Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Norgine Pharmaceuticals Ltd, Moorhall Road, Harefield, Middlesex, UB9 6NS
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.
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.
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.
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).
Xifaxanta 200 mg film-coated tablets are not recommended for use in children (<18 years old).
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.
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.
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.
Animal studies do not indicate direct or in direct harmful effects with respect to male and female fertility.
In clinical controlled trials dizziness and somnolence have been reported but rifaximin has negligible influence on the ability to drive and use machines.
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.
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).
Uncommon: Candidiasis, Herpes simplex, Nasopharyngitis, Pharyngitis, Upper respiratory tract infection
Frequency not Known: Clostridial infections
Uncommon: Lymphocytosis, Monocytosis, Neutropenia
Frequency not Known: Thrombocytopenia
Frequency not Known: Anaphylactic reactions, Hypersensitivity
Uncommon: Decreased appetite, Dehydration
Uncommon: Abnormal dreams, Depressed mood, Insomnia, Nervousness
Common: Dizziness, Headache
Uncommon: Hypoesthesia, Migraine, Paraesthesia, Sinus headache, Somnolence
Frequency not Known: Presyncope
Uncommon: Diplopia
Uncommon: Ear pain, Vertigo
Uncommon: Palpitations
Uncommon: Blood pressure increased, Hot flush
Uncommon: Cough, Dry throat, Dyspnoea, Nasal congestion, Oropharyngeal pain, Rhinorrhea
Common: Abdominal pain, Constipation, Defecation urgency, Diarrhoea, Flatulence, Abdominal distension, Nausea, Vomiting, Rectal tenesmus
Uncommon: Abdominal pain upper, Dry lips, Dyspepsia, Gastrointestinal motility disorder, Faeces hard, Haematochezia, Mucous stools, Taste disorders
Uncommon: Aspartate aminotransferase increased
Frequency not Known: Liver function test abnormalities
Uncommon: Rashes, eruptions and exanthemas, Sunburn
Frequency not Known: Angioedema, Dermatitis, Dermatitis exfoliative, Eczema, Erythemas, Pruritus, Purpura, Urticarias
Uncommon: Back pain, Muscle spasms, Muscular weakness, Myalgia, Neck pain
Uncommon: Blood in urine, Glycosuria, Pollakiuria, Polyuria, Proteinuria
Uncommon: Polymenorrhoea
Common: Pyrexia
Uncommon: Asthenic conditions, Chills, Cold sweat, Hyperhidrosis, Influenza like illness, Oedema peripheral, Pain and discomfort
International normalised ratio abnormalities
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.
Not applicable.
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