Livact

L-isoleucine, L-leucine, L-valine.

Each packet (4.15 g) contains the following ingredients: L-isoleucine 952 mg, L-leucine 1904 mg and L-valine 1144 mg.
It also contains povidone, partially hydrolyzed polyvinyl alcohol, tartaric acid, saccharin sodium hydrate and flavoring agents as additives.

Pharmacology: The effects of Livact were investigated in rats with carbon tetrachloride-induced chronic liver damage as a rat model of hepatic cirrhosis with malnutrition (hypoalbuminemia).
Rats were fed diets containing the same composition of branched-chain amino acids as Livact at concentrations of 0, 2.5, 5.0 and 10.0% ad libitum. The results showed that 2.5% branched-chain amino acid supplementation group was most superior among other supplementation groups in respect of nutritional parameters eg, nitrogen balance, nitrogen balance efficiency, plasma total protein levels and plasma albumin levels, and exhibited an adequate correction of plasma Fischer ratio.
Rats were fed free access to diets supplemented with different branched-chain amino acids composition ratios as follows: L-isoleucine:L-leucine:L-valine composition ratio, I (2:1:1), II (1:2:1.2), and III (1:1:2). The results revealed that rats receiving the diet containing the same branched-chain amino acids composition (II) as Livact displayed better about nitrogen balance, plasma total protein levels and plasma albumin levels than the other composition ratio groups, and exhibited an adequate correction of plasma Fischer ratio.
Rats were fed ad libitum on diets supplemented with the same branched-chain amino acid composition as Livact or with a combination of essential amino acids comparable to Livact in terms of nitrogen and energy quantities. Greater nutritional effects were observed in the branched-chain amino acid diet group, compared with the essential amino acid diet group. In addition, suppression of thrombocytopenia and of decrease in liver weight was evident in the branched-chain amino acid diet group.
The effect of Livact was examined in rats with portocaval shunt as an animal model of hepatic encephalopathy. Plasma and brain amino acid concentrations and the brain monoamine level normalized in rats receiving the branched-chain amino acids as Livact, whereas a trend of aggravation rather than improvement was observed in rats administered a combination of essential amino acids equivalent in nitrogen quantity and amount of energy to Livact.
Clinical Studies: A 6-month open clinical trial performed in hypoalbuminemic patients with decompensated hepatic cirrhosis revealed resolution of hypoalbuminemia as indicated by increased serum albumin levels, improvement in nutritional parameters eg, serum total protein, transferrin and body weight, and improvement of malaise and fatigability during 2-weeks to 2-month period of the study treatment. Subsidence in ascites was noted at the fifth month. These improvements kept until the completion of the study. The usefulness rate of Livact, determined based on overall assessment of data regarding subjective symptom, objective symptom, nutriture, psychoneurological symptoms, quality of life, and safety, was 51.2% (104/203 patients). A subsequent survey on prognosis of these patients revealed a more favorable life prognosis in those showing improvement in nutriture after the study and in patients receiving long-term Livact therapy.
A 12-week double-blind placebo-controlled clinical study was conducted in hypoalbuminemic patients with decompensated hepatic cirrhosis. Treatment with Livact increased the serum albumin level, the primary endpoint, by 0.2 g/dL on average, and 31.5% of patients treated (17/54 patients) showed serum albumin levels increased by 0.4 g/dL or more, indicating a significantly greater improvement as compared with the placebo treatment. The total improvement rate, determined based on overall assessment of data regarding subjective and objective symptoms, nutriture, psychoneurological symptoms and quality of life, was 45.8% (38/83 patients) for the Livact-treated group and 17.3% (14/81 patients) for the placebo group. The usefulness rate, determined based on evaluation of safety in addition to the above variables, was 49.4% (42/85 patients) for the Livact-treated group and 18.1% (15/83 patients) for the placebo group.
An open-label follow-up clinical trial was performed for 2 years to investigate the relationship between serum albumin levels and clinical manifestations and prognosis for survival. The results revealed that changes in serum albumin levels over time were significantly correlated with status of ascites, oedema and performance status. As for the relationship to prognosis for survival, the risk of mortality (hazard ratio) per unit time based on no change group in serum albumin levels invariance was estimated to be 0.77 for subjects showing a serum albumin level increased by 0.2 g/dL, and to be 0.59 for those showing a serum albumin level increased by 0.4 g/dL in a year.
To evaluate the effect of Livact on the prognosis for survival, randomized controlled clinical trials were conducted for at least 2 years by comparison with dietary treatment in terms of study treatment time to discontinuation or dropout using significant events related to the prognosis for survival eg, exacerbation of hepatic insufficiency in patients with liver cirrhosis, as indicated by occurrence of ascites, oedema, hepatic encephalopathy and jaundice; rupture of oesophageal varices (rupture of gastric varices); development of hepatic cancer; and death, which were determined as serious complications occurring in association with advancing hepatic cirrhosis. The results showed that Livact significantly inhibited the development of the above serious complications of hepatic cirrhosis among 622 patients included in the analyses (308 and 314 patients in dietary-treated patients and Livact-treated patients, respectively). The hazard ratio for Livact-treated patients against dietary-treated patients was 0.67 with 95% confidence interval ranging from 0.49-0.93.
Pharmacokinetics: Absorption, Distribution, Metabolism and Excretion in Rats: The branched-chain amino acids administered to rats were rapidly absorbed, reaching a peak concentration in plasma and whole blood 4 hrs after dosing, followed by a slow decline. The branched-chain amino acids in plasma were promptly utilized for protein synthesis. The branched-chain amino acids absorbed were distributed extensively to the whole body, conspicuously in those tissues actively involved in protein synthesis. During a 168-hr period after dosing, the branched-chain amino acids administered was excreted in urine and feces, and in expired breath, 4% and 41%, respectively. It indicated that the branched-chain amino acids administered were utilized in part as a source of energy. It was also demonstrated that their absorption, distribution and excretion were not significantly affected in repeat-dose studies.
In hepatically impaired rats, absorption of the branched-chain amino acids administered proceeded slower than in normal rats, but their transition to plasma protein, distribution in tissues and excretion in urine and feces were essentially comparable with those seen in normal rats. It was thus indicated that the branched-chain amino acids administered were effectively utilized as substrates for protein synthesis in hepatically impaired rats as well. Compared with normal rats, the excretion in expired breath was greater in the hepatically impaired rats, in which the branched-chain amino acids administered were thus more efficiently utilized as a source of energy.

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Improves hypoalbuminemia in patients with decompensated hepatic cirrhosis presenting with hypoalbuminemia despite adequate dietary intake.
Livact is indicated for use in patients presenting with hypoalbuminemia despite adequate dietary intake or in whom total dietary calories and protein (amino acids) intake is restricted due to complicated diabetes mellitus or hepatic encephalopathy, among patients with decompensated hepatic cirrhosis presenting with hypoalbuminemia as indicated by a serum albumin level of ≤3.5 g/dL with current or a history of ascites/edema or hepatic encephalopathy. A dietetic instruction should be provided to the patient in case of dietary deficiency despite the patient being amply capable of food ingestion in the absence of diabetes mellitus and hepatic encephalopathy. If the patient is deficient in dietary intake due to development of hepatic encephalopathy, a drug containing calories and protein (amino acids) should be administered.
Livact should not be administered to the following patients with markedly advanced hepatic cirrhosis since such patients may not respond to Livact therapy: Patients with stage III or more in the severity of coma due to hepatic encephalopathy.
Patients with a total bilirubin level of ≥3 mg/dL.
Patients with a markedly depressed hepatic function for protein synthesis.

Usual Dose: Adults: 1 packet (4.15 g) orally 3 times a day.

Patients with congenital branched-chain amino acid metabolic abnormalities. (Convulsions and respiratory disturbances may develop in patients with maple syrup urine disease.)

Livact, consisting only of branched-chain amino acid alone and does not contain all amino acid required for protein synthesis. Therefore, the patient taking Livact must ingest the amount of protein (amino acids) and calories required (daily protein intake, ≥40 g; and daily calorie intake, ≥1000 kCal) in the diet according to the patient's condition. If the patient is on restricted protein intake, in particular, caution must be exercised in that the patient may not respond with Livact therapy and, moreover, long-term use of Livact may lead to aggravation of nutriture unless the minimum protein and calorie requirements are secured.
If abnormal BUN or blood ammonia is noted following administration of Livact, caution must be taken because it may be attributable to overdose. Caution should also be observed regarding long-term overdosage since it may give rise to aggravation of nutriture.
If no improvement in hypoalbuminemia is attained within ≥2 months with the use of Livact, appropriate measures should be taken eg, replacement with another therapy.
Use in pregnancy & lactation: The safety of Livact in pregnant women and nursing mothers has not been established. Therefore, Livact should not be used in pregnant women, and women suspected of being pregnant, and nursing mothers unless the expected benefits outweigh any potential risk.
Use in the elderly: Livact should be administered to elderly patients with caution since such patients often have decreased physiological functions, and metabolic disorders eg, blood ammonia elevation can be more sensitive to develop during Livact therapy.
Use in children: The safety of Livact in children has not been established. (No clinical experience).

The safety of Livact in pregnant women and nursing mothers has not been established. Therefore, Livact should not be used in pregnant women, and women suspected of being pregnant, and nursing mothers unless the expected benefits outweigh any potential risk.

Among 2898 patients studied in clinical trials conducted prior to application for approval and in post-marketing drug use investigations, 249 adverse reactions were reported in 169 cases (5.8%). Major adverse reactions included sensation of abdominal bloating (18 cases, 0.6%), retching/nausea (17 cases, 0.6%), diarrhea (16 cases, 0.6%), elevation in blood urea nitrogen (15 cases, 0.5%), and increased blood ammonia (15 cases, 0.5%). (At the 4th Periodic Safety Update Reporting.)
Gastrointestinal¹: 0.1 to <5%: Abdominal distension, queasy , diarrhoea, constipation, abdominal discomfort, abdominal pain, vomiting, anorexia, heartburn, etc. <0.1%: Thirst, eructation.
Renal¹: 0.1 to <5%: Increased BUN and serum creatinine, etc.
Metabolism¹: 0.1 to <5%: Increased blood ammonia, etc.
Hepatic: 0.1 to <5%: Increased serum AST (GOT), serum ALT (GPT), total bilirubin, etc.
Skin: 0.1 to <5%: Rash, itching, etc.
Others: 0.1 to <5%: Malaise, oedema (facial, lower leg, etc.). Frequency Unknown: Redness, hot flush.
¹The dose should be reduced or administration temporarily discontinued in the event that any abnormality is observed.

Store at room temperature in light-resistant, airtight containers.

Cholagogues, Cholelitholytics & Hepatic Protectors

A16AA - Amino acids and derivatives ; Used in treatment of alimentary tract and metabolism problems.

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