Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Norgine Pharmaceuticals Ltd, Moorhall Road, Harefield, Middlesex, UB9 6NS
Pharmacotherapeutic group: intestinal, anti-infective agents-antibiotics
ATC code: A07AA11
The product Xifaxanta contains rifaximin (4-desoxy-4’methyl pyrido (1',2'-1,2) imidazo (5,4-c) rifamycin SV), in the polymorphic form α.
Rifaximin is an antibacterial agent of the rifamycin class that binds irreversibly to the beta sub-unit of the bacterial enzyme DNA-dependent RNA polymerase and consequently inhibits bacterial RNA synthesis.
Rifaximin has a broad antimicrobial spectrum against most of the Gram-positive and -negative, aerobic and anaerobic bacteria responsible for intestinal infections.
Due to the very low absorption from the gastro-intestinal tract rifaximin in the polymorph α form is locally acting in the intestinal lumen and clinically not effective against invasive pathogens.
The main mechanism of acquiring resistance to rifaximin appears to involve a mutation in the rpoB gene encoding the bacterial RNA polymerase.
The incidence of resistant subpopulations among bacteria isolated from patients with traveller’s diarrhoea was very low.
Clinical studies that investigated changes in the susceptibility of intestinal flora of subjects affected by traveller’s diarrhoea, failed to detect the emergence of drug resistant Gram-positive (e.g. enterococci) and Gram-negative (E. coli) organisms during a three-day course of treatment with rifaximin.
Development of resistance in the normal intestinal bacterial flora was investigated with repeated, high doses of rifaximin in healthy volunteers and Inflammatory Bowel Disease patients. Strains resistant to rifaximin developed, but were unstable and did not colonise the gastrointestinal tract or replace rifaximin-sensitive strains. When treatment was discontinued resistant strains disappeared rapidly.
Experimental and clinical data suggest that the treatment of traveller’s diarrhoea with rifaximin of patients harbouring strains of Mycobacterium tuberculosis or Neisseria meningitidis will not select for rifampicin resistance.
Rifaximin is a non-absorbed antibacterial agent. In vitro susceptibility testing cannot be used to reliably establish susceptibility or resistance of bacteria to rifaximin. There are currently insufficient data available to support the setting of a clinical breakpoint for susceptibility testing.
Rifaximin has been evaluated in vitro on pathogens causing traveller’s diarrhoea. These pathogens were: ETEC (Enterotoxigenic E. coli), EAEC (Enteroaggregative E. coli), Non-V cholerae vibrios. The MIC90, for the bacterial isolates tested, was 32 μg/ml, which can easily be achieved in the intestinal lumen due to high faecal concentrations of rifaximin.
Pharmacokinetic studies in rats, dogs and humans demonstrated that after oral administration rifaximin in the polymorph α form is virtually not absorbed (less than 1%). Following the administration of therapeutic doses of rifaximin in healthy volunteers and patients with damaged intestinal mucosa (Inflammatory Bowel Disease), plasma levels are negligible (less than 10 ng/ml). Systemic absorption of rifaximin is increased but not by a clinically relevant extent by administration within 30 minutes of a high-fat breakfast.
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 rifaximin was administered.
Analysis of faecal extracts demonstrated that rifaximin is found as the intact molecule, implying that it is neither degraded nor metabolised during its passage through the gastrointestinal tract.
In a study using radio-labelled rifaximin, urinary recovery of rifaximin was 0.025% of the administered dose, while <0.01% of the dose was recovered as 25-desacetylrifaximin, the only rifaximin metabolite that has been identified in humans.
A study with radio-labelled rifaximin suggested that 14C-Rifaximin is almost exclusively and completely excreted in faeces (96.9% of the administered dose). The urinary recovery of 14C-Rifaximin does not exceed 0.4% of the administered dose.
The rate and extent of systemic exposure of humans to rifaximin appeared to be characterized by non-linear (dose-dependent) kinetic which is consistent with the possibility of dissolution-rate-limited absorption of rifaximin.
No clinical data are available on the use of rifaximin in patients with impaired renal function.
Clinical data available for patients with hepatic impairment showed a systemic exposure higher than that observed in healthy subjects. The systemic exposure of rifaximin was about 10-, 13-, and 20-fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment, respectively, compared to that in healthy volunteers.
The increase in systemic exposure to rifaximin in subjects with hepatic impairment should be interpreted in light of rifaximin gastrointestinal local action and its low systemic bioavailability, as well as the available rifaximin safety data in subjects with cirrhosis.
Therefore no dosage adjustment is recommended because rifaximin is acting locally.
The pharmacokinetics of rifaximin has not been studied in paediatric patients of any age.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
In a rat embryofoetal development study, a slight and transient delay in ossification that did not affect the normal development of the offspring, was observed at 300 mg/kg/day. In the rabbit, following oral administration of Rifaximin during gestation, an increase in the incidence of fetal skeletal variations was observed at clinically relevant doses.
The clinical relevance of these findings is unknown.
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