Dosage for Hepatic Encephalopathy. The recommended dose of XIFAXAN is one 550 mg tablet taken orally two times day, with or without food[see Clinical Pharmacology (12.3)].