Travyc 200 mg modified-release tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1. NAME OF THE MEDICINAL PRODUCT

Travyc 200 mg modified-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One modified-release tablet contains 200 mg rifamycin sodium.

Excipients with known effect:

Each tablet contains 10 mg soya lecithin and 6.11 mg sodium.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Modified-release tablet

Yellow-brown ellipsoidal tablet marked with “SV2” on one side (approximate tablet dimensions: length: 19 mm, width: 8.9 mm, thickness: 7.2 mm)

4.1 Therapeutic indications

Travyc is indicated in adults for the treatment of traveller’s diarrhoea accompanied by symptoms like nausea, vomiting, gas/flatulence, rectal tenesmus, faecal urgency and abdominal pain or cramps without clinical signs of invasive enteritis such as fever, blood, occult blood or leucocytes in the stools (see sections 4.4 and 5.1).

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

4.2 Posology and method of administration

Posology

Adults (> 18 years of age)

The recommended daily dose is two tablets in the morning and two tablets in the evening (total daily dose: 800 mg rifamycin sodium) for three days.

Travyc should not be used for more than 3 days if the symptoms persist. No second course of treatment may be taken (see section 4.4).

Paediatric population

The safety and efficacy of Travyc in children and adolescents (<18 years) have not been established. Travyc is not intended for use in the paediatric population.

Patients with renal impairment

Due to the low systemic bioavailability of rifamycin sodium, renal impairment is not expected to have an impact on the safety and efficacy of treatment with Travyc and no dosage adjustments should be required.

Patients with hepatic impairment

Due to the low systemic bioavailability of rifamycin sodium, hepatic impairment is not expected to have an impact on the safety and efficacy of treatment with Travyc and no dosage adjustments should be required.

Method of administration

The tablets should be taken orally with a glass of water.

They should be swallowed whole and not be crushed or chewed.

Travyc can be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substance, to any rifamycin class antibiotic (e.g. rifaximin, rifampicin and rifabutin) or to any of the excipients listed in section 6.1.

Gastrointestinal obstructions, perforations in the gastrointestinal tract or severe intestinal ulcerative lesions

Travyc contains soya lecithin. Patients allergic to peanut or soya must not take this medicine.

4.4 Special warnings and precautions for use

Travyc should not be used in patients with clinical signs of invasive enteritis such as fever or blood in the stools.

If a worsening of symptoms is observed, treatment with Travyc should be stopped.

If symptoms have not substantially resolved after 3 days of treatment, Travyc should be discontinued. No second course of treatment should be administered, even if symptoms reoccur shortly after termination of treatment.

Clostridium difficile associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including rifamycin class antibiotics. An association of rifamycin sodium treatment with CDAD or pseudomembranous colitis cannot be excluded.

Patients who are being treated with a rifamycin for mycobacterial disease should not receive Travyc.

As no clinical data with Travyc are available for patients with renal and hepatic impairment, special caution should be applied in these populations.

Patients should be informed that despite the negligible absorption of the active substance (clearly less than 1%), like all rifamycin class antibiotics, Travyc may cause a reddish discolouration of the urine.

The choice of rifamycin should take into account information on resistance to rifamycin in relevant pathogens in the countries visited.

This medicinal product contains less than 1 mmol sodium (23 mg) 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 with the concomitant administration of rifamycin class antibiotics in the treatment of systemic bacterial infections. Due to the potential risk of a severe disruption of the gastrointestinal microbiota, concomitant administration of Travyc and other rifamycin class antibiotics should be avoided.

Effects on CYP substrates

In vitro data show that rifamycin sodium – like other agents of the rifamycin class – is a strong inducer of cytochrome P450 isoenzymes CYP2B6 and CYP3A4. In addition, rifamycin sodium may also moderately inhibit all CYP isoenzymes.

Due to the negligible gastrointestinal absorption of rifamycin sodium, the potential for systemic drug interactions due to CYP induction or inhibition in the liver seems to be low in patients with normal liver function. However, in patients with impaired liver function the systemic exposure could be substantially higher compared to patients with normal liver function due to slower hepatic clearance, as previously demonstrated for rifaximin, a closely related antibiotic. Under impaired hepatic conditions a decrease of the plasma concentrations of CYP3A4 substrates administered concomitantly (e.g. warfarin, antiepileptics, antiarrhythmics, oral contraceptives) cannot be excluded.

As CYP3A4 is also expressed in the gut, an induction of CYP3A4 could potentially influence the pre-systemic metabolism of drugs, which might result in decreased plasma concentrations of the respective drugs. Rifamycin sodium is released in the distal small intestine, colon and rectum. Therefore, the efficacy of CYP3A4 metabolised drugs that are absorbed or acting locally in those parts of the intestine could be reduced by Travyc. Effects in the small intestine, the main site of drug absorption are likely limited.

Effects on BSEP and OATP substrates

An inhibitory effect of rifamycin sodium on the bile salt export pump (BSEP) and hepatic organic anion transporters (OATP) was observed in vitro. While this interaction correlates to an inhibition of biliary excretion of bilirubin, bromsulphalein and indocyanine after systemic administration in man, a clinically relevant inhibition by Travyc is not expected due to the negligible systemic exposure in patients with normal liver function. However, in liver-impaired patients this interaction could potentially be relevant due to the expected increased systemic exposure.

Effects of P-gp and BCRP inhibitors

The potential for drug-drug interactions to occur at the level of gut transporter systems has not been clinically evaluated and cannot be ruled out. An in vitro study suggested that rifamycin is a substrate of P-glycoprotein (P-gp) and possibly a substrate of breast cancer resistance protein (BCRP) similar to rifaximin. Co-administration of rifaximin with ciclosporin, a potent P-gp inhibitor, led to a substantially increased systemic exposure of rifaximin with unknown clinical significance. A similar effect may be expected for rifamycin sodium when co-administered with a P-gp inhibitor. Caution is therefore advised when Travyc is co-administered with a potent P-gp inhibitor, in view of the potentially significant increase in absorption of rifamycin sodium.

Effects on P-gp and BCRP substrates

According to in vitro data rifamycin sodium is also an inhibitor of P-gp and BCRP and may lead to an increase in plasma concentrations of drugs which are substrates to one or both of these membrane transporters. Caution is advised with concomitant administration of rifamycin sodium and drugs which are substrates of P-gp and/or BCRP.

No drug interaction studies investigating the concomitant intake of rifamycin sodium and other drugs commonly used for the treatment of traveller’s diarrhoea (e.g., loperamide and charcoal) have been performed. Patients should be advised to take Travyc at least 2 hours after the administration of charcoal.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amounts of data from the use of rifamycin sodium in pregnant women. Animal studies showed visceral and skeletal variations in the foetus (see section 5.3). As a precautionary measure, Travyc should not be used during pregnancy.

Breast-feeding

It is unknown whether rifamycin sodium is 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 abstain from Travyc therapy taking into account the benefits of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No information on the effects of rifamycin sodium on male and female fertility is available.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

No studies on the effects on the ability to drive and use machines have been performed. Attention should be paid to the occurrence of dizziness and tiredness with regard to the ability to drive and operate machines.

4.8 Undesirable effects

In clinical studies with rifamycin sodium for the treatment of traveller’s diarrhoea, the following adverse reactions considered at least possibly related to rifamycin sodium have been observed:

The following known adverse reactions of the therapeutic class (antibacterial agents of the rifamycin class) could also occur with Travyc (frequency = unknown):

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 the 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 up to 1200 mg/day have been well tolerated without any severe clinical symptoms.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antidiarrheals, intestinal antiinflammatory/antiinfective agents, antibiotics, ATC code: A07AA13

Mechanism of action

Rifamycin sodium is an antibacterial drug of the rifamycin class that irreversibly binds the beta sub-unit of the bacterial enzyme DNA-dependent RNA polymerase and consequently inhibits bacterial RNA synthesis.

Rifamycin sodium has a broad antimicrobial spectrum against most of the Gram-positive and -negative, aerobic and anaerobic bacteria responsible for intestinal infections. Due to the very low absorption from the gastro-intestinal tract, rifamycin sodium is locally acting in the intestinal lumen and clinically not effective against invasive enteritis.

Mechanism of resistance

The main mechanism of acquiring resistance to rifamycin sodium appears to involve a mutation in the rpoB gene encoding the bacterial RNA polymerase.

The incidence of resistant subpopulations among bacteria isolated from patients with traveller’s diarrhoea after treatment with rifamycin sodium was very low.

Susceptibility

Rifamycin sodium is a non-absorbed antibacterial agent. In vitro susceptibility testing cannot be used to reliably establish susceptibility or resistance of bacteria to rifamycin. There are currently insufficient data available to support the setting of a clinical breakpoint for susceptibility testing.

Clinical efficacy and safety

Clinical studies in patients with traveller’s diarrhoea showed the efficacy of rifamycin sodium at reducing the duration of traveller’s diarrhoea as well as the microbiological eradication of enteropathogens associated with traveller’s diarrhoea such as ETEC (Enterotoxigenic E. coli) or EAEC (Enteroaggregative E. coli).

The two randomised, double-blind pivotal studies included 1099 international travellers aged 18 to 87 years with traveller’s diarrhoea. Traveller’s diarrhoea was defined as at least three unformed stools within 24 hours, accompanied by at least one moderate to severe concomitant symptom such as nausea, vomiting, gas/flatulence, rectal tenesmus, faecal urgency and abdominal pain or cramps, without clinical signs of invasive enteritis such as fever or grossly bloody stools. The main efficacy results are presented in the following table:

* TLUS: time to the last unformed stool.

# Clinical cure: a 24-hour period with no clinical symptoms except mild flatulence, no fever, no watery stools and no more than 2 soft stools OR a 48-hour period with no stools or only formed stools and no fever, with our without symptoms of enteric infection.

For information about the observed adverse reactions, see section 4.8.

There is no information available on the effect of Travyc on the enteric flora.

5.2 Pharmacokinetic properties

Absorption

After administration of single doses of 400 mg Travyc to healthy male and female volunteers under fasting and fed conditions, rifamycin sodium above the lower limit of quantification (2 ng/ml) was found in only a few plasma samples and no pharmacokinetic analyses could be conducted. The absolute bioavailability estimated from the fraction of the oral dose excreted in urine compared to i.v. administration of rifamycin sodium was only 0.04%.

The study confirmed that absorption of rifamycin sodium following a single administration of Travyc is negligible under fasting and fed conditions in healthy volunteers. The poor absorption of rifamycin sodium is further reduced by the formulation of the medicinal product, which releases the active compound only in the colon.

Distribution

As rifamycin sodium released from Travyc is virtually not absorbed, it remains almost completely in the lumen of the intestine.

Biotransformation

There are no indications to a relevant biotransformation of rifamycin sodium.

Elimination

After single doses of 400 mg rifamycin sodium released from Travyc, the mean renally excreted fraction of the oral dose was 0.001% under fasting conditions, and 0.0004% under fed conditions. The mean total faecal elimination of rifamycin sodium was 348.7 mg corresponding to 87.2% of the administered dose.

5.3 PRECLINICAL SAFETY DATA

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

In embryo-foetal development studies conducted in rats and rabbits, reduced foetal body weights and a higher incidence of visceral or skeletal variations were observed at maternotoxic dose levels. The clinical relevance of these findings is unknown.

No information on the effects of rifamycin sodium on male and female fertility is available.

6 PHARMACEUTICAL PARTICULARS

6.1 LIST OF EXCIPIENTS

Tablet core

Ammonio methacrylate copolymer (Type B)

Ascorbic acid (E300)

Glycerol distearate

Soya lecithin (E322)

Magnesium stearate

Mannitol

Silica, colloidal anhydrous (E551)

Tablet film-coating

Methacrylic acid-methyl methacrylate copolymer (1:2)

Macrogol 6000 (E1521)

Talc

Titanium dioxide (E171)

Triethyl citrate (E1505)

Iron oxide yellow (E172)

6.2 INCOMPATIBILITIES

Not applicable.

6.3 SHELF LIFE

3 years

6.4 SPECIAL PRECAUTIONS FOR STORAGE

Do not store above 30°C.

6.5 NATURE AND CONTENTS OF CONTAINER

Polyamide/Aluminium/PVC/Aluminium blisters. Pack size: blister packs with 12 tablets.

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Adalvo Competence Center S.R.L

47 Theodor Pallady Blvd

Building HBC, entrance B

032258 Bucharest

Romania

8 MARKETING AUTHORISATION NUMBER(S)

PL 53269/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

30/05/2023

10 DATE OF REVISION OF THE TEXT

13/06/2025