Xifaxan Information
Xifaxan () 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 () 200 mg is indicated for the treatment of patients (≥ 12 years of age) with travelers’ diarrhea caused by noninvasive strains of , and .
Xifaxan () should not be used in patients with diarrhea complicated by fever or blood in the stool or diarrhea due to pathogens other than .
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 .
Xifaxan () Dosage Forms And Strengths
Xifaxan () is a pink-colored biconvex tablet and is available in the following strengths:
Xifaxan () Warnings And Precautions
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 .
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 . The effectiveness of Xifaxan () in travelers’ diarrhea caused by spp. and spp. has not been proven. Xifaxan () should not be used in patients where , spp., or spp. may be suspected as causative pathogens.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of , and surgical evaluation should be instituted as clinically indicated.
Xifaxan () Adverse Reactions
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.
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.
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
Blood and Lymphatic System Disorders:
Ear and Labyrinth Disorders:
Gastrointestinal Disorders:
General Disorders and Administration Site Conditions:
Infections and Infestations:
Injury and Poisoning:
Investigations:
Metabolic and Nutritional Disorders:
Musculoskeletal, Connective Tissue, and Bone Disorders:
Nervous System Disorders:
Psychiatric Disorders:
Renal and Urinary Disorders:
Respiratory, Thoracic, and Mediastinal Disorders:
Skin and Subcutaneous Tissue Disorders:
Vascular Disorders:
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 evaluated 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:
Gastrointestinal Disorders:
General Disorders and Administration Site Conditions:
Injury, Poisoning and Procedural Complications:
Investigations:
Metabolic and Nutritional Disorders:
Musculoskeletal, Connective Tissue, and Bone Disorders:
Nervous System Disorders:
Psychiatric Disorders:
Respiratory, Thoracic, and Mediastinal Disorders:
Vascular Disorders:
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 () .
Cases of -associated colitis have been reported .
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.
Xifaxan () Drug Interactions
An study has suggested that rifaximin induces CYP3A4 . 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 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
Xifaxan () Use In Specific Populations
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.
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
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.
Xifaxan () 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.
Xifaxan () Description
Xifaxan () tablets contain rifaximin, a non-aminoglycoside semi-synthetic, nonsystemic antibiotic derived from rifamycin SV. Rifaximin is a structural analog of rifampin. The chemical name for rifaximin is (2,16,18,20,21,22,23,24,25,26,27,28)-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-á]-benzimidazole-1,15(2)-dione,25-acetate. The empirical formula is CHNO 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 () Clinical Pharmacology
Travelers’ Diarrhea
Systemic absorption of rifaximin (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, AUC 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 .
Hepatic Encephalopathy
After a 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 a history of HE was evaluated after administration of Xifaxan () , 550 mg two times a day. The PK parameters were associated with a high variability and mean rifaximin exposure (AUC) in patients with a history of HE (147 ng•h/mL) was approximately 12-fold higher than that observed in healthy subjects following the same dosing regimen (12.3 ng•h/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).
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 (Table 4).
Xifaxan () can be administered with or without food .
Rifaximin is moderately bound to human plasma proteins. , the mean protein binding ratio was 67.5% in healthy subjects and 62% in patients with hepatic impairment when Xifaxan () 550 mg was administered.
In a mass balance study, after administration of 400 mg C-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 a separate study, rifaximin was detected in the bile after cholecystectomy in patients with intact gastrointestinal mucosa, suggesting biliary excretion of rifaximin.
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 C hepatic impairment was 2-fold higher than in patients with Child-Pugh Class A hepatic impairment (see Table 3), .
Renal Impairment
The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.
In vitro
In an study, rifaximin was shown to induce CYP3A4 at the concentration of 0.2 µM.
An study suggests that rifaximin is a substrate of P-glycoprotein. In the presence of P-glycoprotein inhibitor verapamil, the efflux ratio of rifaximin was reduced greater than 50% . The effect of P-glycoprotein inhibition on rifaximin was not evaluated .
The inhibitory effect of rifaximin on P-gp transporter was observed in an study. The effect of rifaximin on P-gp transporter was not evaluated.
Midazolam
The effect of rifaximin 200 mg administered orally every 8 hours for 3 days and for 7 days on the pharmacokinetics of a single dose of either midazolam 2 mg intravenous or midazolam 6 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 a day dosing regimen.
After Xifaxan () 550 mg was administered three times a day for 7 days and 14 days to healthy subjects, the mean AUC of single midazolam 2 mg orally was 3.8% and 8.8% lower, respectively, than when midazolam was administered alone. The mean C 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 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 rifaximin .
Effect of rifaximin on oral contraceptives was not studied for Xifaxan () 550 mg twice a day, the dosing regimen for hepatic encephalopathy.
Rifaximin is a 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.
Rifaximin is a 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 section: (enterotoxigenic and enteroaggregative strains).
For HE, rifaximin is thought to have an effect on the gastrointestinal flora.
Xifaxan () Nonclinical Toxicology
Malignant schwannomas in the heart were significantly increased in male Crl:CD® (SD) rats that received rifaximin by oral gavage for two years at 150 to 250 mg/kg/day (doses equivalent to 2.4 to 4 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 9 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 5 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).
Xifaxan () Clinical Studies
The efficacy of Xifaxan () given as 200 mg orally taken three times a day for 3 days was evaluated in 2 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 1 to 3 days following the end of treatment to identify enteric pathogens. The predominant pathogen in both studies was .
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 5 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.
Microbiological eradication (defined as the absence of a baseline pathogen in culture of stool after 72 hours of therapy) rates for Study 1 are presented in Table 6 for patients with any pathogen at baseline and for the subset of patients with at baseline. was the only pathogen with sufficient numbers to allow comparisons between treatment groups.
Even though Xifaxan () had microbiologic activity similar to placebo, it demonstrated a clinically significant reduction in duration of diarrhea and a higher clinical cure rate than placebo. Therefore, patients should be managed based on clinical response to therapy rather than microbiologic response.
The results of Study 2 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 , isolated in the baseline stool.
Also in this study, the majority of the subjects treated with Xifaxan () who had isolated as a 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 isolated at baseline were much lower than the eradication rates seen for .
In an unrelated open-label, pharmacokinetic study of oral Xifaxan () 200 mg taken every 8 hours for 3 days, 15 adult subjects were challenged with 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 in the stool (1); five of the 13 subjects received ciprofloxacin although they did not have evidence of severe disease or relapse.
The efficacy of Xifaxan () 550 mg taken orally two times a day was evaluated in a 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 0 or 1) from hepatic encephalopathy (HE). Eligible subjects had ≥ 2 episodes of HE associated with chronic liver disease in the previous 6 months.
A total of 299 subjects were randomized to receive either Xifaxan () (n=140) or placebo (n=159) in this study. Patients had a mean age of 56 years (range, 21-82 years), 81% 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 a 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. A breakthrough overt HE episode was defined as a marked deterioration in neurological function and an increase of Conn score to Grade ≥ 2. In patients with a baseline Conn score of 0, a breakthrough overt HE episode was defined as an increase in Conn score of 1 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 1 is the Kaplan-Meier event-free curve for all subjects (n = 299) in the study.
Figure 1: Kaplan-Meier Event-Free Curves in HE Study (Time to First Breakthrough-HE Episode up to 6 Months of Treatment, Day 170) (ITT Population)
1
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 C (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 Curves in Pivotal HE Study (Time to First HE-Related Hospitalization in HE Study up to 6 Months of Treatment, Day 170) (ITT Population)
Xifaxan () References
Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. National Committee for Clinical Laboratory Standards, Sixth Edition, Wayne PA. January 2003; 23 (2).
Xifaxan () Patient Counseling Information
Clostridium difficile
C. difficile
Warnings and Precautions ()
Patients should be informed that in patients with severe hepatic impairment (Child-Pugh C) there is an increase in systemic exposure to Xifaxan () .
Manufactured for:
Salix Pharmaceuticals, Inc.
Raleigh, NC 27615
Xifaxan () is a trademark of Salix Pharmaceuticals, Inc., under license from Alfa Wassermann S.p.A.Copyright © 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.
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VENART-156-2
OCT 2011
Xifaxan () Package Label - Principal Display
Xifaxan () Package Label - Principal Display
60 Tablets Unit Dose
Rx ONLY
