What Is The Drug Xifaxan Used For?

CLINICAL PHARMACOLOGY

Mechanism Of Action

Rifaximin is an antibacterial drug [see Microbiology].

Pharmacokinetics

Absorption

In salubrious subjects, the mean time to reach peak rifaximin plasma concentrations was about an 60 minutes and the mean Cmax ranged 2.four to 4 ng/mL after a unmarried dose and multiple doses of XIFAXAN 550 mg.

Travelers Diarrhea

Systemic absorption of XIFAXAN (200 mg three times daily) was evaluated in xiii subjects challenged with shigellosis on Days ane and 3 of a three-24-hour interval grade of treatment. Rifaximin plasma concentrations and exposures were low and variable. There was no show of aggregating of rifaximin following repeated administration for 3 days (9 doses). Peak plasma rifaximin concentrations after iii and 9 consecutive doses ranged from 0.81 to 3.iv ng/mL on Mean solar day 1 and 0.68 to 2.26 ng/mL on 24-hour interval 3. Similarly, AUC0-last estimates were half dozen.95 ± v.15 ng•h/mL on Day 1 and 7.83 ± 4.94 ng•h/mL on Day iii. XIFAXAN is not suitable for treating systemic bacterial infections because of limited systemic exposure after oral administration [come across WARNINGS AND PRECAUTIONS].

Hepatic Encephalopathy

Hateful rifaximin exposure (AUC τ) in patients with a history of HE was approximately 12-fold higher than that observed in salubrious subjects. Among patients with a history of HE, the mean AUC in patients with Child-Pugh Grade C hepatic impairment was 2-fold higher than in patients with Child-Pugh Class A hepatic harm [meet WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Irritable Bowel Syndrome With Diarrhea

In patients with irritable bowel syndrome with diarrhea (IBS-D) treated with XIFAXAN 550 mg three times a mean solar day for 14 days, the median Tmax was 1 hour and hateful Cmax and AUCtau were generally comparable with those in good for you subjects. After multiple doses, AUC was i.65-fold higher than that on Twenty-four hours 1 in IBS-D patients (Table 2).

Table two: Mean (± SD) Pharmacokinetic Parameters of Rifaximin Following XIFAXAN 550 mg Three Times a Mean solar day in IBS-D Patients and Healthy Subjects

	Healthy Subjects		IBS-D Patients
	Single-Dose (Day one) n=12	Multiple-Dose (Day fourteen) n=fourteen	Single-Dose (Day ane) n=24	Multiple-Dose (Day 14) n=24
C max (ng/mL)	4.04 (1.51)	2.39 (one.28)	3.49 (i.36)	four.22 (2.66)
T max (h) *	0.75 (0.v-2.ane)	1.00 (0.5-2.0)	0.78 (0-2)	i.00 (0.v-2)
AUC tau (ng•h/mL)	10.4 (three.47)	9.30 (2.7)	9.69 (4.sixteen)	16.0 (9.59)
Half-life (h)	i.83 (1.38)	5.63 (5.27)	3.fourteen (1.71)	half-dozen.08 (1.68)
* Median (range)

Food Issue In Healthy Subjects

A high-fat repast consumed 30 minutes prior to XIFAXAN dosing in good for you subjects delayed the mean time to summit plasma concentration from 0.75 to 1.5 hours and increased the systemic exposure (AUC) of rifaximin by 2-fold only did non significantly affect Cmax.

Distribution

Rifaximin is moderately spring to human being plasma proteins. In vivo, the mean protein bounden ratio was 67.five% in good for you subjects and 62% in patients with hepatic damage when XIFAXAN was administered.

Emptying

The mean half-life of rifaximin in healthy subjects at steady-state was 5.6 hours and was 6 hours in IBSD patients.

Metabolism

In an in vitro study rifaximin was metabolized mainly past CYP3A4. Rifaximin accounted for 18% of radioactive decay in plasma suggesting that the absorbed rifaximin undergoes extensive metabolism.

Excretion

In a mass remainder study, later 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 mostly as the unchanged drug and 0.32% was recovered in urine more often than not as metabolites with 0.03% equally the unchanged drug.

Biliary excretion of rifaximin was suggested by a dissever study in which rifaximin was detected in the bile subsequently cholecystectomy in patients with intact gastrointestinal mucosa.

Specific Populations

Hepatic Impairment

The systemic exposure of rifaximin was markedly elevated in patients with hepatic damage compared to healthy subjects.

The pharmacokinetics of rifaximin in patients with a history of HE was evaluated after administration of XIFAXAN 550 mg twice a day. The pharmacokinetic parameters were associated with a high variability and mean rifaximin exposure (AUC τ) in patients with a history of HE was higher compared to those in healthy subjects. The mean AUC τ in patients with hepatic impairment of Child-Pugh Class A, B, and C was ten-, 14-, and 21-fold higher, respectively, compared to that in healthy subjects (Table three).

Tabular array 3: Mean (± SD) Pharmacokinetic Parameters of Rifaximin at Steady-State in Patients with a History of Hepatic Encephalopathy by Child-Pugh Class*

	Healthy Subjects (northward=fourteen)	Child-Pugh Class
		A (n=18)	B (n=fifteen)	C (n=half dozen)
AUC tau (ng•h/mL)	12.3 ± 4.8	118 ± 67.viii	169 ± 55.7	257 ± 100.2
C max (ng/mL)	3.iv ± ane.half-dozen	xix.5 ± eleven.4	25.iv ± 11.9	39.vii ± 13.four
T max† (h)	0.8 (0.5, 4.0)	1 (0.9, x)	i (1.0, four.ii)	1 (0, ii)
*Cantankerous-study comparing with pharmacokinetic parameters in healthy subjects † Median (range)

Renal Harm

The pharmacokinetics of rifaximin in patients with impaired renal part has not been studied.

Drug Interaction Studies

Outcome Of Other Drugs On Rifaximin

An in vitro study suggests that rifaximin is a substrate of CYP3A4.

In vitro rifaximin is a substrate of P-glycoprotein, OATP1A2, OATP1B1, and OATP1B3. Rifaximin is not a substrate of OATP2B1.

Cyclosporine

In vitro in the presence of P-glycoprotein inhibitor, verapamil, the efflux ratio of rifaximin was reduced greater than fifty%. In a clinical drug interaction study, mean Cmax for rifaximin was increased 83-fold, from 0.48 to twoscore.0 ng/mL; hateful AUC∞ was increased 124-fold, from 2.54 to 314 ng•h/mL post-obit co-administration of a single dose of XIFAXAN 550 mg with a single 600 mg dose of cyclosporine, an inhibitor of P-glycoprotein [see DRUG INTERACTIONS] .

Cyclosporine is also an inhibitor of OATP, breast cancer resistance poly peptide (BCRP) and a weak inhibitor of CYP3A4. The relative contribution of inhibition of each transporter by cyclosporine to the increase in rifaximin exposure is unknown.

Upshot Of Rifaximin On Other Drugs

In in vitro drug interaction studies the IC50 values for rifaximin was >fifty micromolar (~60 mcg) for CYP isoforms 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, and 2E1. In vitro IC50 value of rifaximin for CYP3A4 was 25 micromolar. Based on in vitro studies, clinically pregnant drug interaction via inhibition of 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 by rifaximin is not expected.

The inhibitory issue of rifaximin on P-glycoprotein transport was observed in an in vitro study. The upshot of rifaximin on P-gp transporter was not evaluated in vivo.

In in vitro studies, rifaximin at 3 micromolar inhibited the uptake of estradiol glucuronide via OATP1B1 by 64% and via OATP1B3 by seventy% while the uptake of estrone sulfate via OATP1A2 was inhibited by 40%. The inhibitory potential of rifaximin on these transporters at the clinically relevant concentrations is unknown.

Midazolam

In an in vitro report, rifaximin was shown to induce CYP3A4 at the concentration of 0.two micromolar. No significant induction of CYP3A4 enzyme using midazolam equally a substrate was observed when rifaximin was administered three times a day for seven days at 200 mg and 550 mg doses in 2 clinical drug interaction studies in healthy subjects.

The effect of XIFAXAN 200 mg administered orally every eight hours for 3 days and for seven days on the pharmacokinetics of a single dose of either 2 mg intravenous midazolam or half-dozen mg oral midazolam was evaluated in salubrious subjects. No significant difference was observed in the systemic exposure or elimination of intravenous or oral midazolam or its major metabolite, 1-hydroxymidazolam, between midazolam alone or together with XIFAXAN. Therefore, XIFAXAN was non shown to significantly impact intestinal or hepatic CYP3A4 activity for the 200 mg three times a twenty-four hours dosing regimen.

When single dose of 2 mg midazolam was orally administered later administration of XIFAXAN 550 mg three times a solar day for 7 days and fourteen days to healthy subjects, the mean AUC of midazolam was three.8% and viii.8% lower, respectively, than when midazolam was administered alone. The mean Cmax of midazolam was lower by 4 to v% when XIFAXAN was administered for 7-14 days prior to midazolam administration. This degree of interaction is not considered clinically meaningful.

Oral Contraceptives Containing Ethinyl Estradiol And Norgestimate

The oral contraceptive written report utilized an open up-label, crossover pattern in 28 healthy female person subjects to decide if XIFAXAN 200 mg orally administered three times a day for 3 days (the dosing regimen for travelers diarrhea) altered the pharmacokinetics of a single dose of an oral contraceptive containing 0.07 mg ethinyl estradiol and 0.v mg norgestimate. Results showed that the pharmacokinetics of single doses of ethinyl estradiol and norgestimate were not altered by XIFAXAN.

An open-characterization oral contraceptive report was conducted in 39 healthy female subjects to decide if XIFAXAN 550 mg orally administered three times a day for seven days altered the pharmacokinetics of a single dose of an oral contraceptive containing 0.025 mg of ethinyl estradiol (EE) and 0.25 mg norgestimate (NGM). Hateful Cmax of EE and NGM was lower by 25% and 13%, after the 7-day XIFAXAN regimen than when the oral contraceptive was given solitary. The mean AUC values of NGM active metabolites were lower past 7% to approximately 11%, while AUC of EE was not contradistinct in presence of rifaximin. The clinical relevance of the C and AUC reductions in the presence of rifaximin is not known.

Microbiology

Mechanism Of Action

Rifaximin is a semi-synthetic derivative of rifampin and acts past binding to the beta-subunit of bacterial DNA-dependent RNA polymerase blocking one of the steps in transcription. This results in inhibition of bacterial poly peptide synthesis and consequently inhibits the growth of leaner.

Drug Resistance And Cross-Resistance

Resistance to rifaximin is caused primarily by mutations in the rpoB gene. This changes the binding site on Dna dependent RNA polymerase and decreases rifaximin binding affinity, thereby reducing efficacy. Cross-resistance betwixt rifaximin and other classes of antimicrobials has not been observed.

Antibacterial Activeness

Rifaximin has been shown to exist agile against the following pathogens both in vitro and in clinical studies of infectious diarrhea equally described in the Indications and Usage ( 1.1) section:

Escherichia coli (enterotoxigenic and enteroaggregative strains).

Susceptibility Tests

In vitro susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI).^1,2,3 However, the correlation between susceptibility testing and clinical outcome has not been determined.

Clinical Studies

Travelers Diarrhea

The efficacy of XIFAXAN given as 200 mg orally taken three times a day for three days was evaluated in 2 randomized, multicenter, double-blind, placebo-controlled studies in adult subjects with travelers diarrhea. I study was conducted at clinical sites in Mexico, Guatemala, and Republic of kenya (Written report 1). The other study was conducted in United mexican states, Guatemala, Peru, and India (Study 2). Stool specimens were collected earlier handling and 1 to 3 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 fourth dimension to concluding unformed stool (TLUS) which was defined as the time to the last unformed stool passed, after which clinical cure was alleged. Table 4 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 grouping.

Tabular array 4: Clinical Response in Study ane (ITT population)

	XIFAXAN (n=125)	Placebo (north=129)	Judge (97.five% CI)
Median TLUS (hours)	32.five	58.6	2 * (1.26, 2.50)
Clinical cure, north (%)	99 (79)	78 (lx)	19 † (5.3, 32.1)
*Take a chance Ratio (p-value <0.001) † Difference in rates (p-value <0.01)

Microbiological eradication (divers every bit the absence of a baseline pathogen in culture of stool afterwards 72 hours of therapy) rates for Report 1 are presented in Table 5 for patients with any pathogen at baseline and for the subset of patients with Escherichia coli at baseline. Escherichia coli was the simply pathogen with sufficient numbers to allow comparisons between treatment groups.

Even though XIFAXAN had microbiologic action like to placebo, it demonstrated a clinically meaning 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.

Table v: Microbiologic Eradication Rates in Study 1 Subjects with a Baseline Pathogen

	XIFAXAN	Placebo
Overall	48/seventy (69)	41/61 (67)
E. coli	38/53 (72)	40/54 (74)

The results of Study 2 supported the results presented for Study 1. In addition, this written report 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 bulk of the subjects treated with XIFAXAN who had Campylobacter jejuni isolated every bit a sole pathogen at baseline failed treatment and the resulting clinical cure rate for these patients was 23.5% (iv/17). In addition to not existence 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-characterization, pharmacokinetic study of oral XIFAXAN 200 mg taken every viii hours for 3 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 claiming trial was not acceptable to assess the effectiveness of XIFAXAN in the treatment of shigellosis, the following observations were noted: eight subjects received rescue handling with ciprofloxacin either because of lack of response to XIFAXAN treatment within 24 hours (2), or considering they adult severe dysentery (5), or because of recurrence of Shigella flexneri in the stool (ane); 5 of the 13 subjects received ciprofloxacin although they did not take evidence of severe illness or relapse.

Hepatic Encephalopathy

The efficacy of XIFAXAN 550 mg taken orally two times a day was evaluated in a randomized, placebo-controlled, double-blind, multi-center half dozen-month trial of adult subjects from the U.S., Canada and Russian federation who were defined as being in remission (Conn score of 0 or 1) from hepatic encephalopathy (HE). Eligible subjects had ≥two episodes of HE associated with chronic liver disease in the previous 6 months.

A total of 299 subjects were randomized to receive either XIFAXAN (north=140) or placebo (north=159) in this report. Patients had a mean historic period of 56 years (range, 21-82 years), 81% <65 years of age, 61% were male person and 86% White. At baseline, 67% of patients had a Conn score of 0 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 a MELD score of >25. Nine percentage of the patients were Kid-Pugh Class C. Lactulose was concomitantly used past 91% of the patients in each treatment arm of the study. Per the report protocol, patients were withdrawn from the study after experiencing a breakthrough HE episode. Other reasons for early on study discontinuation included: adverse reactions (XIFAXAN 6%; placebo iv%), patient request to withdraw (XIFAXAN iv%; placebo six%) and other (XIFAXAN 7%; placebo 5%).

The primary endpoint was the fourth dimension to start quantum overt HE episode. A breakthrough overt HE episode was defined equally a marked deterioration in neurological function and an increase of Conn score to Grade ≥ii. 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 i.

Breakthrough overt HE episodes were experienced past 31 of 140 subjects (22%) in the XIFAXAN group and by 73 of 159 subjects (46%) in the placebo group during the half dozen-month treatment period. Comparing of Kaplan-Meier estimates of event-gratis curves showed XIFAXAN significantly reduced the take a chance of HE breakthrough by 58% during the 6-calendar month treatment menstruum. 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 Curves1 in HE Written report (Time to First Breakthrough-HE Episode up to 6 Months of Treatment, Mean solar day 170) (ITT Population)

Note: Open diamonds and open triangles correspond censored subjects.

ⁱ Outcome-complimentary refers to non-occurrence of breakthrough HE.

When the results were evaluated by the post-obit demographic and baseline characteristics, the handling effect of XIFAXAN 550 mg in reducing the hazard of quantum overt HE recurrence was consistent for: sex, baseline Conn score, duration of electric current remission and diabetes. The differences in handling effect could not be assessed in the following subpopulations due to minor sample size: non- White (northward=42), baseline MELD >19 (n=26), Child-Pugh Form C (n=31), and those without concomitant lactulose apply (due north=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 outcome-free curves showed XIFAXAN significantly reduced the gamble of HE-related hospitalizations by 50% during the half-dozen-month treatment flow. Comparison of Kaplan-Meier estimates of event-free curves is shown in Figure 2.

Figure ii: Kaplan-Meier Issue-Free Curves1 in Pivotal HE Study (Time to First HE-Related Hospitalization in HE Study upwardly to half-dozen Months of Handling, Day 170) (ITT Population)

Note: Open diamonds and open triangles represent censored subjects.

^oneEvent-gratis refers to non-occurrence of HE-related hospitalization.

Irritable Bowel Syndrome With Diarrhea

The efficacy of XIFAXAN for the treatment of IBS-D was established in 3 randomized, multicenter, double-bullheaded, placebo-controlled trials in adult patients.

Trials 1 And two - Pattern

The get-go two trials, Trials one and 2 were of identical design. In these trials, a total of 1258 patients meeting Rome Ii criteria for IBS* were randomized to receive XIFAXAN 550 mg three times a day (north=624) or placebo (n=634) for 14 days and then followed for a 10-week treatment-free flow. The Rome II criteria further categorizes IBS patients into 3 subtypes: diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), or alternating IBS (bowel habits alternating between diarrhea and constipation). Patients with both IBS-D and alternate IBS were included in Trials 1 and ii. XIFAXAN is recommended for utilize in patients with IBS-D.

*Rome II Criteria: At least 12 weeks, which need non be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two out of three features: 1. Relieved with defecation; and/or two. Onset associated with a change in frequency of stool; and/or three. Onset associated with a change in course (appearance) of stool.

Symptoms That Cumulatively Back up The Diagnosis Of Irritable Bowel Syndrome

Abnormal stool frequency (for research purposes "abnormal" may exist defined as greater than 3 bowel movements per twenty-four hour period and less than 3 bowel movements per calendar week); Abnormal stool course (lumpy/difficult or loose/watery stool); Abnormal stool passage (straining, urgency, or feeling of incomplete evacuation); Passage of mucus; Bloating or feeling of abdominal amplification .

Trial 3 - Pattern

Trial 3 evaluated repeat treatment in adults with IBS-D coming together Rome III criteria** for upward to 46 weeks. A total of 2579 were enrolled to receive open-label XIFAXAN for fourteen days. Of 2438 evaluable patients, 1074 (44%) responded to initial treatment and were evaluated over 22 weeks for continued response or recurrence of IBS-symptoms. A total of 636 patients had symptom recurrence and were randomized into the double-blind phase of the study. These patients were scheduled to receive XIFAXAN 550 mg three times a day (north=328) or placebo (n=308) for ii additional 14-day repeat handling courses separated by 10 weeks. See Figure 3.

Figure 3: Trial iii Study Design

The IBS-D population from the three studies had mean age of 47 (range: xviii to 88) years of which approximately 11% of patients were ≥65 years quondam, 72% were female person and 88% were White.

**Rome Three Criteria: Recurrent abdominal hurting or discomfort (uncomfortable sensation not described as pain) at least three days/calendar month in concluding 3 months associated with 2 or more of the following: ane. Improvement with defecation; two. Onset associated with a modify in frequency of stool; 3. Onset associated with a modify in form (appearance) of stool.

Trials 1 And 2 - Results

Trials 1 and two included 1258 IBS-D patients (309 XIFAXAN, 314 placebo); (315 XIFAXAN, 320 placebo). The primary endpoint for both trials was the proportion of patients who achieved adequate relief of IBS signs and symptoms for at to the lowest degree two of 4 weeks during the month post-obit 14 days of treatment. Adequate relief was defined equally a response of "yep" to the following weekly Subject Global Assessment (SGA) question: "In regards to your IBS symptoms, compared to the manner you felt before you lot started written report medication, have you, in the past 7 days, had adequate relief of your IBS symptoms? [Yeah/No]."

Acceptable relief of IBS symptoms was experienced past more patients receiving XIFAXAN than those receiving placebo during the month following ii weeks of treatment (SGA-IBS Weekly Results: 41% vs. 31%, p=0.0125; 41% vs. 32%, p=0.0263 (Come across Table vi).

Table 6: Adequate Relief of IBS Symptoms During the Calendar month Following Two Weeks of Treatment

Endpoint	T rial 1			Trial two
	XIFAXAN n=309 north (%)	Placebo due north=314 n (%)	Treatment Difference (95% CI*)	XIFAXAN n=315 north (%)	Placebo due north=320 n (%)	Handling Difference (95% CI*)
Adequate Relief of IBS Symptoms †	126 (41)	98 (31)	10% (2.ane%, 17.one%)	128 (41)	103(32)	8% (1.0%, 15.nine%)
*Confidence Interval † The p-value for the primary endpoint for Trial i and for Trial 2 was <0.05.

The trials examined a composite endpoint which defined responders by IBS-related intestinal pain and stool consistency measures. Patients were monthly responders if they met both of the following criteria:

• experienced a ≥30% decrease from baseline in intestinal pain for ≥ii weeks during the calendar month post-obit 2 weeks of treatment
• had a weekly mean stool consistency score <four (loose stool) for ≥ii weeks during the calendar month following two weeks of treatment

More than patients receiving XIFAXAN were monthly responders for intestinal hurting and stool consistency in Trials 1 and two (see Table seven).

Table 7: Efficacy Responder Rates in Trial 1 and two During the Month Post-obit Two Weeks of Treatment

Endpoint	T rial one			Trial 2
	XIFAXAN n=309 n (%)	Placebo n=314 n (%)	Treatment Difference (95% CI*)	XIFAXAN north=315 north (%)	Placebo n=320 n (%)	Treatment Difference (95% CI*)
Abdominal Pain and Stool Consistency Responders †	144 (47)	121 (39)	8% (0.3%, 15.9%)	147 (47)	116 (36)	11% (2.seven%, eighteen.0%)
Abdominal Hurting Responders	159 (51)	132 (42)	9% (1.8%, 17.five%)	165 (52)	138 (43)	iii 70 (ane.5%, 17.0%)
Stool Consistency Responders	244 (79)	212 (68)	11% (4.4%, eighteen.2%)	233 (74)	206 (64)	10% (2.3%, 16.7%)
*Confidence Interval † The p-value for the composite endpoint for Trial 1 and 2 was <0.05 and <0.01, respectively.

Trial three - Results

In TARGET three, 2579 patients were scheduled to receive an initial xiv-mean solar day course of open up-characterization XIFAXAN followed by iv weeks of treatment-gratuitous follow-up. At the end of the follow-upwards period, patients were assessed for response to treatment. Patients were considered a responder if they achieved both of the following:

• ≥30% improvement from baseline in the weekly average abdominal hurting score based on the daily question: "In regards to your specific IBS symptoms of abdominal pain, on a scale of 0-10, what was your worst IBS-related abdominal pain over the concluding 24 hours? 'Naught' means you take no pain at all; '10' means the worst possible pain you can imagine".
• at least a 50% reduction in the number of days in a week with a daily stool consistency of Bristol Stool Calibration type 6 or 7 compared with baseline where 6=fluffy pieces with ragged edges, a mushy stool; 7=watery stool, no solid pieces; entirely liquid.

Responders were and so followed for recurrence of their IBS-related symptoms of intestinal pain or mushy/watery stool consistency for up to twenty treatment-free weeks.

When patients experienced recurrence of their symptoms of intestinal pain or mushy/watery stool consistency for 3 weeks of a rolling iv-calendar week period, they were randomized into the double-blind, placebo-controlled repeat treatment phase. Of 1074 patients who responded to open-label XIFAXAN, 382 experienced a period of symptom inactivity or decrease that did non require repeat treatment by the fourth dimension they discontinued, including patients who completed the 22 weeks afterward initial treatment with XIFAXAN. See Figure 3.

Overall, 1257 of 2579 patients (49%) were nonresponders in the open up-characterization stage and per the study protocol were withdrawn from the study. Other reasons for discontinuation include: patient asking (five%), patient lost to follow-upwards (4%), adverse reaction (iii%), and other (0.8%).

In that location were 1074 (44%) of 2438 evaluable patients who responded to initial handling with improvement in abdominal pain and stool consistency. The response rate for each IBS symptom during the open up-characterization stage of Trial three is similar to the rates seen in Trials 1 and ii (see Table 7). A full of 636 patients subsequently had sign and symptom recurrence and were randomized to the repeat treatment stage. The median fourth dimension to recurrence for patients who experienced initial response during the openlabel phase with XIFAXAN was 10 weeks (range 6 to 24 weeks).

The XIFAXAN and placebo treatment groups had similar baseline IBS symptom scores at the time of recurrence and randomization to the double-blind phase, but symptom scores were less severe than at written report entry into the open up-label stage.

Patients were accounted to have recurrent signs and symptoms by the following criteria: a return of abdominal hurting or lack of stool consistency for at least iii weeks during a 4-week follow-up menstruation. The main endpoint in the double-blind, placebo-controlled portion of the trial was the proportion of patients who were responders to repeat treatment in both IBS-related abdominal pain and stool consistency as defined higher up during the 4 weeks following the outset echo handling with XIFAXAN. The primary analysis was performed using the worst case assay method where patients with <4 days of diary entries in a given week are considered equally non-responders for that week.

More patients receiving XIFAXAN were monthly responders for abdominal pain and stool consistency in the primary analysis in Trial 3 (run across Table viii).

Table 8: Efficacy Responder Rates in Trial 3 in a Given Week for at Least 2 Weeks During Weeks iii to 6 of the Double-Blind, Start Repeat Treatment Phase

	Placebo (n=308) n (%)	XIFAXAN (north=328) due north (%)	Handling Divergence (95% CI*)
Combined Responder †: Intestinal Pain and Stool Consistency Responders‡	97 (31)	125 (38)	7% (0.9%, sixteen.9%)
Abdominal Pain Responders ( ≥30% reduction in abdominal pain)	130 (42)	166 (51)	9% (i.6%, 17.0%)
Stool Consistency Responders ( ≥fifty% reduction from baseline in days/week with loose or watery stools)	154 (l)	170 (52)	2% (-4.7%, 11.0%)
*Confidence Intervals were derived based on CMH exam adjusting for centre and patients' time to recurrence during maintenance phase. † Primary endpoint ‡ Subjects were IBS-related intestinal pain and stool consistency responders if they were both weekly IBS-related abdominal pain responders and weekly stool consistency responders in a given week for at least 2 weeks during Weeks three to 6 in the double-blind starting time repeat treatment phase. Weekly responder in IBS-related abdominal pain was defined as a 30% or greater improvement from baseline in the weekly boilerplate abdominal pain score. Weekly responder in stool consistency was defined as a 50% or greater reduction in the number of days in a calendar week with stool consistency of type six or seven compared with baseline. The p-value for this composite endpoint was <0.05.

30 six of 308 (eleven.7%) of placebo patients and 56 of 328 (17.i%) of XIFAXAN-treated patients responded to the first repeat handling and did non have recurrence of signs and symptoms through the treatment-gratis follow-up catamenia (ten weeks after first repeat treatment). The response rate difference was five.4% with 95% confidence interval (1.2% to xi.half dozen%).

REFERENCES

ane. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Canonical Standard Ninth Edition. CLSI document M07-A9. Wayne, PA: Clinical and Laboratory Standards Found, 2012.

2. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard 8th Edition. CLSI certificate M11-A8. Wayne, PA: Clinical and Laboratory Standards Institute, 2012.

iii. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Fourth Informational Supplement. CLSI document M100-S2. Wayne, PA: Clinical and Laboratory Standards Institute, 2014.

What Is The Drug Xifaxan Used For?,

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