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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Travelers’ Diarrhea Not Caused by E. coli : XIFAXAN was not effective in diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than E. coli . If diarrhea symptoms get worse or persist for more than 24 to 48 hours, discontinue XIFAXAN and consider alternative antibiotics. ( 5.1 ) • Clostridium difficile -Associated Diarrhea: Evaluate if diarrhea occurs after therapy or does not improve or worsens during therapy. ( 5.2 ) • Hepatic Impairment: Use with caution in patients with severe (Child-Pugh Class C) hepatic impairment. ( 5.4 , 8.7 ) • Concomitant P-glycoprotein (P-gp) inhibitors (e.g., cyclosporine): Caution should be exercised when concomitant use of XIFAXAN and a P-glycoprotein inhibitor is needed. ( 5.5, 7.1 ) 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 to 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 [ see Indications and Usage ( 1.1 )]. 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 evaluation 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 Class C) Hepatic Impairment There is increased systemic exposure 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 Class C) [ see Use in Specific Populations ( 8.7 ), Clinical Studies ( 14.2 )]. 5.5 Concomitant Use with P-glycoprotein Inhibitors Concomitant administration of drugs that are P-glycoprotein (P-gp) inhibitors with XIFAXAN can substantially increase the systemic exposure to rifaximin. Caution should be exercised when concomitant use of XIFAXAN and a P-gp inhibitor such as cyclosporine is needed. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-gp inhibitors may further increase the systemic exposure to rifaximin [see Drug Interactions ( 7.1 ), 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%) 6 (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.