Xifaxan Dose For Hepatic Encephalopathy

Rifaximin Approved For Hepatic Encephalopathy

The Food and Drug Administration has approved the oral antibiotic rifaximin as a treatment to reduce the risk of developing episodes of overt hepatic encephalopathy in adults with chronic liver disease, making this the second drug approved for this indication.

Approved in 2004 for treating travelers’ diarrhea caused by noninvasive strains of Escherichia coli in people aged 12 and older, rifaximin is a poorly absorbed oral antibiotic derived from rifamycin, and has a broad spectrum of activity against gram-positive and gram-negative, aerobic and anaerobic enteric bacteria.

Rifaximin reduces levels of gut-derived neurotoxins such as ammonia, which is known to cause hepatic encephalopathy in patients with hepatic impairment, according to the manufacturer, Salix Pharmaceuticals, which markets the drug as Xifaxan.

The approval is for reduction in risk of overt hepatic encephalopathy recurrence in patients aged 18 and older. The approved dosage is one 550-mg tablet taken orally twice a day, with or without food.

Approva l was based on a study comparing treatment with rifaximin to placebo in 299 patients with advanced liver disease. The study was published on March 25, the same day that the FDA announced the approval .

The safety of rifaximin was uncertain when used for more severe liver disease, as was its efficacy as a single agent.

Neurologic impairment was also evaluated with the Asterixis score, which ranges from grade 0 and grade 1 to grade 2 , grade 3 , and grade 4 .

Oxidative And Nitrosative Stress

Enhanced production of reactive nitrogen species and reactive oxygen species occurs in cultured astrocytes that are exposed to ammonia, inflammatory cytokines, hyponatremia or benzodiazepines. It’s suggested that glutamine formed in the cytoplasm enters the mitochondrial matrix and is cleaved to release ammonia while still inside the mitochondria. Evidence indicating a close association and interplay between astrocyte swelling and ROS is now growing.

Assessment Of The Need For Long

Patients with cirrhosis are at risk of developing new episodes of encephalopathy. Several factors need to be considered:

Diet and Nutrition

Low-protein diets are often erroneously recommended for patients with cirrhosis, in hopes of decreasing intestinal ammonia production and of preventing exacerbations of HE. An obvious consequence was the worsening of preexisting protein-energy malnutrition. Protein restriction may be appropriate in some patients immediately following a severe flare of symptoms . However, protein restriction is rarely justified in patients with cirrhosis and persistent HE. Indeed, malnutrition is a more serious clinical problem than HE for many of these patients.

It is the infrequent patient who is intolerant of a diet high in protein. Most patients with mild chronic HE tolerate more than 60 to 80 g of protein per day.

Diets containing vegetable proteins appear to be better tolerated than diets rich in animal protein. This may be because of increased content of dietary fiber, a natural cathartic, and decreased levels of AAA. AAA, as precursors for the false neurotransmitters tyramine and octopamine, are thought to inhibit dopaminergic neurotransmission and worsen HE. Ingestion of red meat protein should be discouraged.

Control of Potential Precipitating Factors

Higher Likelihood of Recurrent Encephalopathy

Patient Education

Assessment of the Need for Liver Transplantation

Hepatic Encephalopathy and Fitness to Drive

Specific Measures

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Rifaximin May Cause Side Effects Tell Your Doctor If Any Of These Symptoms Are Severe Or Do Not Go Away:

• nausea

• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• hoarseness

Rifaximin may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration’s MedWatch Adverse Event Reporting program online or by phone .

Why Do We Use Lactulose And Rifaximin For Hepatic Encephalopathy

Lactulose and Rifaximin are standards of care for the prevention of overt hepatic encephalopathy in patients with cirrhosis.

Have you ever wondered why? Join us!

First, if you want a refresher on hepatic encephalopathy , check out our Quick Tips post by Lizzie Aby.

What is the first step in treating HE?

Reverse the underlying cause!!!

Infections, GI bleeding, medications, and dehydration can precipitate HE and treating these factors is most important in reversing an acute episode of HE.

So what next?

Medical therapy!

Lactulose, a non-absorbable sugar composed of galactose and glucose was first made in 1929. It was first used in 1966 by Bircher et al. to treat HE:

In this case report, the authors describe the proposed mechanism of action for the drug:

The non-absorbed lactulose passes intact into the ascending colon, where it is split by bacterial action into lower molecular organic acids . Their osmotic effect creates a fermentive diarrhea identical to the lactose-induced diarrhea in lactase-deficient subjects. The lowered fecal pH caused by the presence of these organic acids should hypothetically entail a change in colonic bacterial flora or a change in bacterial metabolism. An increase in fermentation and a decrease in putrefaction is to be expected this should decrease the amount of nitrogenous compounds which are toxic in the portal-systemic encephalopathy.

So doc, what else can I use for an acute episode of HE?

Here comes RIFAXIMIN!!!!

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Efficacy And Safety Of Rifaximin Versus Placebo Or Other Active Drugs In Critical Ill Patients With Hepatic Encephalopathy

• 1Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
• 2Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
• 3Institute of Digestive Diseases, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
• 4School of Basic Medicine, Fourth Military Medical University, Xian, China
• 5Department of Anorectal Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
• 6Anorectal Disease Institute of Shuguang Hospital, Shanghai, China

Objective: Rifaximin has been approved for use as a first-line therapy for secondary prophylaxis of hepatic encephalopathy . This article is to update existing evidence on efficacy and safety of rifaximin treatment and prevention for HE.

Methods: We systematically searched multiple databases until January 31 2021. The studies compared rifaximin vs. placebo or other active drugs , and probiotics) for patients with overt HE , minimal HE , and recurrent HE.

Rifaximin therapy is effective and well-tolerated in different types of HE, which might be recommended as an alternative to conventional oral drugs in clinical settings.

How Was Your Experience With Rifaximin

Rifaximin is a prescription medication used to treat travelers diarrhea caused by noninvasive strains of Escherichia coli and irritable bowel syndrome with diarrhea in adults and children at least 12 years old. It is also used to reduce the recurrence of hepatic encephalopathy in adults. Hepatic encephalopathy is a condition that causes changes in thinking, behavior, and personality caused by a build-up of toxins in the brain in people who have liver disease. Rifaximin should not be used if diarrhea is accompanied by fever or blood in the stool.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

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Why Is This Medication Prescribed

Rifaximin 200-mg tablets are used to treat traveler’s diarrhea caused by certain bacteria in adults and children at least 12 years of age. Rifaximin 550-mg tablets are used to prevent episodes of hepatic encephalopathy in adults who have liver disease and to treat irritable bowel syndrome in adults. Rifaximin is in a class of medications called antibiotics. Rifaximin treats traveler’s diarrhea and irritable bowel syndrome by stopping the growth of the bacteria that cause diarrhea. Rifaximin treats hepatic encephalopathy by stopping the growth of bacteria that produce toxins and that may worsen liver disease. Rifaximin will not work to treat traveler’s diarrhea that is bloody or occurs with fever.

Antibiotics such as rifaximin will not work for colds, flu, or other viral infections. Taking antibiotics when they are not needed increases your risk of getting an infection later that resists antibiotic treatment.

Provision Of Supportive Care

Standard supportive care is required for all hospitalized patients with HE. Patient safety and frequent bedside monitoring of mental status are crucial. This can require additional personnel and, in the case of comatose patients, admission to the intensive care unit, endotracheal intubation, or both. Although temporary restriction of dietary protein may be necessary, patients with HE should avoid prolonged periods of fasting. Although the restriction of dietary protein at the time of acute HE can be part of therapy, protracted nitrogen restriction can lead to malnutrition. Appropriate enteral nutrition, by mouth or nasogastric feeding tube, should be administered as soon as feasible.

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Minimal Or Subclinical Encephalopathy

Patients with minimal hepatic encephalopathy have a normal neurological examination however they may still be symptomatic. Symptoms relate to disturbances in sleep, memory, attention, concentration and other areas of cognition. A classic sign of HE is a sleep disturbance. On a sleep questionnaire, disturbance is seen in 47% of cirrhotics compared with 4.5% of controls. A higher frequency of sleep disturbance in cirrhotic patients with MHE has been confirmed in studies using health-related quality of life questionnaires. Sleep disturbance in cirrhosis is not associated with cognitive impairment thus it may not truly be an MHE symptom. Unsatisfactory sleep is associated with higher scores for depression and anxiety, raising the possibility that the effects of chronic disease may underlie the pathogenesis of sleep disturbance. Disturbances in cirrhotics may also be related to abnormalities of circadian rhythm.

Defective memory may be a sign of MHE. Patients with MHE have impaired short- and long-term memory. This impairment is predominantly related to deficits in attention and visual perception. Memory deficit of MHE seems to comprise short-term but not long-term memory impairment. This can be described as an encoding defect, in which memory recall is intact.

Several cognitive statements and/or complaints, have predictive value for MHE, including impaired psychomotor performance impaired sleep or rest decreased attention and poor memory .

Treatment And Prevention Of Ohe

The initial treatment of OHE is non-absorbable disaccharides like lactulose. The dosing of lactulose should be initiated with 25mL of lactulose every 12hours and the dose should be titrated to achieve two soft or loose bowel movements per day. The working mechanism of lactulose is not fully understood, but it is assumed that the prebiotic effects and acidifying nature of lactulose have an additional benefit beyond the laxative effect.

There is currently no treatment registered for primary prevention of HE. Secondary prevention of HE can be achieved by combination therapy of lactulose with rifaximin, a poorly absorbed antibiotic. In the Netherlands, rifaximin has been approved since 2016 and will be reimbursed only to prevent a third episode of OHE.

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Randomisation And Concealment Of Allocation

After the screening visit, eligible study subjects will be stratified for MELD score < 10and > 10. Study subjects are stratified randomised to the treatment or placebo in a 1:1 ratio. Randomisation with random blocks of sizes 4, 6 or 8 is performed by Castor Electronic Data Capture in an automated way and sent to the local clinical trial pharmacy. Neither the treating physician nor the patient is aware of the randomisation result. Deblinding is possible in the case standard of care that might be withheld .

Is It Safe To Use

This product is an antibiotic. The goal is to prevent HE, which is caused by various factors including liver disease. When the liver is unable to function it can result in this condition, which affects brain function. Antibiotics are designed to kill bacteria, which could trigger Hepatic Encephalopathy episodes.

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Clinical Scales For Grading He

A number of scales have been devised for the diagnosis of HE the first of its kind was proposed by Parsonsmith and colleagues in 1957. For patients with moderate to severe HE, the Glasgow Coma scale can also be employed.

Table 1: West-Haven Criteria for Hepatic Encephalopathy

MHE, minimal hepatic encephalopathy.

The West-Haven Classification Table

Stage 0. MHE . Lack of detectable changes in personality or behavior. Minimal changes in memory, concentration, intellectual function, and coordination. Asterixis is absent.

Stage 1. Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria, depression, or irritability. Mild confusion. Slowing of ability to perform mental tasks. Asterixis can be detected.

Stage 2. Lethargy or apathy. Minimal disorientation. Inappropriate behavior. Slurred speech. Obvious asterixis. Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, and intermittent disorientation, usually regarding time.

Stage 3. Somnolent but can be aroused, unable to perform mental tasks, gross disorientation about time and place, marked confusion, amnesia, occasional fits of rage, present but incomprehensible speech.

How Many Can You Take In A Day

Your doctor will provide you with the daily dosage of Rifaximin you should take. This can help to provide the best results. There are various factors that will help to determine the particular dosage including the condition youre treating. Its important to avoid taking more than youre required to take per day. That can help to avoid certain side-effects.

This medicine is usually taken 2x per day to help prevent HE. However, you should talk to your doctor about the number of times you should take the medicine per day.

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Neuropsychological Test In Mhe

Neuropsychological testing is useful methodology for quantifying cognitive impairment due to various forms of encephalopathy, including low-grade or MHE. Neuropsychological tests directly measure cognitive functions that are directly relevant to activities of daily living. They have been applied for the diagnosis of HE for more than 50 years.

The neuropsychological features of MHE point to a disorder of executive functioning, particularly selective attention, visuospatial abilities and fine motor skills. Although these domains are most commonly implicated in MHE, impairments of memory have also been reported.

The attention impairments in MHE are observed on a variety of measures. These include measures of cognitive processing speed involving psychomotor responding, such as the Number Connection tests , block design test ,the Digit Symbol test , line drawing test, circle-dotting test, serial-dotting test, figure connection test. Impairments on measures of cognitive processing speed and response inhibition that do not require a motor response have also been reported . Visuospatial impairments have been primarily reported on block design tasks , but also on more pure measures of visuospatial perception, such as line orientation or the Hooper test. Fine motor skill impairments have been noted on measures such as the grooved pegboard task, and on line tracing tasks .

Xifaxan: Hepatic Encephalopathy Prevention

Xifaxan is sometimes used to prevent hepatic encephalopathy . This condition is related to a late-stage liver disease known as liver cirrhosis. This is Stage 3 of liver disease and involves major tissue scarring that affects liver function.

HE causes various symptoms. They include reduced brain function that causes symptoms like lack of focus and confusion. It can also affect physical movement and even result in comas. Health experts believe that gut toxins are closely linked to HE symptoms.

The treatment strategies for HE focus on reducing ammonia and other gut toxins. Theres also a focus on treating conditions that trigger HE symptoms. The standard treatment for HE is a medicine thats believed to reduce the bodys ammonia absorption.

Xifaxan is an antibiotic thats slightly absorbed. Its believed it might reduce the bodys ammonia production. Thats by reducing ammonia-making bacteria. Several small studies show that the antibiotic is effective in treating HE.

The body also seems to tolerate the drug effectively. Various studies have been done to test the effectiveness of the antibiotic in preventing HE from returning. In one study the Xifaxan had a nearly 60% drop in HE. There was also a 50% drop in HE-related hospitalizations within 6 months. In fact, the side-effects were also similar to the fake pills.

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Analysis Of Outcome Measures

A comprehensive statistical analysis plan will be provided separately. Data will be analysed according to the intention to treat principle. Descriptive methods will be used to assess quality of data, homogeneity of treatment groups and endpoints. A p value < 0.05 is considered statistically significant. A brief outline is given in the next paragraph.

Primary outcome measurement

The primary outcome, development of OHE within 3months after TIPS placement determined by the West Haven criteria, will be compared between the intervention and placebo group. Percentage differences with corresponding 95% CI will be reported as absolute improvement in percentages.

Secondary outcomes

Secondary outcomes will be analysed using either a t-test or Mann-Whitney U test for continuous data or a 2 test for categorical data, as appropriate. Kaplan-Meier curves will be used to determine transplant-free survival. Kaplan-Meier curves will be used to determine the length of time for the subjects to reach the primary or secondary endpoint with regards to OHE. Censoring will be applied in analysis for liver transplantation or death by any cause. When censoring is applied, Cox proportional hazards model will be used. Comparison of peripheral and portal blood samples at TIPS placement will be analysed using a Wilcoxon signed rank test. Repeatedly measured endpoints will be analysed with mixed models, for the time point they are measured .

Comparison With Other Systematic Reviews

To date, several meta-analyses have assessed the therapeutic effects of rifaximin vs. control interventions on patients with HE . These systematic reviews included 319 trials that were published between 1985 and 2017. In contrast, our meta-analysis had the largest sample size on this topic that included 28 RCTs with 2,979 patients and comprehensively evaluated the efficacy and safety of rifaximin treatment for different types of HE. Moreover, we involved a variety of outcomes in terms of clinical efficacy and safety. Similar to the findings of three previous reviews, we found that rifaximin can significantly reverse MHE and prevent recurrent HE compared with placebo . Unlike the findings of other three meta-analyses , our results showed that rifaximin was superior to other active drugs in improving HE clinical syndrome . By contrast, they concluded that clinical efficacy of rifaximin was equivalent to that of other oral drugs . Kimer reported that rifaximin could significantly reduce the mortality of patients with HE compared with nonabsorbable disaccharides . By contrast, we did not find statistically significant difference in mortality between the two groups. Furthermore, we assessed the risk of bias, GRADE evidence, and publication bias for all included studies, which indicated that our results were stable and reliable. By contrast, most of the previous meta-analyses did not conduct these analyses to evaluate the quality of evidence.

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