4.1. Therapeutic indications

Rifaximin 550mg is indicated for the reduction in recurrence of episodes of overt hepatic encephalopathy in patients ≥ 18 years of age (see section 5.1).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Posology

Recommended dose: 550mg twice a day as long term treatment for the reduction in recurrence of episodes of overt hepatic encephalopathy (see sections 4.4, 5.1 and 5.2).

In the pivotal study, 91% of the patients were using concomitant lactulose (see also section 5.1).

Rifaximin 550mg can be administered with or without food.

Paediatric population

The safety and efficacy of Rifaximin 550mg in paediatric patients (aged less than 18 years) have not been established.

Elderly

No dosage adjustment is necessary as the safety and efficacy data of Rifaximin 550mg showed no differences between the elderly and the younger patients.

Hepatic impairment

No dosage adjustment is necessary for patients with hepatic insufficiency (see section 4.4).

Renal impairment

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

Method of administration

Orally with a glass of water.

4.3. Contraindications

• Hypersensitivity to rifaximin, rifamycin-derivatives or to any of the excipients listed in section 6.1.

• Cases of intestinal obstruction.

4.4. Special warnings and precautions for use

Severe skin reactions

Severe cutaneous adverse reactions (SCAR) including: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported (frequency unknown) in association with rifaximin treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, rifaximin should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJS or TEN with the use of rifaximin, treatment with rifaximin must not be restarted in this patient at any time.

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including rifaximin. The potential association of rifaximin treatment with CDAD and pseudomembranous colitis (PMC) cannot be ruled out.

Due to the lack of data and the potential for severe disruption of gut flora with unknown consequences, concomitant administration of rifaximin with other rifamycins is not recommended.

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.

Hepatic Impairment: use with caution in patients with severe (Child-Pugh C) hepatic impairment and in patients with MELD (Model for End-Stage Liver Disease) score > 25 (see section 5.2).

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

Both decreases and increases in international normalized ratio (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 (see section 4.5).

This medicine contains less than 1 mmol sodium (23mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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) drug metabolizing enzymes (CYPs1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4). In in vitro induction studies, rifaximin did not induce CYP1A2 and CYP 2B6 but was a weak inducer of CYP3A4.

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, oral contraceptives), due to the higher systemic exposure with respect to healthy subjects.

Both decreases and increases in international normalized ratio 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 P-glycoprotein(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 ciclosporin (600mg), 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 for drug-drug interactions to occur at the level of transporter systems has been evaluated in 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 (MRP2, MRP4, BCRP and BSEP).

4.6. Fertility, pregnancy and lactation

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).

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

Breastfeeding

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 indirect harmful effects with respect to male and female fertility.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of safety profile:

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with rifaximin treatment (see section 4.4).

Clinical Trials:

The safety of rifaximin in patients in remission from hepatic encephalopathy (HE) was evaluated in two studies, a randomised, double-blind, placebo-controlled phase 3 study RFHE3001 and a long-term, open-label study RFHE3002.

Study RFHE3001 compared 140 patients treated with rifaximin (dose of 550 mg twice daily for 6 months) to 159 patients treated with placebo, while study RFHE3002 treated 322 patients, of whom 152 from the RFHE3001 study, with rifaximin 550 mg twice daily for 12 months (66% of patients) and for 24 months (39% of patients), for a median exposition of 512.5 days.

In addition, in three supportive studies 152 HE patients were treated with varying doses of rifaximin from 600 mg to 2400 mg per day for up to 14 days.

All adverse reactions that occurred in patients treated with rifaximin at an incidence ≥ 5% and at a higher incidence (≥1%) than placebo patients in RFHE3001 are reported in the following table.

Table 1: Adverse reactions occurring in ≥ 5% of patients receiving rifaximin and at a higher incidence than placebo in RFHE3001.

MedDRA

System Organ Class

Event

Placebo

N=159

n        %

Rifaximin

N= 140

n        %

Blood and lymphatic system disorders

Anaemia

6

3.8

11

7.9

Gastrointestinal disorders

Ascites

15

9.4

16

11.4

Nausea

21

13.2

20

14.3

Abdominal pain upper

8

5.0

9

6.4

General disorders and administration site conditions

Oedema peripheral

13

8.2

21

15.0

Pyrexia

5

3.1

9

6.4

Musculoskeletal and connective tissue disorders

Muscle spasms

11

6.9

13

9.3

Arthralgia

4

2.5

9

6.4

Nervous system disorders

Dizziness

13

8.2

18

12.9

Psychiatric disorders

Depression

8

5.0

10

7.1

Respiratory, thoracic and mediastinal disorders

Dyspnoea

7

4.4

9

6.4

Skin and subcutaneous tissue disorders

Pruritus

10

6.3

13

9.3

Rash

6

3.8

7

5.0

Table 2 includes adverse reactions observed in the placebo-controlled study RFHE3001, long term study RFHE3002 and from post-marketing experience, listed by MedDRA system organ class and frequency category.

Frequency categories are defined using the following convention:

Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000), Not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse reactions listed by MedDRA system organ class and frequency category.

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

Stevens-Johnson syndrome(SJS), Toxic epidermal necrolysis(TEN), 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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No case of overdose has been reported.

In clinical trials with patients suffering from traveller's diarrhoea doses of up to 1800mg/day have been tolerated without any severe clinical sign. Even in patients/subjects with normal bacterial flora rifaximin in dosages of up to 2400mg/day for 7 days did not result in any relevant clinical symptoms related to the high dosage.

In case of accidental overdose, symptomatic treatment and supportive care are suggested.