*Approved: June 2018

Rx Prescription drug

- Branched-Chain Amino Acid Preparation -LIVACT® Granules< L-Isoleucine, L-Leucine and L-Valine Granules JP (Japanese Pharmacopoeia) >DESCRIPTIONPRECAUTIONS
Read carefully the instructions before use. For further information please
consult your doctor.
This drug is used upon doctor’s prescription only.

1. Composition
Each packet (4.15 g) of LIVACT® Granules contains the following ingredients.

1. Use in the Elderly
L-Isoleucine
L-Leucine
L-Valine

952 mg1,904 mg
1,144 mg

Excipients: Povidone, partially hydrolyzed polyvinyl alcohol, tartaric acid,saccharin sodium hydrate and perfume agents as additives.

LIVACT® Granules should be administered to elderly patients with caution
since such patients often have decreased physiological functions, and metabolic
disorders such as blood ammonia elevation can be more sensitive to develop
during LIVACT® Granules therapy.
2. Use during Pregnancy, Delivery, or Lactation

2. Product description
LIVACT® Granules is white coated granules having a slightly fragrant odor.
INDICATIONSLIVACT® Granules is indicated for improvement of hypoalbuminemia in patientswith decompensated hepatic cirrhosis with an albumin level of 3.5 g/dL or lessdespite adequate dietary intake.

The safety of LIVACT® Granules in pregnant women and nursing mothers has notbeen established. Therefore, the product should not be used in pregnant women,women suspected of being pregnant, and nursing mothers unless the expected
beneﬁts outweigh the potential risks.
3. Pediatric Use
The safety of LIVACT® Granules in children has not been established. (no clinicalexperience)<Precautions>
1. LIVACT ® Granules is indicated for use in patients presenting withhypoalbuminemia despite adequate dietary intake or in whom total dietarycalories 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 or less with current or a history of ascites/oedema or hepatic
encephalopathy. A dietetic instruction should be provided to the patient in caseof dietary deﬁciency despite the patient being amply capable of food ingestionin 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.
This product should not be administered to the following patients with markedly
advanced hepatic cirrhosis since such patients may not respond to LIVACT®
Granules:(1) Patients with stage III or more in the severity of coma due to hepaticencephalopathy(2) Patients with a total bilirubin level of 3 mg/dL or more
(3) Patients with a markedly depressed hepatic function for protein synthesis
DOSAGE AND ADMINISTRATIONThe usual adult dose for oral use is one packet three times a day after meals or asprescribed by physician.
<Precautions>
1. LIVACT® Granules consists of branched-chain amino acids alone and does notcontain all amino acid required for protein synthesis. Therefore, the patient
taking LIVACT® Granules must ingest the amount of protein (amino acids) andcalories required (daily protein intake, 40 g or more; and daily calorie intake,1000 kcal or more) in the diet according to the patient’s condition. If the patientis on restricted protein intake, in particular, caution must be exercised in thatthe patient may not respond LIVACT® Granules therapy and, moreover, longterm use of this product may lead to aggravation of nutriture unless the minimum
protein and calorie requirements are secured.
2. If abnormal BUN or blood ammonia is noted following administration of
LIVACT® Granules, caution must be taken because it may be attributable tooverdose. Caution should also be observed regarding long-term overdosage since
it may give rise to aggravation of nutriture.
3. If no improvement in hypoalbuminemia is attained in 2 months or longer
with the use of LIVACT® Granules, appropriate measures should be taken suchas replacement with other therapy.
CONTRAINDICATIONS (LIVACT ® Granules is contraindicated in thefollowing patients.)
Patients with congenital branched-chain amino acid metabolic abnormality[The use of LIVACT® Granules may be induced with convulsions or respiratory
disturbances in patients with maple syrup urine disease.]
Do not use for patient who is allergic to any ingredient of LIVACT® Granules.

INTERACTION WITH OTHER DRUGS AND OTHER FORMS OF
INTERACTIONSThere is no report to indicate the interaction with other drugs
EFFECTS ON ABILITY TO DRIVE AND OPERATE MACHINE
In case of LIVACT® Granules, no instance which ability to drive or operatemachinery might be affected, has been reported.
ADVERSE REACTIONS
Among 420 cases studied prior to the time of approval, 40 adverse reactions werereported in 27 cases (6.4%). The commonly reported adverse reactions by thetime of approval included abdominal distension (9 reactions, 2.1%), diarrhea (5reactions, 1.2%) and constipation (4 reactions, 1.0%).(At the approval)
267 adverse reactions were reported in 178 cases (6.2%) of 2,877 cases surveyed
in the postmarketing surveillance. The commonly reported adverse reactions
included hyperammonemia (23 reactions, 0.8%), queasy (15 reactions, 0.5%),
diarrhea (14 reactions, 0.5%), increased BUN (14 reactions, 0.5%) and abdominal
pain (12 reactions, 0.4%).(Data from the result of re-examination)
63 adverse reactions were reported in 41 cases (12.3%) of 334 cases inpostmarketing clinical studies (including long-term studies). The commonly
reported adverse reactions included abdominal distension (13 reactions, 3.9%),
constipation (9 reactions, 2.7%), diarrhea (5 reactions, 1.5%), itching (4 reactions,1.2%), queasy (3 reactions, 0.9%) and vomiting (3 reactions, 0.9%).(Data fromthe result of re-examination)
0.1 to 5%<0.1%

Incidence
unknown

GastrointestinalNote 1) Abdominal distension,
Thirst,queasy, diarrhea,
eructation
constipation, abdominal
discomfort, abdominal
pain, vomiting, anorexia,
heartburn, etc.
Increased BUN, increased
RenalNote 1)
serum creatinine, etc.
Increased blood ammonia,
MetabolismNote 1)
etc.
Hepatic
Increased serum AST (GOT),
increased serum ALT (GPT),
increased total bilirubin, etc.
Skin

Rash, itching, etc.

OthersMalaise, oedema (facial,lower extremities, etc.)

Redness,
hot ﬂushes

Note 1): If any of these reactions are noted, the dose of LIVACT® Granules should
be reduced or the treatment should be interrupted.
Inform your doctor of undesirable effects occurred during the use of drug.The pharmacokinetic parameters of LIVACT® Granules
ingredients Cmax (μg/mL) AUC(μg･hr/mL) Tmax(hr)t1/2(hr)
L-isoleucine 30.982±5.872
43.126±9.884 0.677±0.178 0.787±0.305
L-leucine
58.531±10.587 103.088±19.671 0.688±0.175 1.428±0.243
L-valine
46.796±8.332 92.495±19.948 0.724±0.173 1.823±0.492
1) Distribution: Amino acids administrated orally are promptly distributed andused via the same pathway as internal amino acids.
2) Absorption: When LIVACT® Granules are administrated orally, each aminoacid is absorbed via its transporter in small intestine.
3) Metabolism: Each amino acid is pooled and can be used as substrates forsynthesis of protein and bioactive substances. On the other hand, deaminatedamino acids enter TCA cycle, gluconeogenesis or biosynthesis of fatty acids asenergy substrate. Nitrogen in amino acids decomposes into urea in urea cycle.
4) Excretion: The carbon skeleton in each amino acid could be decomposed
into CO2 and H2O. CO2 could be excreted into expiration. Nitrogen could beexcreted into urine as urea or ammonia.
CLINICAL STUDIES
1. A six-month open clinical trial performed in hypoalbuminemic patients withdecompensated hepatic cirrhosis revealed resolution of hypoalbuminemia
as indicated by increased serum albumin levels; improvement in nutritionalparameters such as serum total protein, transferrin and body weight; andimprovement 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® Granules, determined based on overall assessment of data regarding
subjective symptom, objective symptom, nutriture, psychoneurologicalsymptoms, 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® Granules therapy.
2. A 12-week double-blind placebo-controlled clinical study was conducted in
hypoalbuminemic patients with decompensated hepatic cirrhosis. Treatment withLIVACT® Granules increased the serum albumin level, the primary endpoint,
by 0.2 g/dL on average, and 31.5% of patients treated (17/54) 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 andobjective symptoms, nutriture, psychoneurological symptoms, and quality oflife, was 45.8% (38/83 patients) for the LIVACT® Granules -treated group and17.3% (14/81 patients) for the placebo group. The usefulness rate, determinedbased on evaluation of safety in addition to the above variables, was 49.4% (42/85patients) for the LIVACT® Granules -treated group and 18.1% (15/83 patients)
for the placebo group.
3. An open-label follow-up clinical trial was performed for 2 years to investigate
the relationship between serum albumin levels and clinical manifestations andprognosis for survival. The results revealed that changes in serum albumin
levels over time were signiﬁcantly correlated with status of ascites, oedema andperformance status. As for the relationship to prognosis for survival, the risk ofmortality (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.
4. To evaluate the effect of LIVACT® Granules 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 todiscontinuation or dropout using signiﬁcant events related to the prognosis forsurvival such as exacerbation of hepatic insufficiency in patients with livercirrhosis, as indicated by occurrence of ascites, oedema, hepatic encephalopathy,
and jaundice; rupture of oesophageal varices (rupture of the 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® Granules signiﬁcantly inhibited the developmentof the above serious complications of hepatic cirrhosis among the 622 patients
included in the analyses (308 and 314 patients in dietary-treated patientsand LIVACT® Granules -treated patients, respectively). The hazard ratio for
LIVACT® Granules -treated patients against dietary-treated patients was 0.67
with 95% conﬁdence interval ranging from 0.49-0.93.

Cumulative percentages of patients without events

PHARMACOKINETICS
Plasma concentrations of branched-chain amino acids were measured in healthy
adult male volunteers (n = 48) taken with single oral LIVACT® Granules (1packet; containing L-isoleucine 952 mg, L-leucine 1904 mg, and L-valine 1144mg) on an empty stomach. The pharmacokinetic parameters (AUC, Cmax, etc.)
calculated from the change in concentration from the baseline are presented
below.

(%)
100

Log-rank test p=0.015
Hazard ratio 0.67

8060
40314 LIVACT Granules -treated patients
308 dietary-treated patients

2000200

400
600
Days of treatment

800

1000

PHARMACODYNAMICS
1. Effect and action
The dose responsiveness trial was conducted on liver cirrhosis patients withhypoalbuminemia to confirm the priority of the clinical dose. In the trial, 6g,12g, 18g of LIVACT ® Granules were administrated per day and comparedwith placebo administration in a non-blind trial. A signiﬁcant increase in serum
albumin level was seen in 12g group and 18g group compared to placebogroup. Also, the significant increase of Fischer’s ratio in blood between preadministration data and data collected in the 12th week after administration wasobserved. The improvement of general symptoms was shown in 12g group and18g group compared to other two groups.
2. Mechanism of action
Administration of LIVACT® Granules in patients with decompensated hepatic
cirrhosis will promote albumin synthesis in liver through the improvement of theimbalance of amino acids in blood.
OVERDOSES AND TREATMENT
Well-controlled clinical study for overdoses of LIVACT® Granules has not been
conducted.
PACKING SIZEBox of 84 sachets x 4.15 g
STORAGEStore at temperature below 30°C .
Keep out of reach of children.
Do not use the medicine after the expiry date stated on the package.
Product licence holder:
EA Pharma Co., Ltd.
1-1, Irifune 2-chome, Chuo-ku, Tokyo, Japan
Manufactured by:
AJINOMOTO CO., INC. TOKAI PLANT
1730, Hinaga, Yokkaichi-shi, Mie, Japan