• Composition
• Dosage and Administration
• Method of use and preparation
• Clinical Studies
• Pharmacology

Composition

• Q. Does this product have calories?

  A.

  As one sachet of this product contains 4 g of branched-chain amino acids, it contains 16 kcal/sachet.

  [Supplementary information]
  The amount of energy generated by metabolizing 1 g of amino acids is 4 kcal.

  Prepared in November 2020

Dosage and Administration

• Q. [1] What is the ground for the daily dosage of 12 g?
  [2] It is specified that this product should be administered at 3 sachets/day without description of dose adjustment as required. Is the product effective when administered at 2 sachets/day?

  A.

  [1] The dose–response study performed during the development stage showed that, among the dosages of 6, 12, and 18 g of BCAA/day, 12 g/day was associated with the highest efficacy and safety.
  [2] Considering that the incidence of adverse drug reactions tended to increase with the increased dosage, it is appropriate to administer this product at 3 sachets/day, and it is not specified that the dosage should be adjusted as required.
  

  Therefore, no sufficient effect is likely to occur when administered at 2 sachets/day.
  *Note: The dosage of 18 g/day is above the approved dose.

  [Supplementary information]
  In the dose–response study, this product was administered in the 4 dosage groups, including 0 (placebo), 6, 12, and 18 g*/day, for 12 weeks to evaluate albumin level, performance status (PS), and subjective and objective symptoms. The results showed a dose response in increased albumin level: albumin level was significantly more increased in the 12 or 18 g* group than the placebo group. The 12 and 18 g* groups also showed a higher overall improvement rate based on multiple endpoints than the other groups. The incidence rate of adverse drug reactions was higher in the 18 g* group than in the 12 g group. Blood ammonia concentration increased and BUN increased possibly because of the excessive intake of amino acids were reported in the 18 g group. A significantly larger number of subjects in the 18 g*/day group evaluated this product as difficult to take than the other groups^1,2).
  Based on the abovementioned results and in view of the ease of taking this product for patients, it was considered appropriate to set the dosage at 12 g.
  *Note: The dosage of 18 g/day is above the approved dose.

  [Supplementary information]
  Considering the changes in the serum albumin level and Fisher's ratio over time, overall improvement as judged by the primary physician, adverse reactions, and ease of taking the product, the optimal dosage of Livact^® Granules was set at 12 g of branched-chain amino acids per day²⁾.

  [References/materials]

  1) Yasutoshi Muto, et al.: JJPEN. Vol. 14: No. 3,360-393, 1992
  2) Interview Form of Livact^® Granules
  Reference: Livact Granules

  Prepared in November 2020

Method of use and preparation

• Q. Is there any method to make it easier to take this product?

  A.

  This product may be taken using the following methods: moistening the oral cavity before taking this product; dividing the large amount of granules into two or three, wrap each portion with an oblate membrane, and take each, while avoiding spreading the product in the oral cavity; and taking this product using an oral jelly.
  This product tastes like amino acids (tastes slightly bitter) when it remains in the mouth and the coating comes off.

  Prepared in November 2020

• Q. Is it acceptable to open and repackage this product?

  A.

  Opening and repackaging this product is not recommended.
  The stability study at 25°C and 75%RH showed mild agglutination due to moisture absorption on Day 2. Although the content of each component met the specification up to Week 4, the product may be contaminated with bacteria or solidified owing to agglutination

  [Supplementary information]
  (2) Physical properties of the drug product¹⁾
  1) Livact Granules
  Hygroscopicity: When this product was stored at 25°C and 75%RH with the package opened for 24 hours, moisture in the product was slightly increased (by 0.3%–0.4%) without change in appearance. When it was stored under the same conditions for 48 hours, moisture was increased by 0.4%–0.8% with slight agglutination.

  [References/materials]

  1) Interview Form of Livact^® Granules
  Reference: Livact Granules

  Prepared in November 2020

• Q. Is it acceptable to crush this product before use?

  A.

  We do not recommend crushing this product before use in view of the proper use of the product because it is not included in the approved administration method and was not examined for pharmacokinetics, safety, and efficacy.
  In addition, crushing this product may cause a severe bitterness characteristic of branched amino acids, making it difficult to take¹⁾.

  [Supplementary information]
  As BCAA has characteristics including strong bitterness, high water repellency, low solubility, and different crystal habits, it was necessary to pretreat it for formulation. Livact^® Granules contain sucrose as a flavoring substance and undercoat BCAA to prevent the Maillard reaction between BCAA and sucrose. The first improvement for Livact Granules was to replace sucrose with saccharin sodium to avoid browning and improve flavor.
  Therefore, crushing this product may cause a bitterness characteristic of BCAA.

  [Supplementary information]
  1. Physicochemical properties of each component (Table III-1) ¹⁾

  Table III-1. Appearance/description, Solubility, and pH of Solution of Each Component
  

  Component	Appearance/description, solubility	pH of solution
  L-isoleucine	Occurs as white crystals or crystalline powder, is odorless or has a faint characteristic odor, and has a slightly bitter taste. Freely soluble in formic acid, sparingly soluble in water, and practically insoluble in ethanol (95). It dissolves in dilute hydrochloric acid.	5.5 - 6.5 (1.0→100)
  L-leucine	Occurs as white crystals or crystalline powder, is odorless or has a faint characteristic odor, and has a slightly bitter taste. Freely soluble in formic acid, sparingly soluble in water, and practically insoluble in ethanol (95). It dissolves in dilute hydrochloric acid.	5.5 - 6.5 (1.0→100)
  L-Valine	Occurs as white crystals or crystalline powder, is odorless or has a faint, characteristic odor, and has a slightly sweet taste, followed by a bitter taste. Freely soluble in formic acid, soluble in water, and practically insoluble in ethanol (95). It dissolves in dilute hydrochloric acid.	5.5 - 6.5 (0.5→20)

  1) Interview Form of Livact^® Granules
  Reference: Livact Granules

  Prepared in November 2020

• Q. How should this product and Hepan ED® (elemental diet for hepatic failure) be used differently?

  A.

  Usually, Livact is indicated for patients with sufficient daily food intake, while Hepan ED is indicated for those with insufficient daily food intake. However, it is recommended to use them appropriately, considering patient physical condition and diet if it is necessary to limit calories owing to the complication of diabetes mellitus, if it is necessary to perform fluid intake restriction, or if patients have encephalopathy. As these products are indicated for different stages of hepatic cirrhosis, check their indications before use to select the product suitable for patient disease condition.

  [Supplementary information]

  [1] Livact^® Granules [INDICATIONS] ¹⁾
  Improvement of hypoalbuminaemia in patients with decompensated cirrhosis who have hypoalbuminaemia despite adequate dietary intake
  [2] Hepan ED_® [Indications] ²⁾ Improvement of nutrition condition in patients with chronic hepatic failure associated with hepatic encephalopathy

  [References/materials]

  1) Package Insert of Livact^® Granules
  2) Package insert of Hepan ED_®
  Reference material: Livact Granules/Hepan ED

  Prepared in November 2020

Clinical Studies

• Q. What is the maximum allowable dosage of this product?

  A.

  The dose–response study reported cases who received 18 g*/day. However, BUN and blood ammonia concentration increased probably resulting from the excessive dosage were observed at 18 g*.
  As amino acid imbalance by high amino acid load may worsen the nutrition condition, general precautions for excessive dosage are specified in the Precautions section.
  *Note: The dosage of 18 g/day is above the approved dose.

  [Supplementary information]
  In the dose–response study, this product was administered in the 4 dosage groups, including 0 (placebo), 6, 12, and 18 g*/day, for 12 weeks to evaluate albumin level, performance status (PS), and subjective and objective symptoms. The results showed a dose response in increased albumin level: albumin level was significantly more increased in the 12 or 18 g* group than the placebo group. The 12 and 18 g* groups also showed a higher overall improvement rate based on multiple endpoints than the other groups. The incidence rate of adverse drug reactions was higher in the 18 g* group than in the 12 g group. Blood ammonia concentration increased and BUN increased possibly because of the excessive intake of amino acids were reported in the 18 g group. A significantly larger number of subjects in the 18 g*/day group evaluated this product as difficult to take than the other groups^1,2).
  Based on the abovementioned results and in view of the ease of taking this product for patients, it was considered appropriate to set the dosage at 12 g.
  *Note: The dosage of 18 g/day is above the approved dose.

  [References/materials]

  1) Yasutoshi Muto et al.: JJPEN.Vol.14:No.3,360-393,1992
  2) Interview Form of Livact^® Granules
  Reference: Livact Granules

  Prepared in November 2020

Pharmacology

• Q. What is the mechanism of action of this product?

  A.

  This product is considered to exert its effect by correcting blood amino acid imbalance in patients with decompensated cirrhosis to induce albumin synthesis.

  [Supplementary information]
  A pharmacological effect of leucine to promote albumin synthesis through mTOR in rats has been reported²⁾.
  *mTOR, mammalian target of rapamycin

  [References/materials]

  1) Interview Form of Livact^® Granules
  2) Ijichi C, et al. BBRC,303, 59-64,2003
  Reference: Livact Granules

  Prepared in November 2020

• Q. What is the reason if albumin level does not increase after the administration of this product?

  A.

  This product is considered to exert its effect by correcting blood amino acid imbalance in patients with decompensated cirrhosis to induce albumin synthesis.

  It is known that albumin is reduced by 0.15 g/dL per year in patients with hepatic cirrhosis without aggressive treatment. (Graph) ¹⁾
  This indicates that drugs for hepatic cirrhosis are considered effective as long as they prevent the reduction in albumin level even if they do not increase it.
  The failure of this product to increase the albumin level is explained by the following reasons:

  1. BCAA is used as an energy source
     Reportedly, BCAA is quite easily used as an energy source in patients with hepatic cirrhosis.
  2. Albumin synthesis, degradation, and turnover are improved.
     It is assumed that the albumin degradation rate is reduced and half-life prolonged compensatorily by homeostasis, resulting in the use of old albumin as long as possible in patients with hepatic cirrhosis as compared to healthy individuals because such patients have impaired liver albumin synthesis. The treatment with a BCAA preparation may improve turnover to nearly a normal level and replace old albumin with fresh albumin³⁾.
     That is, this product may improve the quality of albumin without increasing the albumin level, which is clinically significant for patients.
  3. Albumin synthesis capacity is markedly decreased.
     This product is unlikely to provide a sufficient effect to improve hypoalbuminaemia in patients with markedly reduced hepatic protein synthesis capacity. The analysis results of the clinical study show that other therapies (e.g., the treatment with an albumin preparation) should be preferred in patients with a pretreatment serum albumin of not more than 2.6 g/dL because this product is likely to take a long time before providing only a limited effect to improve hypoalbuminaemia.
     In addition, there is a case where a patient without increased serum albumin after 2 months of treatment with this product experienced increased serum albumin by continued treatment²⁾.
     
     

  [Supplementary information]
  <Precautions for Indications> ⁴⁾ 2. This product should not be administered in the following patients because it is unlikely to exert its effect owing to severely advanced hepatic cirrhosis.

  1. Patients with coma grade ≥ 3 of hepatic encephalopathy
  2. Patients with total bilirubin of 3 mg/dL or higher
  3. Patients with markedly reduced hepatic protein synthesis ability

  [References/materials]

  1. Nobuo Yamada et al.: Kitasato Medical,1 6 : 268- 277,1986
  2. Masahiko Kato: LIVERSIDE Press, 3(5): 1-2,1998
  3. Masahiko Kato et al.: Kanzo,3 2(7): 692-699,1991
  4. Package Insert of Livact^® Granules

  Reference: Livact Granules

  Prepared in November 2020