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 If signs and symptoms suggestive of these reactions appear, rifaximin should be withdrawn immediately and an alternative treatment considered (as appropriate).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.

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.

Skin and subcutaneous tissue disorders

Rashes, pruritus

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

10     DATE OF REVISION OF THE TEXT

 May 2024

What is in this leaflet:

1. What Targaxan is and what it is used for

2. What you need to know before you use take TARGAXAN

2. What you need to know before you use take TARGAXAN

Warning and Precautions

Talk to your doctor or pharmacist before taking Targaxan.

If you have ever developed a severe skin rash or skin peeling, blistering and/or mouth sores after taking rifaximin. 

Take special care with rifaximin:

Serious skin reactions including including Stevens-Johnson-syndrome and toxic epidermal necrolysis, have been reported in association with rifaximin treatment. Stop using rifaximin and seek medical attention immediately of you notice any of the symptoms related to these serious skin reactions described in section 4.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop using taking Targaxan and seek medical attention immediately IMMEDIATELY if you have notice any of the following symptoms 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):

• reddish non-elevated, target-like or circular patches on the trunk, often with central blisters, skin peeling, ulcers of mouth, throat, nose, genitals and eyes. These skin rashes can be preceded by fever and flu-like symptoms.
• 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.

Reporting of side effects:

By reporting side effects, you can help provide more information on the safety of this medicine.

6. Contents of the pack and other information

This leaflet was last revised in 03/2021 May 2024

This medicineal product is authorised in the Member States of the European Economic Area under the following names:

4.1      Therapeutic indications

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

4.2      Posology and method of administration

TARGAXANargaxan can be administered with or without food.

Paediatric population

The safety and efficacy of TARGAXANargaxan 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 TARGAXANargaxan showed no differences between the elderly and the younger patients.

5         PHARMACOLOGICAL PROPERTIES

TARGAXANargaxan contains rifaximin (4-desoxy-4’methyl pyrido (1’,2’-1,2) imidazo (5,4-c) rifamycin SV), in the polymorphic form a.

5.1      Pharmacodynamic properties

The primary endpoint was the time to first breakthrough overt HE episode and patients were withdrawn after a breakthrough overt HE episode. A breakthrough overt HE episode was defined as a marked deterioration in neurological function and an increase of Conn score to Grade ≥ 2. In patients with a baseline Conn score of 0, a breakthrough overt HE episode was defined as an increase in Conn score of 1 and asterixis grade of 1.

10       DATE OF REVISION OF THE TEXT

21 April 2021 19 September 2022

4.2       Posology and method of administration

Posology

Recommended dose: 550 mg twice a day as long term treatment for the reduction in recurrence of episodes of overt hepatic encephalopathy. The clinical benefit was established from a controlled study in which subjects were treated for 6 months. Treatment beyond 6 months should take into consideration the individual balance between benefits and risks, including those associated with the progression of hepatic dysfunction (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).

5.1       Pharmacodynamic properties

Clinical efficacy

Two-hundred ninety-nine subjects were randomised to treatment with rifaximin 550 mg twice daily (n=140) or placebo (n= 159) for 6 months. In the pivotal study, 91% of the subjects in both groups received concomitant lactulose. No patients were enrolled with a MELD score > 25.

Combination therapy with rifaximin and lactulose showed a statistically significant reduction in mortality in HE patients compared with lactulose alone in a systematic review and meta-analysis of four randomized and three observational studies involving 1822 patients (risk difference (RD) -0.11, 95% CI -0.19 to -0.03, P=0.009). Additional sensitivity analyses confirmed these results. Notably, a pooled analysis of two randomized trials - including 320 patients treated for up to 10 days and followed-up during hospitalisation - demonstrated a statistically significant decrease in mortality (RD -0.22, 95% CI -0.33 to -0.12, P<0.0001).

10      DATE OF REVISION OF THE TEXT

21 April 2021

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.Continue taking

Targaxan until your doctor tells you to stop.

This leaflet was last revised in 04 /2021

4.4       Special warnings and precautions for use

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

4.8       Undesirable effects

Reporting of suspected adverse reactions

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin2; Tel:+353 1 6764971; Fax:+353 1 6762517. Website: www.hpra.ie.; Email: medsafety@hpra.ie.

By reporting side effects you can help provide more information on the safety of this medicine.

10        DATE OF REVISION OF THE TEXT

            06 January 2021

Section 2. What you need to know before you take TARGAXAN

Targaxan contains sodium

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

Section 4. Possible Side Effects

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin2; Tel:+353 1 6764971; Fax:+353 1 6762517. Website: www.hpra.ie.; Email: medsafety@hpra.ie.

By reporting side effects you can help provide more information on the safety of this medicine.

Section 6. Contents of the pack and other information

This leaflet was last revised in 01/2021.

Other sources of information

If you need the information on this leaflet in an alternative format, such as large print, please ring 00 44 1895 826 606.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

United Kingdom: You can also report side effects directly via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Ireland: You can also report side effects directly 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.

By reporting side effects you can help provide more information on the safety of this medicine.

Marketing Authorisation Holder (UK):

Norgine Pharmaceuticals Limited

Norgine House, Widewater Place,

Moorhall Road, Harefield, Uxbridge,

UB9 6NS, UK

Marketing Authorisation Holder (IE):

Norgine B.V.

Antonio Vivaldistraat 150,

1083HP Amsterdam

Netherlands

This leaflet was last revised in 07/201903/2020

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'.
.
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