Rifaximin 550 mg · Tablets

Rifaximin is an antibacterial drug [see Clinical Pharmacology (12.4)].

Absorption — In healthy subjects, the mean time to reach peak rifaximin plasma concentrations was about an hour and the mean Cmax ranged 2.4 to 4 ng/mL after a single dose and multiple doses of XIFAXAN 550 mg.

Travelers’ Diarrhea — Systemic absorption of XIFAXAN (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 (5.1)].

Hepatic Encephalopathy — Mean rifaximin exposure (AUCτ) in patients with a history of HE was approximately 12-fold higher than that observed in healthy subjects. Among patients with a history of HE, 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 Warnings and Precautions (5.4), Use in Specific Populations (8.7)].

Irritable Bowel Syndrome with Diarrhea — In patients with irritable bowel syndrome with diarrhea (IBS-D) treated with XIFAXAN 550 mg three times a day for 14 days, the median Tmax was 1 hour and mean Cmax and AUC were generally comparable with those in healthy subjects. After multiple doses, AUCtau was 1.65-fold higher than that on Day 1 in IBS-D patients (see 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 but did not significantly affect Cmax.

Dose-Proportionality — After oral administration of XIFAXAN 200 mg, 400 mg, or 600 mg, rifaximin systemic exposures increased dose- dependently by approximately 2-fold for both AUClast and Cmax from 200 mg to 400 mg, but with a less than dose- proportional increase of 1.3-fold for both AUClast and Cmax from 400 mg to 600 mg administration.

Distribution — 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 was administered.

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

Metabolism — In an in vitro study, rifaximin was metabolized mainly by CYP3A4. Rifaximin accounted for 18% of radioactivity in plasma suggesting that the absorbed rifaximin undergoes extensive metabolism.

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 mostly as the unchanged drug and 0.32% was recovered in urine mostly as metabolites with 0.03% as the unchanged drug.

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

Hepatic Impairment — The systemic exposure of rifaximin was markedly elevated in patients with hepatic impairment compared to healthy subjects.