- Acute and chronic intestinal infections sustained by Gram-positive and Gram-negative bacteria; diarrhoeic syndrome.
- Diarrhoea caused by an altered equilibrium in the intestinal microbial flora (summer diarrhoea, traveller’s diarrhoea, enterocolitis).
- Pre- and postoperative prophylaxis of infective complications in gastrointestinal tract surgery.
- Coadjuvant in treatment of hyperammonemia

Anti-diarrhoeic treatment
Recommended dose:
- Adults and children over 12 years: one 200 mg tablets every 6 hours.
Pre- and postoperative treatment
Recommended dose:
- Adults and children over 12 years: two 200 mg tablets  every 12 hours.

Coadjuvant in treatment of hyperammonemia
Recommended dose:
- Adults and children over 12 years: two 200 mg tablets every 8 hours.

This medicine can be administered with or without food.

Depending on the physician’s advice these doses may be modified in quantity and frequency. Unless otherwise prescribed, treatment should not exceed 7 days.
Elderly
The pharmacokinetic of rifaximin has not been studied in elderly patients, anyway no dosage adjustment is necessary as the safety and efficacy data of XIFAXAN showed no differences between the elderly and the younger patients.
Hepatic impairment
No dosage adjustment is necessary for patients with hepatic insufficiency.
Renal impairment
Although no dosage change is anticipated, caution should be used in patients with impaired renal function.
Pediatric population
The safety and efficacy of Rifaximin in children younger than 12 years of age have not been established.
Currently available data are described in section 5.1, but no recommendation on a posology can be made.
Method of administration
- Film-coated tablets: orally with a glass of water.
 

Hypersensitivity to the active substance, rifamycins or any of the excipients listed Cases of intestinal obstruction, even partial, or severe ulcerous lesions of the intestine. Rifaximin should not be administered in patients with diarrhoea complicated by fever or blood in the stool.

Clinical data have shown that rifaximin is not effective in the treatment of intestinal infections due to invasive intestinal pathogens such as Campylobacter jejuni species, Salmonella species and Shigella species which typically cause diarrhoea, fever, blood in the stools and high stool frequency.
Treatment should be discontinued if the symptoms get worse or persist for more than 48 hours and an alternative antibiotic therapy should be considered.
Clostridium-difficile associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including rifaximin. The potential association of rifaximin treatment with CDAD or pseudomembranous colitis cannot be ruled out.
Hepatic impairment: Although no dosage change is anticipated, caution should be used in patients

with severe hepatic impairment.
Caution should be exercised when concomitant use of rifaximin and a P-glycoprotein inhibitor such as cyclosporine is needed.
Patients should be informed that, despite the negligible absorption of the drug (less than 1%), like all rifamycin derivatives, rifaximin may cause a reddish discoloration of the urine.
Both decreases and increases in international normalized ratio -INR (in some cases with bleeding events) have been reported in patients maintained on warfarin and prescribed rifaximin. If co-administration is necessary, the international normalized ratio should be carefully monitored with the addition or withdrawal of treatment with rifaximin. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.
Important information on some excipients
 

There is no experience regarding administration of rifaximin to subjects who are taking another rifamycin antibacterial agent to treat a systemic bacterial infection.
In vitro data show that rifaximin did not inhibit the major cytochrome P-450 (CYP) which are responsible for drug metabolism (CYPs1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4). In in vitro induction studies, rifaximin did not induce CYP1A2 and CYP2B6, but was a weak inducer of CYP3A4.
In healthy subjects, clinical drug-drug interaction studies demonstrated that rifaximin did not significantly affect the pharmacokinetics of CYP3A4 substrates. However, in hepatic impaired patients it cannot be excluded that rifaximin may decrease the exposure of concomitant CYP3A4 substrates administered (e.g. warfarin, antiepileptics, antiarrhythmics, oral contraceptives), due to the higher systemic exposure with respect to healthy subjects.
Both decreases and increases in international normalized ratio (INR) have been reported in patients maintained on warfarin and prescribed rifaximin. If co-administration is necessary, the international normalized ratio should be carefully monitored with the addition or withdrawal of rifaximin. Adjustments in the dose of oral anticoagulants may be necessary.
An in vitro study suggested that rifaximin is a moderate substrate of Pglycoprotein (P-gp) and metabolized by CYP3A4. It is unknown whether concomitant drugs which inhibit CYP3A4 can increase the systemic exposure of rifaximin.
In healthy subjects, co-administration of a single dose of cyclosporine (600 mg), a potent P-glycoprotein inhibitor, with a single dose of rifaximin (550mg) resulted in 83-fold and 124-fold increases in rifaximin mean Cmax and AUC∞. The clinical significance of this increase in systemic exposure is unknown.
The potential interaction with other drugs at carrier level has been evaluated in vitro. These studies suggest that a clinical interaction between rifaximin and other compounds which undergo efflux via P-gp and other transport proteins (MRP2, MRP4, BCRP and BSEP) is unlikely.
Patients should take Rifaximin at least 2 hours after the administration of charcoal.

Pregnancy
There are no or limited data on the use of Rifaximin in pregnant women.
Animal studies showed transient effects on ossification and skeletal variations in the foetus. The clinical relevance of these findings is not known.
As a precautionary measure, use of rifaximin during pregnancy is not recommended.
Breast-feeding
It is unknown whether rifaximin and rifaximin metabolites are excreted in human milk.
A risk to the breast-fed child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from rifaximin therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility
Animal studies do not indicate direct or indirect harmful effects on male and female fertility.

Dizziness and somnolence have been reported in clinical controlled trials. However rifaximin has negligible influence on the ability to drive or use machines.

Clinical Trials
During double-blind controlled clinical trials or clinical-pharmacology studies, rifaximin effects have been compared to placebo or other antibiotics,. therefore quantitative safety data are available.
Note: Many of the adverse reactions listed (in particular gastrointestinal reactions) may be the same symptoms attributable to the underlying diseases being treated and, during clinical trials, have been reported in the same frequency in placebo-treated patients.
Post-marketing experience
During post-approval use of the product further undesirable effects have been reported, the frequency of these reactions is not known (cannot be estimated from the available data)
Frequency categories are defined using the convention below:
Very common (≥ 1/10); Common (≥ 1/100 < 1/10); Uncommon (≥ 1/1000 < 1/100); Rare (≥ 1/10000 < 1/1000); Very rare (< 1/10000); Not known (frequency cannot be estimated from the available data).

MedDRA System Organ Class	Common	Uncommon	Rare	Not known
Infections and infestations		Candidiasis, herpes simplex, nasopharyngitis, pharyngitis, upper-respiratory-tract infections		Clostridial infection
Blood- and lymphatic-system disorder		Lymphocytosis, monocytosis, neutropenia		Thrombocytopenia
Immune-system disorders				Anaphylactic responses, hypersensitivity
Metabolism and nutrition disorders		Decreased appetite, dehydration
Psychiatric disorders		Insomnia, abnormal dreams, depressed mood, nervousness
Nervous-system disorders	Dizziness, headache	Migraine, hypoesthesia, paraesthesia, sinus headache, somnolence		Presyncope
Eye disorders		Diplopia
Ear and labyrinth disorders		Vertigo, ear pain
Cardiac disorders		Palpitations
Vascular disorders		Blood pressure increased, hot flush
Respiratory, thoracic and mediastinal disorders		Dyspnoea, nasal congestion, dry throat, oropharyngeal pain, cough, rhinorrhea
Gastrointestinal disorders	Constipation, abdominal pain, abdominal distension, diarrhoea, flatulence, nausea, rectal tenesmus , defecation urgency, vomiting symptoms	Ascites, dyspepsia, gastrointestinal-motility disorder, abdominal pain upper, haematochezia, mucous stools, faeces hard, dry lip, taste disorders
Hepatobiliary disorders		Aspartate aminotransferase increased		Liver-function-test abnormalities
Skin and subcutaneous-tissue disorders		Rashes, eruptions and exanthemas, sunburn1		Angioedema, dermatitis, dermatitis exfoliative, eczema, erythemas, purpura, pruritus, urticarias
Musculoskeletal and connective-tissue disorders		Back pain, muscular weakness, muscle spasm, neck pain, myalgia,
Renal and urinary disorders		Blood in urine, glycosuria, pollakiuria, polyuria, proteinuria

Reproductive-system disorders		Polymenorrhoea
General disorders and administration-site conditions	Pyrexia	Asthenic conditions, chills, cold sweat, pain and discomfort, oedema peripheral, influenza-like illness, hyperhidrosis,
Investigations				International normalised ratio abnormal

1 As the investigator reported “sunburn”, this is considered as actually a “sunburn”, not as referring to photosensitivity reactions.

 

Reporting of suspected adverse reactions
Reporting of suspected adverse reactions appearing after approval of the medicinal product is important as it permits continuous monitoring of the benefit/risk ratio of the product. Health operators are requested to report any suspected adverse reaction to the Italian Drug Agency, web site: http://www.agenziafarmaco.gov.it/it/responsabili

In clinical trials with patients suffering from traveller’s diarrhoea, doses of up to 1,800 mg/day have been tolerated without any severe clinical symptom. Even in patients/subjects with normal bacterial flora rifaximin at doses of up to 2,400 mg/day for 7 days did not result in any relevant clinical symptoms related to the high dosage.
In case of accidental overdosage, symptomatic treatments and supportive care are suggested. In case of recent administration the gastric emptying could be useful.

Pharmacotherapeutic group: antidiarrhoeals, anti-inflammatories and intestinal anti-infectives, antibiotics
Class ATC A07AA11
Mechanism of action
Rifaximin is an antibacterial drug of the rifamycin class that irreversibly binds the beta subunit of the bacterial enzyme DNA-dependent RNA polymerase and consequently inhibits bacterial-RNA synthesis.
Rifaximin has a broad antibacterial spectrum against most of the Gram-positive and -negative aerobic and anaerobic bacteria.
Due to the very low absorption from the gastro-intestinal tract rifaximin in the polymorph form α is locally acting in the intestinal lumen and is clinically not effective against invasive pathogens, even though these bacteria are susceptible in vitro.

Mechanism of resistance
The development of resistance to rifaximin is primarily a reversible chromosomal one-step alteration 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 in patients 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 patients with inflammatory bowel disease. 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 treatment with rifaximin of patients harbouring Mycobacterium tuberculosis or Neisseria meningitidis will not select for rifampicin resistance.
Susceptibility
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.
Due to the very low absorption from the gastro-intestinal tract rifaximin is not clinically effective against invasive pathogens, even though these bacteria are susceptible in vitro.
Clinical efficacy
Clinical studies in patients with traveller’s diarrhoea demonstrated clinical effectiveness of rifaximin against ETEC (Enterotoxigenic E. coli) and EAEC (Enteroaggregative E. coli). These bacteria are predominantly responsible for causing traveller’s diarrhoea in subjects travelling to Mediterranean countries or tropical and subtropical regions.
Paediatric population
The efficacy, safety and posology of rifaximin in paediatric patients younger than 12 years of age have not been established.
A review of scientific literature identified 9 efficacy studies in the paediatric population which have included 371 children, 233 having received rifaximin. Most of the enrolled children aged more than 2 years. The characteristic which was present in all studies was diarrhoea of bacterial origin (proven before, during or after treatment).
The data (the studies “per se” and a meta-analysis) show that there is a positive trend to demonstrate efficacy of rifaximin in a special condition (acute diarrhoeas - mainly recurrent or relapsing - which are known or supposed to be caused by non-invasive rifaximin-sensitive bacteria such as Escherichia coli).
The most used dosage in children from 2 to 12 years in these limited studies with few patients was in the range of 20-30 mg/kg/d in 2 to 4 administrations.

Absorption
Pharmacokinetic studies in rat, dog and humans demonstrated that rifaximin in the polymorphic form α is practically not absorbed (less than 1%) when administered by the oral route. In pharmacokinetic comparative studies, it has been demonstrated that rifaximin in the polymorphicforms different from the α form has absorbance considerably higher.
After repeated therapeutic doses of rifaximin in healthy volunteers and patients with damaged intestinal mucosa (inflammatory bowel disease) the rifaximin plasma levels were negligible (less than 10 ng/ml). A clinically non-relevant increase of the rifaximin systemic absorption was observed when it was administered within 30 minutes of a high-fat meal.
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 rifaximin was administered.
Biotransformation
An 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.
A study using radio-labelled rifaximin showed a urinary recovery of rifaximin of 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.
Elimination
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.
Linearity/Non-linearity
The rate and extent of systemic exposure of humans to rifaximin appeared to be characterized by non-linear (dose-dependent) kinetics, which is consistent with the possibility of dissolution-rate-limited absorption of rifaximin.

Preclinical data reveal no special hazards 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 skeletalvariations was observed. The clinical relevance of these findings is unknown.

Film-coated tablets
Tablet core
Sodium starch glycolate, type A
Glycerol distearate
Colloidal anhydrous silica
Talc
Microcrystalline cellulose
Tablet coating
Hypromellose
Titanium dioxide E171
Disodium edetate
Propylene glycol
Red iron oxide E172

Not applicable.

Film-coated tablets : 3 years.

Film-coated tablets: this medicinal product does not require any special storage conditions.

Film-coated tablets:
One blister pack constituted by PVC-PE-PVDC/Aluminium containing 12 film-coated tablets.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.