tial of rifaximin on these transporters at the clinically relevant concentrations is unknown.
Midazolam
In an in vitro study, rifaximin was shown to induce CYP3A4 at the concentration of 0.2 micromolar. No significant induction of CYP3A4 enzyme using midazolam as a substrate was observed when rifaximin was administered three times a day for 7 days at 200 mg and 550 mg doses in two clinical drug interaction studies in healthy subjects.
The effect of XIFAXAN 200 mg administered orally every 8 hours for 3 days and for 7 days on the pharmacokinetics of a single dose of either 2 mg intravenous midazolam or 6 mg oral midazolam was eva luated in healthy 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 not shown to significantly affect intestinal or hepatic CYP3A4 activity for the 200 mg three times a day dosing regimen.
When single dose of 2 mg midazolam was orally administered after administration of XIFAXAN 550 mg three times a day for 7 days and 14 days to healthy subjects, the mean AUC of midazolam was 3.8% and 8.8% lower, respectively, than when midazolam was administered alone. The mean Cmax of midazolam was lower by 4 to 5% 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 study utilized an open-label, crossover design in 28 healthy female subjects to determine 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 0.5 mg norgestimate. Results showed that the pharmacokinetics of single doses of ethinyl estradiol and norgestimate were not altered by XIFAXAN.
An open-label oral contraceptive study was conducted in 39 healthy female subjects to determine if XIFAXAN 550 mg orally administered three times a day for 7 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). Mean Cmax of EE and NGM was lower by 25% and 13%, after the 7-day XIFAXAN regimen than when the oral contraceptive was given alone. The mean AUC values of NGM active metabolites were lower by 7% to approximately 11%, while AUC of EE was not altered in presence of rifaximin. The clinical relevance of the Cmax and AUC reductions in the presence of rifaximin is not known.
12.4 Microbiology
Mechanism of Action
Rifaximin is a semi-synthetic derivative of rifampin and acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase blocking one of the steps in transcription. This results in inhibition of bacterial protein synthesis and consequently inhibits the growth of bacteria.
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 between rifaximin and other classes of antimicrobials has not been observed.
Antibacterial Activity
Rifaximin has been shown to be active against the following pathogens both in vitro and in clinical studies of inf |
