Rifaximin for Hepatic Encephalopathy

Rifaximin is a minimally absorbed oral rifamycin antibiotic that acts in the gut. It reduces the risk of recurrent overt hepatic encephalopathy when added to lactulose, and it is also used for travellers' diarrhoea and irritable bowel syndrome with diarrhoea.

Classification. Rifamycin antibiotic; non-absorbable gut antimicrobial.

Mechanism. Binds the beta subunit of bacterial DNA-dependent RNA polymerase, blocking transcription. It reduces ammonia-producing gut bacteria and their toxins, and changes the gut microbiome, lowering ammonia and endotoxin burden.

Pharmacodynamics. Reduces blood ammonia, endotoxaemia and recurrence of encephalopathy; effect builds over days to weeks.

Pharmacokinetics. Less than 0.4% absorbed in healthy people, but absorption is higher in Child-Pugh C cirrhosis and with inflammation. Protein binding about 67%. Excreted in faeces.

Metabolism. Little hepatic metabolism; minor CYP3A4 involvement.

Adult oral doses.

Reduction of risk of recurrence of overt hepatic encephalopathy (after a second episode).

• 550 mg twice daily.

• Continue long term, together with lactulose.

• Reassess regularly for the need to continue.

Treatment of acute episodes (adjunct). 550 mg twice daily with lactulose; a dose of 400 mg three times daily has also been used.

Travellers' diarrhoea (noninvasive). 200 mg three times daily for 3 days.

Irritable bowel syndrome with diarrhoea. 550 mg three times daily for 14 days; retreatment up to two times if symptoms return.

Small intestinal bacterial overgrowth. 400 mg three times daily for 7 to 10 days (specialist directed).

Children. Hepatic encephalopathy not established. Travellers' diarrhoea: 200 mg three times daily for 3 days from age 12 years.

Kidney and liver adjustment.

• Kidney impairment: no adjustment.

• Liver impairment: no adjustment; systemic levels rise in severe impairment (Child-Pugh C), so use with caution.

Contraindications. Hypersensitivity to rifamycins; diarrhoea with fever or blood in stool (travellers' diarrhoea).

Common adverse effects. Peripheral oedema, nausea, dizziness, fatigue, ascites, headache and abdominal pain.

Serious adverse effects.

• Clostridioides difficile-associated diarrhoea.

• Hypersensitivity, including angioedema.

• Possible emergence of rifampicin resistance in tuberculosis if used in patients with undiagnosed active tuberculosis (a minor concern given low absorption).

Major interactions.

• P-glycoprotein inhibitors (ciclosporin): markedly raise rifaximin levels; caution.

• Warfarin: INR may change; monitor.

• Midazolam: modestly reduced levels after long courses.

• Oral contraceptives: no clinically important effect.

• CYP3A4 substrates: little effect at normal doses.

Special groups.

• Pregnancy: avoid; limited data.

• Breastfeeding: avoid; unknown.

• Children: not established for encephalopathy.

• Older adults: no adjustment.

• Kidney impairment: no adjustment.

• Liver impairment: use with caution in Child-Pugh C.

• Regional: availability and cost limit use in East Africa; lactulose alone remains the usual treatment.

Formulations. Tablets 200 mg, 400 mg and 550 mg.

Administration. Take with or without food, with water. Continue lactulose at the same dose, aiming for 2 to 3 soft stools daily. Tablets may be crushed if swallowing is difficult.

Baseline. Liver function, mental state grade, precipitants of encephalopathy (infection, bleeding, constipation, sedatives, electrolyte disturbance, dehydration), and tuberculosis risk.

Monitoring.

• Mental state, sleep pattern and asterixis.

• Stool frequency and diarrhoea.

• Liver and kidney function, sodium and potassium.

• Signs of C. difficile infection if diarrhoea develops.

• Adherence to lactulose.

Therapeutic drug monitoring. Not applicable.

Stopping. No taper is needed. Stop for hypersensitivity, C. difficile infection or when no longer needed after resolution of precipitants.

Referral and escalation. Refer for liver transplant assessment after the first episode of overt hepatic encephalopathy. Urgent admission for grade 3 or 4 encephalopathy, bleeding or sepsis.