Treatment

Treatment news

In this section you will find a series of summaries of recent interesting and important studies reporting progress in the management of hepatic encephalopathy.

This study evaluated the efficacy and safety of rifaximin plus lactulose vs. lactulose alone for treatment of overt HE. In this prospective double-blind randomised controlled trial, 120 patients with overt HE were randomised into two groups: (group A lactulose plus rifaximin 1,200 mg/day; n=63) and group B (lactulose (n=57) plus placebo). The primary end point was complete reversal of HE and the secondary end points were mortality and hospital stay.

There was a significant decrease in mortality after treatment with lactulose plus rifaximin vs. lactulose and placebo (23.8% vs. 49.1%, p<0.05). There were significantly more deaths in group B because of sepsis (group A vs. group B: 7:17, p=0.01), whereas there were no differences because of gastrointestinal bleed (group A vs. group B: 4:4, p=non-significant) and hepatorenal syndrome (group A vs. group B: 4:7, p=non-significant). Patients in the lactulose plus rifaximin group had shorter hospital stay (5.8±3.4 vs. 8.2±4.6 days, p=0.001)

Combination of lactulose plus rifaximin is more effective than lactulose alone in the treatment of overt HE.1

The purpose of this study was to update the meta-analysis to re-evaluate the safety and efficacy of LOLA on HE in patients with cirrhosis.

Eight randomised controlled trials with 646 patients were included. When comparing placebo/no-intervention control, LOLA was significantly more effective in the improvement of HE in the total (RR: 1.49, 95% confidence interval [CI]: 1.10 to 2.01), overt HE (RR: 1.33, 95% CI: 1.04 to 1.69), and minimal HE patients (RR: 2.25, 95% CI: 1.33 to 3.82). Furthermore, the reduction of fasting ammonia significantly favoured LOLA (post-treatment value, MD: -18.26, 95% CI: -26.96 to -9.56; change, MD: 8.59, 95% CI: 5.22 to 11.96). The tolerance ratio, incidence of adverse events, and mortality were not significantly different between LOLA and the placebo/no-intervention control. LOLA and lactulose demonstrated similar effectiveness in the improvement of HE (RR: 0.88, 95% CI: 0.57 to 1.35).

OLA benefits both overt and minimal HE patients in the improvement of HE by reducing the serum ammonia concentration compared with the placebo/no-intervention control.2

Hepatic encephalopathy refers to a complex neuropsychiatric syndrome that is progressive but potentially reversible and may have a significant impact on quality of life, as it is characterized by alterations in cognitive function, behaviour and personality as well as transient neurological symptoms and electroencephalographic abnormalities. The aim of this study was to evaluate scientific evidence for the effectiveness and safety of LOLA infusions for treatment of clinical hepatic encephalopathy in patients with chronic liver disease. Six publications were selected as having met the inclusion criteria. A total of 623 patients were observed in studies published in these publications.

The available scientific evidence supports the adoption of LOLA infusion as a treatment for clinical encephalopathy in patients with liver failure, because it has been shown to improve neuropsychiatric status and decrease serum levels of ammonia with a low incidence of adverse effects (less than 5%).3

This randomised placebo controlled study aimed to evaluate the efficacy of LOLA as an adjuvant therapy in cirrhotic patients with HE. Patients with HE were randomised to receive LOLA or placebo medicine as an adjuvant to treatment of HE. Number connection test-A (NCT-A), ammonia level, clinical grade of HE and duration of hospitalisation were assessed.

Improvement in HE was higher (n=40, 66.7%) in LOLA group as compared to the placebo group (n=28, 46.7%, p=0.027). In patients with grade I or less encephalopathy, improvement was seen in 6 (35.3%) and 3 (20%) patients in LOLA and placebo groups respectively (p=0.667). Patients with HE grade II and above showed improvement in 34 (79.1%) and 25 (55.6%) cases in LOLA and placebo group respectively (p=0.019). Duration of hospitalisation was 93.6 ± 25.7 hours and 135.2 ± 103.5 hours in LOLA and placebo groups respectively (p=0.025). No side effects were observed in either group.

In cirrhotic patients with advanced hepatic encephalopathy treatment with LOLA was safe and associated with relatively rapid improvement and shorter hospital stay.4

1. Sharma BC et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013;108(9):1458-63.
2. Bai M et al. l-ornithine-l-aspartate for hepatic encephalopathy in patients with cirrhosis: a meta-analysis of randomized controlled trials. J Gastroenterol Hepatol. 2013;28(5):783-92.
3. Pérez Hernández JL et al. Critical analysis of studies evaluating the efficacy of infusion of L-ornithine L-aspartate in clinical hepatic encephalopathy in patients with liver failure. Ann Hepatol. 2011;10 Suppl 2:S66-9.
4. Abid S et al. Efficacy of L-ornithine-L-aspartate as an adjuvant therapy in cirrhotic patients with hepatic encephalopathy. J Coll Physicians Surg Pak. 2011;21(11):666-71.

Hepa-Merz® – Summary of prescribing information

Hepa-Merz® Granules. Composition: One sachet with 5 g of Granules contains: Active substance: 3 g L-ornithine- L-aspartate. Excipients: citric acid, aspartame (E951), povidone 25, fructose, flavorings, orange yellow S (E110). Note for diabetics: One sachet of Hepa-Merz® Granules contains 1.13 g of fructose (corresponds to approx. 0.11 BU). Therapeutic indications: Treatment of concomitant disease and sequelae due to impaired detoxification activity (e.g. in cirrhosis of the liver) with the symptoms of latent and manifest hepatic encephalopathy. Contraindications: Absolute: Hypersensitivity to L-ornithine-L-aspartate, orange yellow S or any of the other excipients. Severely impaired renal function (renal insufficiency). A serum creatinine value over 3 mg/100 ml can be used as a guideline value. Relative: Pregnancy and lactation: No clinical data are available relating to intake of Hepa-Merz® Granules in children and during pregnancy. No exhaustive animal studies have been performed for L-ornithine-L-aspartate, to investigate its toxicity in relation to reproduction. Administration of Hepa-Merz® Granules during pregnancy should therefore be avoided. If, however, treatment with Hepa-Merz® Granules is considered necessary, careful consideration should be given to the benefit versus risk ratio. It is not known whether L-ornithine-L-aspartate is excreted into the breast milk. Administration of Hepa-Merz® Granules should therefore be avoided during lactation. If, however, treatment with Hepa-Merz® Granules is considered necessary, careful consideration should be given to the benefit versus risk ratio. No data regarding fertility. Undesirable effects: Uncommon (³ 1/1,000 to < 1/100): Nausea, vomiting, stomach ache, flatulence, diarrhea. Very rare (< 1/10,000): Pain in the limbs. These undesirable effects are usually transient and do not require withdrawal of the medicine. Orange yellow S (E110) can trigger allergic reactions. Warnings: Hepa-Merz® Granules contain fructose. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Aspartame (E951): Contains a source of phenylalanine. May be harmful for people with phenylketonuria. Further precautions: As a result of the disease, the ability to drive and operate machinery may be impaired during treatment with L-ornithine-L-aspartate.

Hepa-Merz® Granules. Composition: One sachet with 5 g of Granules contains: Active substance: 3 g L-ornithine- L-aspartate. Excipients: citric acid, saccharin sodium, sodium cyclamate, povidone 25, fructose, flavorings, orange yellow S (E110). Note for diabetics: One sachet of Hepa-Merz® Granules contains 1.13 g of fructose (corresponds to approx. 0.11 BU). Therapeutic indications: Treatment of concomitant disease and sequelae due to impaired detoxification activity (e.g. in cirrhosis of the liver) with the symptoms of latent and manifest hepatic encephalopathy. Contraindications: Absolute: Hypersensitivity to L-ornithine-L-aspartate, orange yellow S or any of the other excipients. Severely impaired renal function (renal insufficiency). A serum creatinine value over 3 mg/100 ml can be used as a guideline value. Relative: Pregnancy and lactation: No clinical data are available relating to intake of Hepa-Merz® Granules in children and during pregnancy. No exhaustive animal studies have been performed for L-ornithine-L-aspartate, to investigate its toxicity in relation to reproduction. Administration of Hepa-Merz® Granules during pregnancy should therefore be avoided. If, however, treatment with Hepa-Merz® Granules is considered necessary, careful consideration should be given to the benefit versus risk ratio. It is not known whether L-ornithine-L-aspartate is excreted into the breast milk. Administration of Hepa-Merz® Granules should therefore be avoided during lactation. If, however, treatment with Hepa-Merz® Granules is considered necessary, careful consideration should be given to the benefit versus risk ratio. No data regarding fertility. Undesirable effects: Uncommon (³ 1/1,000 to < 1/100): Nausea, vomiting, stomach ache, flatulence, diarrhea. Very rare (< 1/10,000): Pain in the limbs. These undesirable effects are usually transient and do not require withdrawal of the medicine. Orange yellow S (E110) can trigger allergic reactions. Warnings : Hepa-Merz® Granules contain fructose. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Further precautions: As a result of the disease, the ability to drive and operate machinery may be impaired during treatment with L-ornithine-L-aspartate.

Hepa-Merz® Infusion concentrate. Composition: One ampoule of 10 ml contains: Active substance: 5 g L-ornithine-L-aspartate. Excipients: Water for injections. Therapeutic indications: Latent and manifest hepatic encephalopathy. Contraindications: Absolute: Hypersensitivity to L-ornithine-L-aspartate. Severe renal impairment (renal failure). A serum creatinine level in excess of 3 mg/100 ml can be taken as a guide. Relative: Pregnancy and lactation: There are no clinical data available on the use of Hepa-Merz® Infusion concentrate in children and during pregnancy. L-ornithine L-aspartate has been investigated for reproduction toxicity only to a limited extent in experimental animal studies. The administration of Hepa-Merz® Infusion concentrate in pregnancy should therefore be avoided. If treatment with Hepa-Merz® is nevertheless thought to be necessary, the benefits and risks should be carefully assessed. It is not known whether L-ornithine-L-aspartate passes into breast milk. Administration of Hepa-Merz® should therefore be avoided during lactation. If treatment with Hepa-Merz® is nevertheless thought to be necessary, the benefits and risks should be carefully assessed. No data regarding fertility. Undesirable effects: Uncommon (³ 1/1,000 to < 1/100): Nausea. Rare (³ 1/10,000 to < 1/1,000): vomiting. Frequency not known (frequency cannot be estimated from the available data): hypersensitivity, anaphylactic reaction. Generally however, the gastrointestinal symptoms are transient, and do not necessitate discontinuation of treatment. They disappear on reduction of the dose or the infusion rate. Further precautions: Hepa-Merz concentrate for solution for infusion can be mixed with the usual infusion solutions. So far, no peculiarities have been observed with regard to miscibility. However, the ampoules should be admixed to the infusion solution only immediately before application. At high doses of Hepa-Merz® Infusion concentrate, serum and urine urea levels should be monitored. If liver function is substantially impaired, the infusion rate must be adjusted to the individual patient in order to prevent nausea and vomiting. Depending on the underlying disease, the ability to drive and operate machines may also be impaired on treatment with L-ornithine L-aspartate. Hepa-Merz® Infusion concentrate must not be injected into an artery. Status: January 2016. Merz Pharmaceuticals GmbH, 60048 Frankfurt.