- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyRecommended dose: 550 mg twice a day. The clinical benefit was established from a controlled study in which subjects were treated for 6 months. Treatment beyond 6 months should take into consideration the individual balance between benefits and risks, including those associated with the progression of hepatic dysfunction (see sections 4.4, 5.1 and 5.2).TARGAXAN can be administered with or without food.
Paediatric populationThe safety and efficacy of TARGAXAN in paediatric patients (aged less than 18 years) have not been established.
ElderlyNo dosage adjustment is necessary as the safety and efficacy data of TARGAXAN showed no differences between the elderly and the younger patients.
Hepatic impairmentNo dosage adjustment is necessary for patients with hepatic insufficiency (see section 4.4).
Renal impairmentAlthough dosing change is not anticipated, caution should be used in patients with impaired renal function (see section 5.2).
Method of administrationOrally with a glass of water.
PregnancyThere is no or limited data from the use of rifaximin in pregnant women.Animal studies showed transient effects on ossification and skeletal variations in the foetus (see section 5.3).As a precautionary measure, use of rifaximin during pregnancy is not recommended.
BreastfeedingIt is unknown whether 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.
FertilityAnimal studies do not indicate direct or indirect harmful effects with respect to male and female fertility.
|MedDRA System Organ Class||Event||Placebo N=159||Rifaximin N= 140|
|Blood and lymphatic system disorders||Anaemia||6||3.8||11||7.9|
|Abdominal pain upper||8||5.0||9||6.4|
|General disorders and administration site conditions||Oedema peripheral||13||8.2||21||15.0|
|Musculoskeletal and connective tissue disorders||Muscle spasms||11||6.9||13||9.3|
|Nervous system disorders||Dizziness||13||8.2||18||12.9|
|Respiratory, thoracic and mediastinal disorders||Dyspnoea||7||4.4||9||6.4|
|Skin and subcutaneous tissue disorders||Pruritus||10||6.3||13||9.3|
|MedDRA System Organ Class||Common||Uncommon||Rare||Not known|
|Infections and infestations||Clostridial infection, urinary tract infection, candidiasis||Pneumonia, cellulitis, upper respiratory tract infections, rhinitis|
|Blood and lymphatic system disorders||Anaemia||Thrombocytopenia|
|Immune system disorders||Anaphylactic reactions, angioedemas, hypersensitivity|
|Metabolism and nutrition disorders||Anorexia, hyperkalaemia||Dehydration|
|Psychiatric disorders||Depression||Confusional state, anxiety, hypersomnia, insomnia|
|Nervous system disorders||Dizziness, headache||Balance disorders, amnesia, convulsion, attention disorders, hypoesthesia, memory impairment|
|Vascular disorders||Hot flush||Hypertension, hypotension||Presyncope, syncope|
|Respiratory, thoracic, and mediastinal disorders||Dyspnoea||Pleural effusion||Chronic obstructive pulmonary disease|
|Gastrointestinal disorders||Abdominal pain upper, abdominal distension, diarrhoea, nausea, vomiting, ascites||Abdominal pain, oesophageal varices haemorrhage, dry mouth, stomach discomfort||Constipation|
|Hepatobiliary disorders||Liver function tests abnormalities|
|Skin and subcutaneous tissue disorders||Rashes, pruritus||Dermatitis, eczema|
|Musculoskeletal and connective tissue disorders||Muscle spasms, arthralgia||Myalgia||Back pain|
|Renal and urinary disorders||Dysuria, pollakiuria||Proteinuria,|
|General disorders and administration site conditions||Oedema peripheral||Oedema, pyrexia||Asthenia|
|Investigations||International normalised ratio abnormalities|
|Injury, poisoning and procedural complications||Fall||Contusions, procedural pain|
Mechanism of actionRifaximin is an antibacterial drug of the rifamycin class that irreversibly binds 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, including ammonia producing species. Rifaximin may inhibit the division of urea-deaminating bacteria, thereby reducing the production of ammonia and other compounds that are believed to be important to the pathogenesis of hepatic encephalopathy.
Mechanism of resistanceThe development of resistance to rifaximin is primarily a reversible chromosomal one-step alteration in the rpoB gene encoding the bacterial RNA polymerase. Clinical studies that investigated changes in the susceptibility of intestinal flora of 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 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 with rifaximin of patients harbouring strains of Mycobacterium tuberculosis or Neisseria meningitidis will not select for rifampicin resistance.
SusceptibilityRifaximin 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 several pathogens including ammonia producing bacteria as Escherichia coli spp, Clostridium spp, Enterobacteriaceae, Bacteroides spp. 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 efficacyThe efficacy and safety of rifaximin 550 mg twice daily in adult patients in remission from HE was evaluated in a phase 3 pivotal, 6-month, randomised, double-blind, placebo-controlled study RFHE3001. Two-hundred ninety-nine subjects were randomised to treatment with rifaximin 550 mg twice daily (n=140) or placebo (n= 159) for 6 months. More than 90% of the subjects in both groups received concomitant lactulose. No patients were enrolled with a MELD score > 25. The primary endpoint was the time to first breakthrough overt HE episode and patients were withdrawn after a breakthrough overt HE episode. Thirty-one of 140 subjects (22%) of rifaximin group and 73 of 159 (46%) subjects of placebo group experienced a breakthrough overt HE episode during the 6-month period. Rifaximin reduced the risk of HE breakthrough by 58% (p< 0.0001) and the risk of HE-related hospitalizations by 50% (p< 0.013), compared with placebo. The longer-term safety and tolerability of rifaximin 550 mg twice daily administered for at least 24 months was evaluated in 322 subjects in remission from HE in study RFHE3002. One hundred fifty-two subjects rolled over from RFHE3001 (70 from the rifaximin group and 82 from the placebo), and 170 subjects were new. Eighty-eight percent of patients were administered concomitant lactulose. Treatment with rifaximin for periods up to 24 months (OLE study RFHE3002) did not result in any loss of effect regarding the protection from breakthrough overt HE episodes and the reduction of the burden of hospitalization. Time to first breakthrough overt HE episode analysis showed long-term maintenance of remission in both groups of patients, new and continuing rifaximin.
AbsorptionPharmacokinetic studies in rats, dogs and humans demonstrated that after oral administration rifaximin in the polymorph α form is poorly absorbed (less than 1%). After repeated 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). In HE patients, administration of rifaximin 550 mg twice a day showed mean rifaximin exposure approximately 12-fold higher than that observed in healthy volunteers following the same dosing regimen. A clinically irrelevant increase of rifaximin systemic absorption was observed when administered within 30 minutes of a high-fat breakfast.
DistributionRifaximin 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 550 mg was administered.
BiotransformationAnalysis 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.
EliminationA 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-linearityThe 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.
Renal impairmentNo clinical data are available on the use of rifaximin in patients with impaired renal function.
Hepatic impairmentClinical 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.
Paediatric populationThe pharmacokinetics of rifaximin has not been studied in paediatric patients of any age. Population studied in both the reduction in recurrence of hepatic encephalopathy (HE) and in the acute treatment of HE included patients aged ≥ 18 years.
Tablet core:Sodium starch glycolate type AGlycerol distearateColloidal anhydrous silicaTalcMicrocrystalline cellulose
Film coat (opadry oy-s-34907):Hypromellose Titanium dioxide (E171) Disodium edetatePropylene glycolRed iron oxide (E172)
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