4.1. Therapeutic indications

Xifaxanta 200mg film-coated tablets are indicated for the treatment of traveller's diarrhoea that is not associated with any of:

Fever

Bloody diarrhoea

Eight or more unformed stools in the previous 24 h

Occult blood or leucocytes in the stool

Xifaxanta 200mg film-coated tablets may shorten the duration of diarrhoea when this is associated with non-invasive strains of E. coli (see sections 4.4 and 5.1).

4.2. Posology and method of administration

Posology

200mg every 8 hours for three days (total 9 doses).

Rifaximin must not be used for more than 3 days even if symptoms continue and a second course of treatment must not be taken (see section 4.4).

Rifaximin can be administered with or without food

Paediatric population

The safety and efficacy of Xifaxanta 200mg film-coated tablets in children (aged less than 18 years) have not been established

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.

Hepatic impairment

A dosage adjustment for patients with hepatic insufficiency is not necessary (see section 5.2).

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 the active substance, to any rifamycin (e.g. rifampicin or rifabutin) 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 (SCARs), 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. Most of the cases were reported in patients with liver disease (such as cirrhosis or hepatitis). 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 If signs and symptoms suggestive of these reactions appear, rifaximin should be withdrawn immediately and an alternative treatment considered (as appropriate).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.

Clinical data have shown that rifaximin is not effective in the treatment of travellers' diarrhoea caused by invasive enteric pathogens such as Campylobacter jejuni, Salmonella spp. and Shighella, which typically produce dysentery-like diarrhoea characterised by fever, blood in the stool and high stool frequency.

If symptoms worsen treatment with rifaximin should be interrupted.

If symptoms have not resolved after 3 days of treatment, or recur shortly afterwards, a second course of rifaximin should not be administered.

Clostridioides 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.

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.

Caution should be exercised when concomitant use of rifaximin and a P-glycoprotein inhibitor 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 (23 mg) per tablet, that is to say essentially 'sodium-free'.

Paediatric population

Xifaxanta 200 mg film-coated tablets are not recommended for use in children (<18 years old).

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 vitro data show that rifaximin did not induce CYP1A2 and CYP 2B6 but is a weak inducer of the CYP3A4 isoenzyme of the P450 cytochrome.

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 (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 gut 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).

No drug interaction studies investigating the concomitant intake of rifaximin and other drugs that might be used during an episode of travellers' diarrhoea (e.g. loperamide, charcoal) are available.

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

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). 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.

4.7. Effects on ability to drive and use machines

In clinical controlled trials dizziness and somnolence have been reported but 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. Most of the cases were reported in patients with liver disease (such as cirrhosis or hepatitis) (see section 4.4).

In clinical studies in subjects who received rifaximin for treatment of travellers' diarrhoea, Adverse Reactions considered as being at least possibly related to rifaximin have been categorised by organ system and frequency.

Post-marketing experience

During post-approval use of rifaximin 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 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).

MedDRA System Organ Class

Common

Uncommon

Frequency not Known

Infections and infestations

Candidiasis

Herpes simplex

Nasopharyngitis

Pharyngitis

Upper respiratory tract infection

Clostridial infections

Blood and lymphatic system disorders

Lymphocytosis

Monocytosis

Neutropenia

Thrombocytopenia

Immune system disorders

Anaphylactic reactions

Hypersensitivity

Metabolism and nutrition disorders

Decreased appetite

Dehydration

Psychiatric disorders

Abnormal dreams

Depressed mood

Insomnia

Nervousness

Nervous system disorders

Dizziness

Headache

Hypoesthesia

Migraine

Paraesthesia

Sinus headache

Somnolence

Presyncope

Eye disorders

Diplopia

Ear and labyrinth disorders

Ear pain

Vertigo

Cardiac disorders

Palpitations

Vascular disorders

Blood pressure increased

Hot flush

Respiratory, thoracic, and mediastinal disorders

Cough

Dry throat

Dyspnoea

Nasal congestion

Oropharyngeal pain

Rhinorrhea

Gastrointestinal disorders

Abdominal pain

Constipation

Defecation urgency

Diarrhoea

Flatulence

Abdominal distension

Nausea

Vomiting

Rectal tenesmus

Abdominal pain upper

Dry lips

Dyspepsia

Gastrointestinal motility disorder

Faeces hard

Haematochezia

Mucous stools

Taste disorders

Hepatobiliary disorders

Aspartate aminotransferase increased

Liver function test abnormalities

Skin and subcutaneous tissue disorders

Rashes, eruptions and exanthemas

Sunburn

Stevens-Johnson syndrome (SJS)

Toxic epidermal necrolysis (TEN)

Angioedema

Dermatitis

Dermatitis exfoliative

Eczema

Erythemas

Pruritus

Purpura

Urticarias

Musculoskeletal and connective tissue disorders

Back pain

Muscle spasms

Muscular weakness

Myalgia

Neck pain

Renal and urinary disorders

Blood in urine

Glycosuria

Pollakiuria

Polyuria

Proteinuria

Reproductive system and breast disorders

Polymenorrhoea

General disorders and administration site conditions

Pyrexia

Asthenic conditions

Chills

Cold sweat

Hyperhidrosis

Influenza like illness

Oedema peripheral

Pain and discomfort

Investigations

International normalised ratio abnormalities

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

In clinical trials with patients suffering from travellers' diarrhoea doses of up to 1800 mg/day have been tolerated without any severe clinical signs.

Dosages of up to 2400mg/day for 7 days in patients/subjects with normal bacterial flora rifaximin did not result in any relevant clinical symptoms related to the high dosage.

In case of overdose symptomatic treatments and supportive care are recommended.