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Mechanism Of Action
Rifaximin is an antibacterial drug.
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, AUC0-last 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 [see WARNINGS AND PRECAUTIONS].
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 (AUCτ) in patients with a history of HE (147 ng•h/mL) was approximately 12fold 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 AUCτ 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 a History of Hepatic Encephalopathy
by Child-Pugh Class1
(n = 14)
(n = 18)
(n = 7)
(n = 4)
|AUCtau (ng•h/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|
|Tmax2 (h)||0.8 (0.5, 4.0)||1 (0.9, 10)||1 (0.97, 1)||1 (0, 2)|
|1Cross-study comparison with PK parameters in healthy
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).
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)
|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 (ng•h/mL)||11.1 ± 4.2||22.5 ± 12|
XIFAXAN can be administered with or without food [see DOSAGE AND ADMINISTRATION].
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 a 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.
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), [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].
The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.
In vitro drug interaction studies have shown that rifaximin, at concentrations ranging from 2 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 μM.
An in vitro 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% in vitro. Following co-administration of a single 600-mg dose of cyclosporine, a potent inhibitor of P-glycoprotein and a weak inhibitor of CYP3A4, OATP, and BCRP, with a single dose of rifaximin 550 mg, rifaximin mean Cmax was increased 83-fold, from 0.48 to 40.0 ng/mL; mean AUC∞ was increased 124-fold, from 2.54 to 314 ng.h/mL.
An inhibitory effect of rifaximin on P-gp transport was observed in an in vitro study. The effect of rifaximin on P-gp transporter inhibition was not evaluated in vivo.
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 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 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.
Mechanism of Action
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.
Drug Resistance and Cross-Resistance
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 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.
Activity In Vitro and in Critical Infections
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.
In vitro susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) agar dilution method M7-A9 [see REFERENCES]. However, the correlation between susceptibility testing and clinical outcome has not been determined.
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 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 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.
Table 5: Clinical Response in Study 1 (ITT population)
|Estimate (97.5% CI)||P-Value|
|Median TLUS (hours)||32.5||58.6||1.78a
|Clinical cure, n (%)||99 (79.2)||78 (60.5)||18.7b
|a Hazard Ratio
bDifference in rates
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 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 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.
Table 6: Microbiologic
Eradication Rates in Study 1 Subjects with a Baseline Pathogen
|Overall||48/70 (68.6)||41/61 (67.2)|
|E. coli||38/53 (71.7)||40/54 (74.1)|
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 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 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 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 8 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 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.
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% < 65 years of age, 61% were male 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 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 Curves1 in
HE Study (Time to First Breakthrough-HE Episode up to 6 Months of Treatment,
Day 170) (ITT Population)
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 6month 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 6 Months of Treatment, Day 170) (ITT
Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
Last reviewed on RxList: 3/28/2014
This monograph has been modified to include the generic and brand name in many instances.
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