What literature supports the use of low-dose rifaximin in patients with hepatic encephalopathy?

Hepatic Encephalopathy
Hepatic encephalopathy is a neuropsychiatric disorder resulting from acute or chronic liver disease.1 Its incidence and prevalence vary according to the type and severity of the underlying liver disease with overt hepatic encephalopathy eventually presenting in approximately 30% to 40% of patients with cirrhosis. However, many more patients may have subclinical (covert) hepatic encephalopathy.

The pathophysiology of hepatic encephalopathy remains incompletely understood; however, hyperammonemia and systemic inflammation remain important components.2 Clinical presentation varies widely with covert hepatic encephalopathy having few, if any, symptoms and overt encephalopathy presenting with cognitive and behavioral changes.2-5 Signs or symptoms may include asterixis, lethargy, confusion, seizures, or comma. Fluctuations in disease severity are common, and treatment is symptom dependent.

Generally, lactulose, a nonabsorbable disaccharide that reduces ammonia production and absorption in the intestine, is first-line therapy for patients with hepatic encephalopathy.4,5 Rifaximin, a poorly absorbed antibiotic which reduces ammonia-producing bacteria in the intestine, can be added to lactulose for patients without adequate response to lactulose monotherapy. Other therapies have been studied including neomycin, vancomycin, metronidazole, branched-chain amino acids, flumazenil, polyethylene glycol, and probiotics, but their place in therapy is less clear.2-5

Both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) recommend lactulose as the first-line therapy for hepatic encephalopathy and rifaximin as additional therapy for some patients.4,5 However, the guidelines do not recommend a specific dosage of rifaximin, and the optimal dosage remains unestablished.

Rifaximin for Hepatic Encephalopathy
Rifaximin is supplied as 200 mg or 550 mg tablets.6 The manufacturer designates the 200 mg dosage form for travelers’ diarrhea while the 550 mg dosage form is recommended for hepatic encephalopathy or irritable bowel syndrome with diarrhea.

The 550 mg twice daily rifaximin dose for hepatic encephalopathy was evaluated in a key clinical trial for rifaximin published in 2010.7 The phase 3 trial enrolled 299 patients in recent remission from an episode of overt hepatic encephalopathy. All patients received lactulose and were randomized to placebo or rifaximin for 6 months. Rifaximin 550 mg twice daily significantly reduced breakthrough episodes of hepatic encephalopathy compared with placebo. Although additional evidence supports the use of the recommended dosage regimen (or a similar 400 mg three time daily regimen), alternative, lower dosage regimens have been considered, primarily as a cost-saving measure.8-12

Literature Evaluation: Alternative Rifaximin Dosing in Hepatic Encephalopathy
Four studies evaluating lower doses of rifamixin for patients with hepatic encephalopathy were identified and are summarized in Table 1.9-12 These studies differed in their patient population, objective, interventions, and measured outcomes.

None of the low-dose studies identified in the literature search evaluated rifaximin in patients with over hepatic encephalopathy, but rather rifaximin at low doses was evaluated as primary or secondary prophylaxis of hepatic encephalopathy.9-12 Three of the studies compared a higher dose (1100 to 1200 mg daily) to a lower dose (440 to 800 mg daily).9,11,12 Generally these studies were unable to differentiate the efficacy of higher and lower doses; however, methodological insufficiencies such as the small sample sizes may have contributed to the lack of significant findings.

Table 1. Studies evaluating low-dose rifaximin for primary or secondary hepatic encephalopathy prophylaxis.9-12
Study design and duration
Subjects
 
Interventions
Results
Conclusions
Tan et al 20229
 
SC, OL, RCT
 
8 weeks
 
N=40 patients with CHE
Rifaximin 800 mg/day (low-dose; n=12)
 
Rifaximin 1200 mg/day (high-dose; n=14)
 
Control (n=14)
  • CHE reversal was higher with rifaximin than control:
    • Low-dose: 41.67%
    • High-dose: 57.14%
    • Control: 7.14%

  • No significant difference between high- and low-dose groups
  • AEs were similar amongst the groups

  • High-dose and low-dose rifaximin have similar efficacy for CHE reversal, and both dosage regimens have better efficacy than control.
Zeng et al 202110
 
MC, OL, RCT
 
6 months
N=200 patients with decompensated cirrhosis
Rifaximin 400 mg twice daily (n=100)
 
Usual therapy (n=100)a
  • The addition of low-dose rifaximin lowered overall complications (23.71% vs 55.10%; p<0.001)
  • Overt hepatic encephalopathy occurred in 9.28% of rifaximin-treated patients and 11.22% of control patients (p<0.001b)
  • AEs were similar between groups (60.2% in control vs 73.2% with rifaximin)
  • Rifaximin in addition to usual care lowers both overall complications and hepatic encephalopathy.
Sarwar et al 201911
 
SC, DB, RCT
 
6 months
N=75 patients with decompensated cirrhosis without encephalopathy
Rifaximin 220 mg twice daily (n=34)
 
Rifaximin 550 mg twice daily (n=41)
 
All patients received lactulose
  • 35.2% of low-dose patients developed encephalopathy vs 29.2% of high-dose patients (p=0.57)
  • Mortality was also similar between groups (17.6% vs 17.07%; p=0.94)
  • The authors concluded that rifaximin was not effective for decompensated cirrhosis; however, this conclusion is not valid due to lack of placebo or control group without rifaximin
  • No differences were noted between high- and low-dose rifaximin
Khokhar et al 201512
 
SB, SC, RCT
 
6 months
N=306 patients with cirrhosis and ≥1 HE episode
Rifaximin 550 mg once daily (n=128)
 
Rifaximin 550 mg twice daily (n=178)
 
All patients received lactulose titrated to bowel movements
  • 21% of patients in the once-daily group had an episode of HE vs 30% in the twice-daily group (p=0.088)
  • Mortality was also similar between groups (17% vs 14%; p=0.63)
  • There are no significant differences between once or twice daily dosing of rifaximin for secondary HE prophylaxis.
Abbreviations: AEs=adverse events; DB=double-blind; CHE=covert hepatic encephalopathy; HE=hepatic encephalopathy; MC=multicenter; OL=open-label; RCT=randomized controlled trial; SB=single-blind; SC=single-center.
aUsual therapy could include antiviral agents, beta-blockers, liver protectants, and diuretics, but further information was not specified. Use of lactulose was not addressed.
bAfter adjustment for baseline differences in history of HE.

Conclusion
Well-designed clinical trials support the use of rifaximin 550 mg twice daily in addition to lactulose for secondary prevention of hepatic encephalopathy in patients with liver disease. However, lower doses of rifaximin may be effective. Three clinical trials have directly compared higher doses of rifaximin with lower doses of rifaximin without finding significant differences in efficacy for hepatic encephalopathy prophylaxis. A lower dose, 400 mg twice daily, has also been studied in primary hepatic encephalopathy prophylaxis and appears to improve outcomes compared with usual care.

Unfortunately, no firm recommendation for a lower dose of rifaximin for hepatic encephalopathy prophylaxis can be made based on the current literature. Limited evidence supports doses as low as 440 mg/day in primary prophylaxis and 550 mg/day in secondary prophylaxis, but the studies suffer major limitations including lack of blinding, small sample sizes, and specific demographic locations making generalization to the larger population of patients difficult.

References

  1. Elsaid MI, Rustgi VK. Epidemiology of hepatic encephalopathy. Clin Liver Dis. 2020;24(2):157-174. doi:10.1016/j.cld.2020.01.001
  2. Rudler M, Weiss N, Bouzbib C, Thabut D. Diagnosis and management of hepatic encephalopathy. Clin Liver Dis. 2021;25(2):393-417. doi:10.1016/j.cld.2021.01.008
  3. Runyon BA. Hepatic encephalopathy in adults: treatment. In: Robson KM, ed. UpToDate. Wolters Kluwer; 2023. Accessed July 7, 2023. https://www.uptodate.com/contents/hepatic-encephalopathy-in-adults-treatment?search=hepatic%20encephalopathy&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H65804868
  4. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715-735. doi:10.1002/hep.27210
  5. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of hepatic encephalopathy. J Hepatol. 2022;77(3):807-824. doi:10.1016/j.jhep.2022.06.001
  6. Xifaxan (rifaximin) [prescribing information]. Salix Pharmaceuticals, Inc; September 2022.
  7. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071-1081. doi:10.1056/NEJMoa0907893
  8. Mullen KD, Sanyal AJ, Bass NM, et al. Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy. Clin Gastroenterol Hepatol. 2014;12(8):1390-7.e2. doi:10.1016/j.cgh.2013.12.021
  9. Tan W, Wang J, Shi PM, et al. Effects of Low-dose and high-dose rifaximin in the treatment of covert hepatic encephalopathy. J Clin Transl Hepatol. 2022;10(6):1099-1106. doi:10.14218/JCTH.2021.00457
  10. Zeng X, Sheng X, Wang PQ, et al. Low-dose rifaximin prevents complications and improves survival in patients with decompensated liver cirrhosis. Hepatol Int. 2021;15(1):155-165. doi:10.1007/s12072-020-10117-y
  11. Sarwar S, Muhyuddin B, Aleem A, Nadeem MA. Primary prophylaxis of hepatic encephalopathy in decompensated cirrhosis: Low dose vs. full dose rifaximin. Pak J Med Sci. 2019;35(5):1446-1450. doi:10.12669/pjms.35.5.549
  12. Khokhar N, Qureshi MO, Ahmad S, et al. Comparison of once a day rifaximin to twice a day dosage in the prevention of recurrence of hepatic encephalopathy in patients with chronic liver disease. J Gastroenterol Hepatol. 2015;30(9):1420-1422. doi:10.1111/jgh.12970

Prepared by:
Courtney Krueger, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

August 2023
The information presented is current as July 7, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.