Targaxan 550mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Rifaximin
Available from:
CST Pharma Ltd
ATC code:
A07AA11
INN (International Name):
Rifaximin
Dosage:
550mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 05010700; GTIN: 5055946806693

PACKAGE LEAFLET: INFORMATION FOR THE USER

Targaxan

®

550mg film-coated tablets

(rifaximin)

Throughout this leaflet Targaxan 550mg film coated tablets will

be referred to as Targaxan.

Read all of this leaflet carefully before you start taking this

medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or

pharmacist

This medicine has been prescribed for you only. Do not pass

it on to others. It may harm them, even if their signs of illness

are the same as yours.

If you get any side effects, talk to your doctor or pharmacist.

This includes any possible side effects not listed in this

leaflet. See section 4.

What is in this leaflet:

What Targaxan is and what it is used for

What you need to know before you take Targaxan

How to take Targaxan

Possible side effects

How to store Targaxan

Contents of the pack and other information

1.

What Targaxan is and what it is used for

Targaxan contains the active substance rifaximin. Targaxan is an

antibiotic that destroys bacteria, which can cause a disease

called hepatic encephalopathy (symptoms include agitation,

confusion, muscle problems, difficulty in speaking and in some

cases coma). Targaxan is used in adults with liver disease to

reduce the recurrence of episodes of overt hepatic

encephalopathy. Targaxan can either be used alone or more

commonly together with medicines containing lactulose (a

laxative).

2.

What you need to know before you take Targaxan

Do not take Targaxan:

if you are allergic to:

rifaximin

similar types of antibiotics (such as rifampicin or rifabutin)

any of the other ingredients of this medicine (listed in

section 6).

if you have a blockage in your intestine

Warnings and precautions

Talk to your doctor or pharmacist before taking Targaxan.

While you are taking Targaxan your urine may turn a reddish

colour. This is quite normal. Treatment with any antibiotic

including rifaximin may cause severe diarrhoea. This can happen

several months after you have finished taking the medicine. If you

have severe diarrhoea during or after using Targaxan you should

stop taking Targaxan and contact your doctor immediately. If yo

liver problems are severe your doctor will need to observe you

carefully.

Children and adolescents

Targaxan is not recommended for children and adolescents aged

under 18 years. This medicine has not been studied in

children and adolescents.

Other medicines and Targaxan

Tell your doctor or pharmacist if you are taking, have recently

taken or might take any other medicines.

Please tell your doctor if you are taking any of the following

medicines:

antibiotics (medicines to treat infections)

warfarin (medicine to prevent blood clotting)

antiepileptics (medicines for the treatment of epilepsy)

antiarrhythmics (medicines to treat abnormal heart beat)

ciclosporin (immunosuppressor)

oral contraceptives

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant

or are planning to have a baby, ask your doctor or pharmacist for

advice before taking any medicine. It is not known if Targaxan

can harm your unborn baby. Targaxan is therefore not to be used

if you are pregnant.

It is not known if rifaximin may be passed to your baby in breast

milk. Targaxan is therefore not to be used if you are

breast-feeding.

Driving and using machines

Targaxan does not normally affect the ability to drive and use

machines, but may cause dizziness in some patients. If you feel

dizzy you should not drive or operate machinery.

3.

How to take Targaxan

Always take this medicine exactly as your doctor has told you.

Check with your doctor or pharmacist if you are not sure.

The recommended dose is 1 tablet twice a day taken with a glass

of water. Your doctor will assess the need for you to continue

treatment after 6 months.

If you take more Targaxan than you should

If you take more than the recommended number of tablets, even

if you do not notice any problems, please contact your doctor.

If you forget to take Targaxan

Take the next dose at its normal time. Do not take a double dose

to make up for a forgotten tablet.

If you stop taking Targaxan

Do not stop taking Targaxan without talking to your doctor first

because your symptoms may return.

If you have any further questions on the use of this medicine, ask

your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although

not everybody gets them.

Stop taking Targaxan and tell your doctor IMMEDIATELY if

you have any of the following side effects:

Uncommon (may affect up to 1 in 100 people):

If you have bleeding from swollen blood vessels in your throat

(oesophageal varices).

If you have severe diarrhoea during or after using this

medicine. This may be due to an infection of the intestine.

Not known (frequency cannot be estimated from the available

data):

If you get an allergic reaction, hypersensitivity or angioedema.

Symptoms include:

swelling of the face, tongue or throat

swallowing difficulties

hives and breathing difficulties.

If you have any unexpected or unusual bleeding or bruising.

This may be due to a decrease in the platelets in your blood

which increases the risk of bleeding. Frequency is not known

(cannot be estimated from the available data).

Other side effects that may occur

Common (may affect up to 1 in 10 people):

Depressed mood

Dizziness

Headache

Shortness of breath

Feeling or being sick

Stomach ache or bloating/swelling

Diarrhoea

Accumulation of fluid in the abdominal cavity (ascites)

Rash or itching

Muscle cramps

Joint pain

Swelling of ankles, feet or fingers

Uncommon (may affect up to 1 in 100 people):

Yeast infections (such as thrush)

Urinary infection (such as cystitis)

Anaemia (reduction in red blood cells which can make the

skin pale and cause weakness or breathlessness)

Loss of appetite

Hyperkalaemia (high level of potassium in the blood)

Confusion

Anxiety

Feeling sleepy

Difficulty sleeping

Feeling unsteady

Loss of or poor memory

Loss of concentration

Reduced sense of touch

Convulsions (fits)

Hot flushes

Fluid around the lungs (pleural effusion)

Abdominal pain

Dry mouth

Muscle pain

Needing to pass urine more often than usual

Difficulty or pain passing urine

Fever

Oedema (swelling due to too much fluid in the body)

Falls

Rare (may affect up to 1 in 1,000 people):

Chest infections including pneumonia

Cellulitis (inflammation of tissue under skin)

Upper respiratory tract infections (nose, mouth, throat)

Rhinitis (inflammation inside the nose)

Dehydration (body water loss)

Changes in blood pressure

Constant breathing problems (such as chronic bronchitis)

Constipation

Back pain

Protein in the urine

Feeling weak

Bruising

Pain following surgery

Not known (frequency cannot be estimated from the available

data):

Fainting or feeling faint

Skin irritation, eczema (itchy, red, dry skin)

Reduction in platelets (seen in the blood)

Changes in the way the liver is working (seen in blood test)

Changes in blood coagulation (International Normalised Ratio

seen in blood test)

Public Assessment Report

Decentralised Procedure

TARGAXAN 550MG FILM-COATED TABLETS

Procedure No: UK/H/4662/001/DC

UK Licence No: PL 20011/0020

Norgine Pharmaceuticals Limited

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LAY SUMMARY

On 29 November 2012, Belgium, Denmark, Finland, Germany, Greece, Ireland, Italy,

Luxembourg, the Netherlands, Norway, Sweden, Spain and the UK agreed to grant a

Marketing Authorisation to Norgine Pharmaceuticals Limited for the medicinal product

Targaxan 550mg Film-Coated Tablets (PL 20011/0020; UK/H/4662/001/DC). The licence

was granted via the Decentralised Procedure (DCP), with the UK as Reference Member State

(RMS). After the national phase, a Marketing Authorisation was granted in the UK on 10

January 2013.

This is a prescription-only medicine that is used in adults with liver disease to reduce the

recurrence of episodes of overt hepatic encephalopathy, either alone or more commonly

together with medicines containing lactulose (a laxative).

Targaxan contains the active substance rifaximin. Targaxan is an antibiotic that destroys

bacteria, which can cause a disease called hepatic encephalopathy (symptoms include

agitation, confusion, muscle problems, difficulty in speaking and in some cases coma).

No new or unexpected safety concerns arose from this application and it was therefore judged

that the benefits of taking Targaxan 550mg Film-Coated Tablets outweigh the risks; hence, a

Marketing Authorisation was granted.

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TABLE OF CONTENTS

Module 1: Information about initial procedure

Page 3

Module 2: Summary of Product Characteristics

Page 4

Module 3: Patient Information Leaflets

Page 22

Module 4: Labelling

Page 24

Module 5: Scientific Discussion

Page 28

1 Introduction

2 Quality aspects

3 Non-clinical aspects

4 Clinical aspects

5 Overall conclusions

Module 6

Steps taken after initial procedure

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Module 1

Product Name

Targaxan 550mg Film-Coated Tablets

Type of Application

Full dossier, Article 8.3

Active Substances

Rifaximin

Form

Film-Coated Tablets

Strength

550mg rifaximin

MA Holder

Norgine Pharmaceuticals Ltd, Norgine House, Widewater

Place, Moorhall Road, Harefield, Middlesex, UB9 6NS, UK

Reference Member State (RMS)

Concerned Member States (CMS)

Belgium, Denmark, Finland, Germany, Greece, Ireland,

Italy, Luxembourg, the Netherlands, Norway, Sweden,

Spain

Procedure Number

UK/H/4662/001/DC

Timetable

Day 210 – 29 November 2012

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Module 2

Summary of Product Characteristics

The current approved UK version of the Summary of Product Characteristics (SmPC) for this

product is available on the MHRA website.

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Module 3

Patient Information Leaflet

The current approved UK version of the Patient Information Leaflet (PIL) for this product is

available on the MHRA website.

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Module 4

Labelling

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Module 5

Scientific discussion during initial procedure

I

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the member states considered

that the application for Targaxan 550mg Film-Coated Tablets (PL 20011/0020;

UK/H/4662/001/DC) could be approved. This application were submitted via the

Decentralised Procedure, with the UK as Reference Member State (RMS), and Belgium,

Denmark, Finland, Germany, Greece, Ireland, Italy, Luxembourg, the Netherlands, Norway,

Sweden, and Spain as Concerned Member States (CMS).

These are prescription-only medicines indicated for the reduction in recurrence of episodes of

overt hepatic encephalopathy (HE) in patients over ≥ 18 years of age.

This was an application made under the Decentralised Procedure (DCP), according to Article

8.3 of Directive 2001/83/EC, as amended (a full-dossier application).

Rifaximin is a structural analogue of rifampicin. The mechanism of action is similar to that of

other rifamycin antibacterial agents involving the inhibition of DNA-dependent RNA

polymerase in susceptible bacteria. The selected polymorphic form is insoluble in water and

has been selected for use for local treatment.

The non-clinical studies conducted for this application were performed in accordance with

Good Laboratory Practice (GLP).

The main studies submitted to support the above application are:

Pharmacokinetic studies:

Food-effect, single-dose, and multiple-dose pharmacokinetics study in

healthy volunteers RFPK1007

Efflux transport studies; PK0903 in Caco-2 cells in vitro

iii.

Drug-interaction studies in healthy volunteers RFDI1008 and RFDI1009

Pharmacokinetic study of rifaximin in the target population, ie subjects

with hepatic cirrhosis and a history of HE; RFHE3002PK. Subjects had

mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh

C) hepatic impairment.

Dose finding studies:

Dose ranging study RFHE9702

Phase 3 studies RFHE9701 and RFHE9901, which investigated rifaximin

therapy for up to 15 days in subjects with active HE.

Clinical safety and Efficacy studies:

Double-blind 6-month, placebo-controlled study RFHE3001

Open-label study RFHE3002.

Supportive data:

Published meta-analyses

Published individual clinical trials of rifaximin in patients with HE

provide

Loguercio et al

Fera et al

Miglio et al

which investigated

the effectiveness of interventional treatment with rifaximin in subjects

with active HE over chronic durations of therapy (3 months or 6 months).

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In addition, data from the previous studies submitted in support of the 200 mg tablets

(approved for the treatment of Traveller’s diarrhoea) as well as clinical studies in other

indications are also mentioned.

The RMS has been assured that acceptable standards of Good Manufacturing Practice are in

place for these product types at all sites responsible for the manufacture, assembly and batch

release of this product.

The RMS and CMS considered that the application could be approved with the end of

procedure (Day 210) on 29 November 2012. After a subsequent national phase, the licence

was granted in the UK on 10 January 2013.

II.

ABOUT THE PRODUCT

Name of the product in the Reference Member State

Targaxan 550mg Film-Coated Tablets

Name(s) of the active substance(s) (INN)

Rifaximin

Pharmacotherapeutic classification

(ATC code)

Antibiotics

(A07 AA11)

Pharmaceutical form and strength(s)

550mg Film-coated tablets

Reference numbers for the Mutual Recognition

Procedure

UK/H/4662/001/DC

Reference Member State

United Kingdom

Member States concerned

Belgium, Denmark, Finland, Germany,

Greece, Ireland, Italy, Luxembourg, the

Netherlands, Norway, Sweden, and Spain

Marketing Authorisation Number(s)

PL 20011/0020

Name and address of the authorisation holder

Norgine Pharmaceuticals Ltd, Norgine

House, Widewater Place, Moorhall Road,

Harefield, Middlesex, UB9 6NS, UK

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III

SCIENTIFIC OVERVIEW AND DISCUSSION

III.1

QUALITY ASPECTS

S.

Active substance – Rifaximin

rINN:

Rifaximin

Chemical name:

(2S, 16Z, 18E, 20S, 21S, 22R, 23R. 24R. 25S, 26S, 27S, 28E)-

5,6,21,23,25-Pentahydroxy-27-methoxy-2,4,11,16,20,22-24,26-

octamethyl-2,7-(epoxypentadeca [1,11,13]trienimino)benzofuro[4,5-

e]pyrido[1,2-a]benzimidazole-1,15(2H)-dione, 25-acetate

[(2S-[2R*, 16Z, 18E, 20R*, 21R*, 22S*, 23S*, 24S*, 25R*, 26S*,

27R*, 28E)]-25-(Acetyloxy)-5,6,21,23-tetrahydroxy-27-methoxy-

2,4,11,16,20,22,24,26-octamethyl-2,7-[epoxypentadeca [1,11,13]-

trienimino]benzofuro[4,5-e]pyrido[1,2-a] benzimidazole-1,15 (2H)-

dione

Structure:

Molecular formula:

Molecular weight:

Appearance:

Red-orange crystalline powder.

Solubility:

Soluble in organic media and insoluble in aqueous media

Rifaximin is the subject of a European Pharmacopoeia monograph.

Synthesis of the drug substance from the designated starting materials has been adequately

described and appropriate in-process controls and intermediate specifications are applied.

Satisfactory specification tests are in place for all starting materials and reagents and these

are supported by relevant certificates of analysis.

Appropriate proof-of-structure data have been supplied for the active substance. All potential

known impurities have been identified and characterised.

An appropriate specification is provided for the active substance. Analytical methods have

been appropriately validated and are satisfactory for ensuring compliance with the relevant

specifications. Satisfactory Certificates of Analysis have been provided for all working

standards. Batch analysis data are provided and comply with the proposed specification.

Suitable specifications have been provided for all packaging used. The primary packaging

has been shown to comply with current guidelines concerning contact with food.

Appropriate stability data have been generated supporting a suitable retest period when stored

in the proposed packaging.

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P.

Medicinal Product

Other Ingredients

Other ingredients consist of the pharmaceutical excipients, namely sodium starch glycolate

type A, glycerol distearate, colloidal anhydrous silica, talc, microcrystalline cellulose,

hypromellose, titanium dioxide (E171), disodium edetate, propylene glycol and red iron

oxide (E172).

All excipients comply with their respective European Pharmacopoeia monograph, with the

exception of red iron oxide (E172), which complies with Directive 2001/128/EC, as

amended. Suitable batch analysis data have been provided for all excipients, showing

compliance with their respective specifications.

None of the excipients are sourced from animal or human origin. No genetically modified

organisms (GMO) have been used in the preparation of this product.

Pharmaceutical Development

The objective of the development programme was to formulate a globally acceptable, stable

product containing rifaximin, that could be used for the reduction in recurrence of episodes of

overt hepatic encephalopathy (HE) in patients ≥18 years of age.

A satisfactory account of the pharmaceutical development has been provided.

Manufacturing Process

Satisfactory batch formulae have been provided for the manufacture of the finished product.

The manufacturing process has been validated using two pilot-scale batches and one

industrial-scale batch, and has shown satisfactory results. The marketing authorisation holder

has committed to completing validation studies for the first two commercial-scale batches,

post authorisation.

Finished Product Specification

The finished product specification proposed is acceptable. Test methods have been described

and have been adequately validated. Batch data have been provided and comply with the

release specifications. Certificates of analysis have been provided for all working standards

used.

Container-Closure System

The finished product is packaged in polyvinylchloride/polyethylene/polyvinylidene

chloride/aluminium blisters, which are packed into cartons in pack sizes of 14, 28, 42, 56 and

98 tablets per carton. The marketing authorisation holder has stated that not all pack sizes are

intended for marketing. They have committed to providing the relevant licensing authority

with the mock-ups for those pack sizes that will be marketed in that country.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging

components. All primary packaging complies with the current European regulations

concerning materials in contact with food.

Stability of the product

Stability studies were performed in accordance with current guidelines on batches of finished

product packed in the packaging proposed for marketing. The data from these studies support

a shelf-life of 3 years, with no specific storage conditions.

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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and

Labels

The SmPC, PIL and labels are pharmaceutically acceptable. A package leaflet has been

submitted to the MHRA along with results of consultations with target patient groups (‘user

testing’), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The

results indicate that the package leaflet is well-structured and organised, easy to understand

and written in a comprehensive manner. The test shows that the patients/users are able to act

upon the information that it contains.

Marketing Authorisation Application (MAA) form

The MAA form is pharmaceutically satisfactory.

Quality Overall Summary (Expert report)

The pharmaceutical expert report has been written by an appropriately qualified person and is

a suitable summary of the pharmaceutical dossier.

Conclusion

The grant of a Marketing Authorisation is recommended.

III.2

NON-CLINICAL ASPECTS

Pharmacology

The applicant has demonstrated the activity of rifaximin against a broad range of bacteria,

including those bacteria known to produce ammonia. The applicant has suggested that

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. Clinical evidence in support of the new indication

(to reduce the recurrence of hepatic encephalopathy episodes) has been provided. The

applicant has investigated the likelihood of development of resistance following the treatment

M. tuberculosis

-infected patients with rifaximin. In addition, the beneficial effects of

rifaximin in an experimental model of colitis have also been demonstrated. Although

rifaximin is poorly absorbed from the gastrointestinal tract, it is noted that the maximum

daily dose is higher (1100 mg) than that previously proposed (600 mg). However, the non-

clinical data and clinical data available/submitted in support of this application do not

indicate an increased probability to interact with secondary pharmacological targets or an

increase in the incidence of adverse events. The safety pharmacology studies conducted

appear to be adequate to support the maximum proposed dose of 1100 mg per day on the

basis of human equivalent dose (but not on the basis of systemic exposures).

Pharmacokinetics

The data provided suggest that following oral administration, rifaximin is poorly absorbed

from the gastrointestinal tract in animals and in man. In the rat, it is confined to the

gastrointestinal tract with small amounts in the liver at 24 hours post-dose, which supports its

use in the treatment of patients with traveller’s diarrhoea and hepatic encephalopathy.

Placental transfer of rifaximin has been demonstrated in the pregnant rabbit; however, actual

exposure to the fetus was considered to be minimal. The applicant has not investigated

whether rifaximin or its metabolites are transferred to maternal milk.

The small proportion of rifaximin that is absorbed following oral administration is

metabolised primarily by CYP3A4 and the predominant metabolite was identified as 25-

desacetyl rifaximin (which is less pharmacologically active than rifaximin). In animals and

in man, the predominant route of excretion is via the feces. The applicant has investigated

the effects of rifaximin on a series of drug transporters and has concluded that the potential

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for pharmacokinetic interactions with concomitantly administered medicinal products is low.

Toxicology

The maximum non-lethal doses in mice and rats are at least 17-fold and 35-fold higher than

the maximum proposed human equivalent dose of rifaximin and the observed safety margins

are considered to be acceptable. The series of repeated-dose studies for up to 26 weeks in the

rat and up to 39 weeks in the dog support the proposed clinical duration. Alterations in

alkaline phosphatase and alanine amino transferase enzymes were observed during the 26-

week study in the rat and in the absence of histological changes and as the incidence in liver

TEAEs are comparable in the 550 mg BID group when compared to placebo, the applicant

considers these changes not to be clinically relevant. It is noted that the increase in liver

enzymes was observed at ≥150 mg/kg/day, where the observed systemic exposures were

lower than those proposed clinically; hence, the non-clinical data available cannot

definitively rule out the possibility of such toxicity.

In vitro

and in

vivo

studies demonstrate that rifaximin is not genotoxic. Moreover, the results

from the 26-week and 104-week carcinogenicity studies in mice and rats, respectively,

suggest that the potential for rifaximin to be carcinogenic is low. A small increase in the

incidence of malignant schwannomas in the endocardial tissue of males at 150/200/250

mg/kg/day was noted (3/60 animals compared to 0-1/60 animals). However, given that the

observed difference is small in magnitude and that endocardial schwannomas are known to

occur sporadically in the rat; this finding was not considered to be treatment related.

The embryofetal development studies performed in the rat and the rabbit suggest that

rifaximin is not teratogenic. However, delayed ossification was observed in the rat at 300

mg/kg/day, while skeletal variations were observed in the rabbit at all doses evaluated (at ≥

62.5 mg/kg/day). The findings from the embryofetal development studies have been

captured within Section 4.6 and 5.3 of the SmPC, which is acceptable.

Following repeated administration of rifaximin (for up to 4 weeks), an increase in the

numbers of CD4+ and CD8+ T-lymphocytes were observed at ≥150 and 500 mg/kg/day,

respectively. However, no other effects on the immune system of toxicological significance

were observed. Moreover, rifaximin did not elicit a sensitisation response in the guinea pig

and in man and the incidence of allergic reactions did not appear to increase with dose (up to

1100 mg). Hence, the observed effects on CD4+ and CD8+ T lymphocytes do not appear to

be clinically relevant.

Ecotoxicity/Environmental Risk Assessment

The applicant has conducted a series of studies to investigate the potential for ecotoxicity,

which are considered to be adequate. The results suggest that rifaximin will not constitute a

risk to the environment.

Non-Clinical Overview

The applicant’s non-clinical expert report has been written by an appropriately qualified

person and is satisfactory, providing an appropriate review of the product’s pharmacology

and toxicology.

Non-Clinical Conclusions

There are no objections to the approval of this product from a non-clinical viewpoint.

III.3

CLINICAL ASPECTS

Active intervention studies in subjects with hepatic encephalopathy

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Three of the controlled clinical studies included a Phase II, dose-finding study (Study

RFHE9702) and two Phase III, double-blind, randomized studies (Studies RFHE9701 and

RIF/HE/INT/99). Each of these three studies followed acute treatment regimens (≤ 21 days).

Rifaximin treatments resulted in improvements in asterixis severity grade, in the mental

status component of the PSE Index, and in other efficacy endpoints in studies RFHE9702,

RFHE9701, and RIF/HE/INT/99.

In study RFHE9701, which compared rifaximin against lactitol, rifaximin was found to be

superior to lactilol in several efficacy endpoints, including the primary efficacy endpoint. In

study RFHE9702, superior efficacy results were observed with respect to asterixis grades;

and, in study RIF/HE/INT/99, similar efficacy results were observed for mental state

improvements between rifaximin-treated subjects versus placebo-treated subjects.

Published meta-analyses

A meta-analysis of data from 22 clinical trials of lactulose or lactilol, antibiotics, no

intervention, or placebo in the treatment of patients with hepatic encephalopathy showed an

inconsistent positive effect of lactulose/lactilol on hepatic encephalopathy symptoms when

compared to no intervention or placebo intervention. In the data from studies included in this

meta-analysis, antibiotics (aminoglycosides or rifaximin) were found to be statistically

superior to lactulose/lactilol in the treatment of hepatic encephalopathy. The authors

concluded that available data were insufficient to recommend the use of lactulose/lactilol for

hepatic encephalopathy and that lactulose/lactilol should not be used as a comparator in

future clinical studies.

In another meta-analysis, 17 clinical trials using rifaximin in patients with hepatic

encephalopathy were reviewed for effectiveness in improving behavioral, laboratory, mental

status and intellectual abnormalities associated with hepatic encephalopathy. The

meta-analysis concluded that rifaximin was as effective, and in some studies, superior, to

comparators such as lactulose, lactitol, neomycin, and paromomycin in reducing symptoms

of hepatic encephalopathy.

CLINICAL SAFETY AND EFFICACY

Dose-finding study

RFHE9702 evaluated three doses of 600mg, 1200mg and 2400mg of Rifaximin for 7 days in

hepatic encephalopathy of Grades I, II and III. Study RFHE9701 compared rifaximin 400mg

tid versus lactilol 20g tid, while RFHE 9901 evaluated rifaximin in patients intolerant to

lactulose or lactilol. The clinical overview mentioned that the dose of 1100mg (550mg bid)

was selected from these studies, as well as other published studies.

Pivotal and long-term studies (RFHE3001 and RFHE3002)

Study RFHE3001 was a Phase III, multicentre, 6-month, double-blind, randomised, placebo-

controlled study evaluating the efficacy and safety of rifaximin 550 mg bid as compared to

placebo. Subjects in remission (Conn score of 0 or 1) from demonstrated recurrent, overt,

episodic hepatic encephalopathy associated with chronic, hepatic cirrhosis were randomised

on Day 0 according to a 1:1 ratio to receive rifaximin 550 mg bid or placebo for 6 months.

Subjects discontinued from the study at the time of breakthrough overt hepatic

encephalopathy episode.

After participation in study RFHE3001, subjects had the option to enroll in the open-label,

treatment extension study (RFHE3002). Study RFHE3002 was a multicentre, open-label,

treatment-extension study evaluating the long-term safety and tolerability of rifaximin 550

mg bid administered for at least 24 months in subjects with a history of recurrent, overt,

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episodic hepatic encephalopathy. Unlike study RFHE3001, subjects with Conn scores of 0, 1,

or 2 were eligible for participation, and subjects were not required to withdraw from the

study after experiencing a breakthrough overt hepatic encephalopathy episode.

Concomitant lactulose therapy was permitted in studies RFHE3001 and RFHE3002. In

RFHE3001, > 90% of subjects in the rifaximin and placebo groups received concomitant

lactulose therapy, in RFHE3002 study 88% of patients were administered concomitant

lactulose.

Pivotal Study RFHE3001

A total of 299 subjects were randomized to receive rifaximin (140 subjects) or placebo (159

subjects)

As specified in the protocol, subjects were to be withdrawn from the study after experiencing

breakthrough

overt

hepatic

encephalopathy

episode.

Breakthrough

overt

hepatic

encephalopathy episode was the primary reason for early study withdrawal for 28 of 140

subjects (20%) in the rifaximin group and 69 of 159 subjects (43.4%) in the placebo group.

Primary reasons for early study discontinuation other than breakthrough overt hepatic

encephalopathy episode were adverse events (15 subjects), subject request (15 subjects),

death (9 subjects), development of exclusion criteria (4 subjects), liver transplant (1 subject),

and other reason (4 subjects).

Primary efficacy endpoint: time to first breakthrough overt hepatic encephalopathy

Breakthrough overt hepatic encephalopathy episodes were experienced by 31 of 140 subjects

in the rifaximin group and by 73 of 159 subjects in the placebo group during the 6-month

treatment period (up to Day 170). Comparison of Kaplan-Meier estimates of time to

breakthrough overt hepatic encephalopathy between groups showed a highly significant

protective effect of rifaximin (p < 0.0001). The hazard ratio for the risk of experiencing

breakthrough overt hepatic encephalopathy in the rifaximin group relative to the risk in the

placebo group was 0.421 (95% confidence interval [CI]: 0.276 to 0.641) during the 6-month

treatment period. These data show that rifaximin treatment resulted in a 57.9% reduction,

when compared with placebo, in the risk of experiencing breakthrough overt hepatic

encephalopathy during the course of this study.

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Sensitivity analyses

Because subjects who had ongoing comorbid conditions (i.e. known precipitating factors for

hepatic encephalopathy episodes, including analgesic use, constipation, infection, and portal

shunt surgery) at the time of randomization may have been unstable, a sensitivity analysis of

the primary efficacy endpoint was carried out, where these subjects were excluded from the

analysis. Rifaximin treatment resulted in significant reductions in the risk of breakthrough

overt hepatic encephalopathy in subjects with or without comorbidities.

Because subjects who took concomitant medications, indicated for the treatment or

prevention of hepatic encephalopathy, may have influenced the effect of rifaximin on the

outcome of the primary endpoint, a second sensitivity analysis was performed whereby

subjects satisfying the above condition were excluded from the ITT population. Rifaximin

treatment resulted in a significant reduction in the risk of breakthrough overt hepatic

encephalopathy; hazard ratio of rifaximin to placebo was 0.419 (95% CI: 0.275 to 0.640) (p <

0.0001).

Subgroup analyses

Subgroup analyses were conducted to determine the robustness and precision of the rifaximin

treatment effect for the primary efficacy endpoint. Outcomes for the primary efficacy

endpoint were evaluated in the following subgroups: geographic analysis region (North

America versus Russia), sex, age (< 65 versus ≥ 65 years), race (white versus non-white),

baseline MELD level (≤ 10, 11 - 18, 19 - 24), baseline Conn score (0 versus 1), prior

lactulose use (yes versus no), diabetes at Baseline (yes versus no), duration of current verified

remission (≤ 90 days versus > 90 days), and the number of hepatic encephalopathy episodes

within the 6 months prior to randomization (2 versus > 2). The effect of rifaximin treatment

in reducing the risk of experiencing breakthrough overt hepatic encephalopathy episodes

during the 6-month treatment period was consistent across all subgroups.

Secondary efficacy endpoints

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Results of “Time to first hepatic encephalopathy-related hospitalization”, “Changes from

baseline in CLDQ fatigue domain score at end of treatment”, “Changes from baseline in

venous ammonia levels at end of treatment”, “Changes from baseline in Conn scores” and

“asterixis grades” were consistent with results of the primary efficacy endpoints.

Safety Results

The mean (± standard deviation) numbers of days of treatment with study drug were 130.3

(±56.47) days in the rifaximin group and 105.7 (±62.7) days in the placebo group. A total of

64 subjects (33 [rifaximin] and 31 [placebo]) received treatment for 141 to 168 days and 98

subjects (57 [rifaximin] and 41 [placebo]) received treatment for > 168 days.

The percentages of subjects who had treatment-emergent adverse events (TEAE), severe

TEAEs, drug-related TEAEs, TEAEs resulting discontinuation, and who died were similar

between placebo and rifaximin groups. A total of 79.9% of subjects (239 of 299) experienced

TEAEs during the course of the study, including 80% of subjects (112 of 140) in the

rifaximin group and 79.9% of subjects (127 of 159) in the placebo group. The most common

TEAEs (ie, in ≥ 10% of total subjects were diarrhea (10.7% [rifaximin] versus 13.2%

[placebo]), nausea (14.3% versus 13.2%), peripheral edema (15% versus 8.2%), fatigue

(12.1% versus 11.3%), dizziness (12.9% versus 8.2%), ascites (11.4% versus 9.4%), and

headache (10% versus 10.7%).

A total of 21 subjects died during the study, 11 subjects in the placebo group and 10 subjects

in the rifaximin group. Deaths were predominantly due to conditions associated with disease

progression, including hepatic cirrhosis, decompensated liver cirrhosis, hepatic failure,

alcoholic cirrhosis, or end-stage liver failure (5 [rifaximin] and 5 [placebo]); and esophageal

varices or esophageal varices hemorrhage (3 [rifaximin] and 2 [placebo]).

Supportive study (Protocol Number: RFHE3002)

This study was a, multicenter, open-label, treatment-extension study evaluating the long-term

safety and tolerability of rifaximin 550 mg bid in up to approximately 500 subjects with a

history of hepatic encephalopathy. All eligible subjects had a history of hepatic

encephalopathy, a Conn score of 0 to 2 at enrollment, and either successfully participated in a

previous hepatic encephalopathy study with rifaximin (i.e. RFHE3001), or were new subjects

enrolled with ≥ 1 verifiable episode of hepatic encephalopathy within 12 months prior to

screening. Subjects who participated in RFHE3001 and experienced an HE episode or

associated symptoms were eligible for this study only if the investigator and subject did not

perceive study medication as a possible cause of the hepatic encephalopathy episode or

symptoms. Treatment in the RFHE3002 study was planned to continue for at least 24 months

on an outpatient basis, or until regulatory approval of rifaximin for reduction in risk of overt

hepatic encephalopathy recurrence, or until the sponsor closed the study, whichever came

first.

Demographics

Most subjects had baseline Conn scores of either 0 (66%) or 1 (30%) and asterixis grades of

0 (71%) or 1 (24%). The mean (standard deviation) duration of current verified remission

from hepatic encephalopathy (time since most recent verified hepatic encephalopathy event)

was substantially shorter in the new rifaximin group compared to the continuing rifaximin

group. New and continuing subjects were also different with respect to the number of hepatic

encephalopathy episodes experienced prior to screening for RFHE3002.

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Unlike study RFHE3001, in which subjects were discontinued from the study after

experiencing their first breakthrough overt hepatic encephalopathy episode, subjects had the

option of continuing rifaximin therapy in study RFHE3002 after experiencing breakthrough

overt hepatic encephalopathy. Therefore, it was possible to evaluate the incidence of

breakthrough overt hepatic encephalopathy over time during rifaximin therapy. In the all

rifaximin group, 42% of subjects (135 of 322) had one breakthrough overt hepatic

encephalopathy episode during the course of the study. Of the 135 subjects with

breakthrough hepatic encephalopathy, most had 1 (64 subjects) or 2 (29 subjects) episodes.

Forty-two subjects (13%) had 3 or more breakthrough hepatic encephalopathy episodes in

RFHE3002.

While 30% of subjects had two hepatic encephalopathy episodes during the 6-month interval

prior to the start of study RFHE3001, only 13% of subjects had two hepatic encephalopathy

episodes during rifaximin therapy for up to 1260 days (median exposure = 513 days [1.4

years]) in study RFHE3002.

Overall, the proportion of subjects who had maintenance or improvement in Conn scores and

in asterixis grades compared to baseline was high and similar between the new and

continuing rifaximin groups.

Hospitalisation

A total of 200 subjects were hospitalized for any cause: 151 in the new rifaximin group, and

49 in the continuing rifaximin group. Normalizing for subject exposure (151/342.3 PEY), this

represents a hospitalization rate of 0.44 event/PEY for the new rifaximin subjects. In the

double-blind study RFHE3001, the all cause hospitalization rate was 0.92 event/PEY in the

rifaximin group and 1.31 event/PEY in the placebo group.

A total of 109 subjects were hospitalized for breakthrough overt hepatic encephalopathy: 79

in the new rifaximin group and 18 in the continuing rifaximin group. Normalizing for subject

exposure, this represents an hepatic encephalopathy hospitalization rate of 0.23 event/PEY

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for the new rifaximin group. In the double-blind study RFHE3001, the hepatic

encephalopathy hospitalization rate was 0.38 event/PEY in the rifaximin group and 0.78

event/PEY in the placebo group.

Safety results

Treatment-emergent adverse events were most frequently reported (i.e. in 25% of all

subjects) in the following System-Organ Classes: gastrointestinal disorders (67%); infections

and infestations (57%); nervous system disorders (48%); general disorders and administration

site conditions (45%); metabolism and nutrition disorders (41%); musculoskeletal and

connective tissue disorders (35%); respiratory, thoracic and mediastinal disorders (35%);

psychiatric disorders (31%); hepatobiliary disorders (30%); injury, poisoning and procedural

complications (29%); skin and subcutaneous tissue disorders (29%); renal and urinary

disorders (28%); blood and lymphatic system disorders (26%); and investigations (25%). The

incidence of TEAEs by System-Organ Class was similar between the new rifaximin and the

continuing rifaximin subjects.

The most common TEAEs (i.e. in 10% of total subjects) experienced by subjects were the

following: hepatic encephalopathy (30%); urinary tract infection (23%); nausea (21%);

peripheral edema (20%); anemia and ascites (16% each); abdominal pain, renal failure acute,

hypokalemia, and vomiting (14% each); dyspnea (13%); diarrhea, constipation, fatigue,

muscle spasms, and depression (12% each); insomnia (11%); and cellulitis, pneumonia,

dizziness (10% each). Note that signs and symptoms associated with hepatic encephalopathy

were not considered adverse events unless they were more severe than expected for the

subject‘s condition or met the definition of an serious adverse event.

Deaths

Assessor’s overall conclusions

The single pivotal study supported by the open-label, long-term study provides adequate

evidence for the use of Rifaximin in the treatment of hepatic encephalopathy.

The number of patients with MELD scores>18 were less that 8%. Systemic exposure to

Rifaximin increases with severity of liver impairment. Pharmacokinetics in renal impairment

has not been studied.

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The safety analyses show a high incidence of adverse effects in both the test and control

arms. Considering the limited options available for the treatment of hepatic encephalopathy

and the severe consequences of uncontrolled/ inadequately controlled hepatic

encephalopathy, the safety profile can be considered acceptable.

Pharmacovigilance system

The RMS considers that the Pharmacovigilance System as described by the applicant fulfils

the requirements and provides adequate evidence that the applicant has the services of a

qualified person responsible for pharmacovigilance and has the necessary means for the

notification of any adverse reaction suspected of occurring either in the Community or in a

third country.

Risk Management Plan

Ongoing safety concerns

Important identified risks

Cases of

Clostridium Difficile

Associated Diarrhoea (CDAD) have been reported with use of

rifaximin with a range in severity from mild diarrhoea to fatal colitis. The potential

association of rifaximin treatment with CDAD and pseudomembranous colitis (PMC) cannot

be ruled out.

Allergic reactions (skin reactions and drug hypersensitivities of various nature and severity)

are expected with rifaximin, despite the low systemic exposure after oral administration.

Important potential risks

Extensive clinical and post-marketing safety data confirms that rifaximin is well tolerated in

a variety of indications and patient populations. The proposed indication does not create a

new potential risk to the intended patient population that is not addressed by the proposed

product labelling.

Summary of safety concerns and planned pharmacovigilance actions

Evaluation of the need for risk minimization activities

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No risk minimisation measures beyond the product information are proposed with

justification that this is not necessary due to:

Extensive clinical and post-marketing experience with rifaximin

No major hazard yet identified

Safety data on drug utilization in studies with other indications/pathologies

Clinical and post-marketing experience on long term treatments

No evidence of potential overuse in post-marketing experience

Product information (SmPC/PIL) sufficient at this stage, covering the limitations of

current safety experience

From global post-marketing safety data analysis, there was no signal associated with

prescription/medical errors or an increasing in errors of drug prescriptions. Therefore the

potential for accidental medication errors by the patient is considered negligible.

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Summary of the risk management plan

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Conclusion

The grant of a Marketing Authorisation is recommended from a clinical viewpoint.

IV

OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT

QUALITY

The important quality characteristics of Targaxan 550mg Film-Coated Tablets are

well-defined and controlled. The specifications and batch analytical results indicate

consistency from batch to batch. There are no outstanding quality issues that would have a

negative impact on the benefit-risk balance.

NON-CLINICAL

Satisfactory data from non-clinical studies have been provided. No new non-clinical concerns

have been raised.

CLINICAL

The use of rifaximin for the reduction of recurrence of episodes of overt hepatic

encephalopathy is supported by a well-conducted, placebo-controlled Phase III study, which

demonstrated convincing evidence of reduced episodes in the rifaximin group compared to

the placebo group. This primary endpoint was also supported by sensitivity analyses and sub

group analyses. A long-term study for 24 months showed the efficacy was maintained over

this duration.

The incidence of adverse events seen in the clinical trials was comparable to that in the

placebo group. These have been mentioned under appropriate sections of the SmPC, as well

as covered in the risk management plan.

There are limited effective options available for the treatment of hepatic encephalopathy.

Rifaximin has been approved and used in a number of European countries and United States.

Published literature also supports the use of rifaximin in hepatic encephalopathy.

BENEFIT-RISK ASSESSMENT

The quality of the product is acceptable, and no new non-clinical or clinical safety concerns

have been identified. Extensive clinical experience with rifaximin is considered to have

demonstrated the therapeutic value of the compound. The benefit-risk is therefore considered

to be positive.

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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date

submitted

Application

type

Scope

Outcome

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