4.4 Special warnings and precautions for use

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 mg (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).

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.

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 P gp and/or 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 (550 mg) resulted in 83-fold and 124-fold increases in rifaximin mean C_max 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 ( MDR1, MRP2, MRP4, BCRP and BSEP).

4.8 Undesirable effects

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

Anaphylactic reactions, angioedemas, hypersensitivity have been moved form MeDRA System Organ Class 'Nervous system disorders' to 'Immune system disorders'.
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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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: + 353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

10 DATE OF REVISION OF THE TEXT

November 2015