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XIFAXANTA 200 mg Film-coated Tablets

Last Updated on eMC 24-Jan-2017 View document  | Norgine Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Updated on 24-Jan-2017 and displayed until Current

Reasons for adding or updating:

  • Change to section 3 - Pharmaceutical form
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 18-Jan-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Changes are to the description of the tablet

Updated on 23-Aug-2016 and displayed until 24-Jan-2017

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 20-Jul-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



The XIFAXANTA 200mg SmPC has been updated following the renewal of the product.

 

Sections 4.4 and 4.5 have been updated to included additional information regarding use of rifaximin with warfarin.

 

Section 9 - Renewal Approval Date – 20th July 2016.

 

Section 10. Date of Revision

 

 

Updated on 23-Nov-2015 and displayed until 23-Aug-2016

Reasons for adding or updating:

  • Change to section 1 - Name of the medicinal product
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.1 - List of excipients
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 01-Nov-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



The following sections have been updated

 

Initial Section of the SmPC – Removal of the black triangle

 

Section 4.2

 

Inclusion of the following:

Elderly

No dosage adjustment is necessary as the safety and efficacy data of Xifaxanta 200 mg film-coated tablets showed no differences between the elderly and the younger patients.

 

Inclusion of the title Hepatic impairment

 

Inclusion of  the text - Renal impairment

Although dosing change is not anticipated, caution should be used in patients with impaired renal function (see section 5.2).

 

Section 4.3

Inclusion of sentence - Cases of intestinal obstruction.

 

Section 4.4

Inclusion of the text

Patients should be informed that despite the negligible absorption of the drug (less than 1%), like all rifamycin derivatives, rifaximin may cause a reddish discolouration of the urine.

Due to the effects on the gut flora, the effectiveness of oral oestrogenic contraceptives could decrease after rifaximin administration. However, such interactions have not been commonly reported. It is recommended to take additional contraceptive precautions, in particular if the oestrogen content of oral contraceptives is less than 50 μg (see also section 4.5).

Caution should be exercised when concomitant use of rifaximin and a P-glycoprotein inhibitor such as ciclosporin is needed (see section 4.5).

 

Section 4.5

Inclusion of the text :

In vitro data show that rrifaximin did not inhibit the major cytochrome P-450 (CYP) drug metabolizing enzymes (CYPs1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4).

 

In healthy subjects, clinical 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) due to the higher systemic exposure with respect to healthy subjects.

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 P-gp and/or CYP3A4 can increase the systemic exposure of rifaximin.

 

The potential for drug-drug interactions to occur at the level of gut transporter systems has been evaluated.

In healthy subjects, co-administration of a single dose of ciclosporin (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∞ respectively. The clinical significance of this increase in systemic exposure is unknown.

 

The potential for drug-drug interactions to occur at the level of transporter systems has been evaluated Iin vitro and these studies suggest that a clinical interaction between rifaximin and other compounds that undergo efflux via P-gp and other transport proteins is unlikely (MDR1, MRP2, MRP4, BCRP and BSEP).

 

In case of administration of charcoal, rrifaximin should be taken at least 2 hours after that administration.

 

Deletion of non applicable text.

 

Section 4.6

 

Inclusion of the text

Pregnancy

There 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). The clinical relevance of these findings in humans is unknown.

As a precautionary measure, use of rifaximin during pregnancy is not recommended.

 

Breast-feeding

It 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.

 

Fertility

Animal studies do not indicate direct or in direct harmful effects with respect to male and female fertility.

 

Deletion of non applicable text.

 

Section 4.8

 

Addition of the side effects - Presyncope, Purpura, Dermatitis exfoliative,

 

Deletion of non applicable text.

 

Section 4.9

Additional wording around patients with with normal bacterial flora rifaximin

Deletion of non applicable text.

 

Section 5.1

Addition of 

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 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 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.

 

 

Additon of information around the effect of Rifaximin in vitro on pathogens causing traveller’s diarrhoea.

 

Deletion of non applicable text.

 

Section 5.2

Addition of the following

 

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

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.

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).

 

Linearity/non-linearity

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.

 

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.

Despite of this, 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 population

The pharmacokinetics of rifaximin has not been studied in paediatric patients of any age.

 

Deletion of non applicable text.

 

Section 5.3

Addition of :-

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 Rrifaximin 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

 

Section 6.1

 

Addition of E171 as an excipient

 

Section 10

 

Date of Revision of the Text

Updated on 04-Jun-2015 and displayed until 23-Nov-2015

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 01-May-2015

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



The following sections have been amended.

 

 

SMPC

Section 4.4 – the following sentence has been added.

 

Caution should be exercised when concomitant use of rifaximin and a P-glycoprotein inhibitor such as ciclosporin is needed (see section 4.5).

 

 

Section 4.5 – the following changes have been made. ( Black strikethrough is removed text. Red text is newly added text )

 

The potential for drug-drug interactions to occur at the level of gut transporter systems has not been evaluated and cannot be ruled out.

 

In healthy subjects, co-administration of a single dose of ciclosporin (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.

 

 

Date of revision of text

Updated on 09-Sep-2011 and displayed until 04-Jun-2015

Reasons for adding or updating:

  • New SPC for new product

Legal Category:POM

Black Triangle (CHM): YES

Company contact details

Norgine Limited

Company image
Address

Norgine House, Widewater Place, Moorhall Road, Harefield, Middlesex, UB9 6NS

Fax

+44 (0)1895 825 865

Medical Information e-mail
Telephone

+44 (0)1895 826 600

Before you contact this company: often several companies will market medicines with the same active ingredient. Please check that this is the correct company before contacting them. Why?

Active ingredients

rifaximin

Legal categories

POM - Prescription Only Medicine

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