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.

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)].

2 DOSAGE AND ADMINISTRATION

2.1 Dosage for Travelers’ Diarrhea

        The recommended dose of XIFAXAN is one 200 mg tablet taken orally three times a day for 3 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 a day, with or without food

3 DOSAGE FORMS AND STRENGTHS

        XIFAXAN is a 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.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

        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 [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Travelers’ Diarrhea Not Caused by Escherichia coli

        XIFAXAN was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than Escherichia coli.

        Discontinue XIFAXAN if diarrhea symptoms get worse or persist more than 24-48 hours and alternative antibiotic therapy should be considered.

        XIFAXAN is not effective in cases of travelers’ diarrhea due to Campylobacter jejuni. The effectiveness of XIFAXAN in travelers’ diarrhea caused by Shigella spp. and Salmonella spp. has not been proven. XIFAXAN should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.

5.2 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 antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile.

        C. difficile produces toxins A and B which contribute to the development of CDAD.  Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.  CDAD must be considered in all patients who present with diarrhea following antibiotic use.  Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

        If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.  Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical eva luation should be instituted as clinically indicated.

5.3 Development of Drug Resistant Bacteria

        Prescribing XIFAXAN for travelers’ diarrhea in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

5.4 Severe (Child-Pugh C) Hepatic Impairment

        There is increased systemic exposure in patients with severe hepatic impairment. Animal toxicity studies did not achieve systemic exposures that were seen in patients with severe hepatic impairment. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C)

6 ADVERSE REACTIONS

6.1 Clinical Studies 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 eva luated 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 irrigation.

        All adverse reactions for XIFAXAN 200 mg three times daily that occurred at a 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.)

        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 a 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 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 hepatic encephalopathy recurrence in adult patients was eva luated in a 6-month placebo-controlled clinical trial (n = 140) and in a long term follow-up study (n = 280).  The population studied had a 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 a 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).

        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 a day for hepatic encephalopathy. The following includes adverse events occurring at a 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 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)].

        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.

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 2 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 a 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 a 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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

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 a study of pregnant rats administered a high dose that resulted in 16 times the therapeutic dose to diarrheic patients or 1 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 1 or 2 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 1 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, a 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 a history of hepatic encephalopathy, the systemic exposure (i.e., AUCτ) 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