Quang Bui - Rifaximin and Hepatic Encephalopathy FINAL
Quang Bui - Rifaximin and Hepatic Encephalopathy FINAL
Quang Bui - Rifaximin and Hepatic Encephalopathy FINAL
Candidate 2010
Rotation: Acute Care 1 at CCRMC
Preceptors: Karen Finck, Pharm D. (CCRMC)
& Adrienne Nazareno, Pharm. D (QVH)
Hepatic Encephalopathy (HE):
Goal & Objectives
• Goal
• Understand the use of rifaximin in HE
• Objectives
• Understand the pathogenesis of HE
• Understand the guideline of HE
• Know the drug of choice for HE
• Know the parameters for using rifaximin
CNS = center nervous system
Pathophysiology 1 BBB = blood brain barrier
• γ-Aminobutyric acid
• Gut derived GABA escapes hepatic
metabolism & crosses BBB
• Endogenous benzodiazepine-like
substances agonizes symptoms
Signs & Symptoms1
• 3 main clinical features
– Altered Mental Status
– Asterixis
• Flapping tremor every 1-2 seconds
– Fector hepaticus
• Sweetish, musty, pungent breath odor
• Result of unmetabolized mercaptans
• Highly efficacious
– May need NG if patient is comatose
or rectal retention enema (300 mL/ 1
L water) retained for 1 hour
– ~70-80% of patients clinically
improve7
Treatment Choices : Lactulose1
• MOA
– Disaccharide form broken down
by GI bacteria into lactic, acetic &
formic acid
– Acidification of the colon converts
ammonia into less readily
absorbed ammonium ion
– Lactulose-induced osmotic
diarrhea decreases intestinal
transit time
Treatment Choices : Lactulose1
• Side effects:
– Dehydration & hypokalemia
• Exacerbate hepatic
encephalopathy
– Syrup is excessive sweat
• May dilute with fruit juice,
carbonated drinks or water
– Well tolerated but 20%
patients have gaseous
distension, flatulence, or
belching
Treatment Choices : Neomycin1
• Goal: Decreases ammonia levels by increasing
protein-metabolizing bacteria in GI tract
• MOA: (non)absorable antimicrobial
• Side effects
– 1-3% of neomycin is absorbed but rarely causes
ototoxicity or nephrotoxicity
• Monitor SCr, urine protein & CrCl for patients
receiving high doses or long duration
– Reversible malabsorption syndrome
• Suppressed absorption of fat, N, carotene, Fe,
Vitamin B12, xylose, and glucose
– Decreased absorption of Digoxin, PCN, and vitaminK
• Hence lactulose is preferred in long term use
Treatment Choices : Rifaximin
• Goal
– Decreases bacterial byproducts
• MOA
– Nonabsorbable rifampin derivative
– Antimicrobial (broad spectrum)
• Side effects
– Has comparable SE to placebo
– May not improve severe
encephalopathy symptoms as rapidly
as lactulose8
Rifaximin vs. Lactitol – Efficacy/Safety9
• Comparison of rifaximin and lactitol in the treatment of
acute hepatic encephalopathy: results of a randomized,
double-blind, double-dummy, controlled clinical trial
– Mas A, Rodes J, Sunyer L, et al
– Journal of Hepatology. 2003;38:51-58
• Objective
– Efficacy & safety of rifaximin vs. lactitol
• Methods
– Randomize 103 patients grade 1-3 acute HE
• 50 patients taking rifaximin 1200 mg/day for 5-10 days
• 53 patients taking lactitol 60g/day for 5-10 days
– Evaluate the changes of the portal-systemic encephalopathy
(PSE) index (2 tail p-value test)
Rifaximin vs. Lactitol – Efficacy/Safety9
• Sample size:
– N = 120 for 80% power. Study has 103
– Exclusion criteria:
• Major pyschiatric illness, chronic renal/respiratory
insufficiency, intercurrent infections, hypersensitivity,
treatment with sedatives or antibiotics within 7 days,
pregnant/lactating, did not fulfill protocol requirements
• Assessments:
– PSE
• Mental status, asterixis, number connection test,
electroencephalogram, blood ammonia levels
– Adverse events
• Time onset, duration, severity, and relationship
• CBC & plasma biochemistry at start & end of study to
evaluate tolerability
Rifaximin vs. Lactitol – Efficacy/Safety9
• Conclusion
– 11 withdrawals due to inefficacy (6 in rifaximin, 5 in lactitol)
– 4 withdrawals due to intolerability (2 & 2)
– Both treatments were well tolerated
– No differences in end treatment
– “In acute HE of moderate to severe grade, rifaximin may be
good alternatives”
• Critiques
– Underpowered
– Good baseline demographic & clinical data homogeneity
– Use of PSE scores
– Rifaximin tablets and lactitol sachets are from same
manufacturer (Alfa Wasserman Pharmaceutical Company in
Italy)
Rifaximin vs. Lactulose – Hospitalization10
• Hospitalizations during the use of rifaximin versus
lactulose for the treatment of hepatic encephalopathy
– Carroll B Leevy and James A Phillips
– Dig Dis Sci. 2007;52:737-741
• Methods
– Retrospective chart review
• Frequencey, duration, and hospitalization charges
• HE discharge diagnosis, clinical status, and adverse events
– Patients with lactulose 30 cc twice daily for ≥ 6 months then
rifaximin 400 mg 3 times daily for ≥ 6 months (start 2004)
– Exclusions: liver transplant during therapy
– Primary end point: mean hospitalization during each treatment
– Secondary end points: average length of hospitalization, mean
total time hospitalized, and hospitalization charges per patient
(2005 dollars)
– Clinical end points: West Haven grades, asterixis, adverse events
Rifaximin vs. Lactulose – Hospitalization10
• Conclusions:
– Reduced need for hospital care and its associated charges in
patients using rifaximin compared to lactulose
• 3 times lower in frequency & duration of hospitalizations over 6
months
• 4 times lower in hospitalization charges over 6 months (>
$42,000)
– Better compliance in rifaximin group (92% rifaximin, 31%
lactulose)
• Poor tolerability in lactulose group due to diarrhea & nausea
• Comparable tolerability between rifaximin & placebo
• Critique
– Patients with rifaximin has less severe illness
– Retrospective & observation study
– Single center with 145 patients
– Tolerability results comparable to published literature
Treatment Choices : Flumazenil1
• MOA
– Antagonizes the GABA-ergic neurotransmitters
– Responses may be due to the reversal of
benzodiazepines
Lactulose 40 x 30 mL
Initial dose 30-45 mL PO TID QVH = 23.26; AWP = 119.20 8.94
Then titrate to symptomatic resolution
or until 3 soft stools per day 480 mL
QVH = 3.09; AWP = 34.70 6.51
Neomycin 100 x 500 mg tabs
1-2 grams PO QID or 1% solution QVH = 14.79; AWP = 57.05 4.56 – 9.13
retention enema x20-60 min QID
Rifaximin 100 x 200 mg
400 mg PO TID QVH = 360.04; AWP = 31.28
521.35
30 x 200 mg 31.28
QVH = 124.21; AWP =
Flumazenil 0.1 mg/mL [10 x 5 mL]
156.39
0.5 mg IV x1min QVH = 49.56; AWP = 886.85 88.69
Or 25 mg PO BID
0.1 mg/mL [10 x 10 mL]
QVH = 19.18; AWP = 78.00 3.90
Case Study Revisit
• TB current medications include:
– Lactulose 30 mL daily, Inderal 20 mg BID
– Spironolactone 100 mg daily, Atarax 25 mg Q4-6h prn
– Omeprazole 20 mg daily, Neomycin 2 tablets Q6h
– Questran powder daily