EA Pharma Co., Ltd.

*Revised: August 2017

- Amino Acids Infusion for Hepatic Failure -Standard Commodity Classification No. of Japan
873253

MORIHEPAMIN
Prescription drug** Caution: Use only as directed by a physician, etc.
Read package insert carefully before use. If you need further information, please contact your doctor.
Inform your doctor any side effects occur when using drug.
Approval No.
22000AMX00198
Date of listing in the NHI reimbursement price
June 2008
Date of initial marketing in Japan
January 1993
Date of latest re-evaluation
March 1998
COMPOSITION - DESCRIPTION
1. Composition
MORIHEPAMIN contains the following ingredients:
Active ingredientsContent perContent per
200mL bag
500mL bag
L-Isoleucine
1.840 g4.600 gL-Leucine
1.890 g4.725 g
L-Lysine Acetate
0.790 g1.975 g
L-Methionine
0.088 g0.220 g
L-Phenylalanine
0.060 g0.150 g
L-Threonine
0.428 g1.070 g
L-Tryptophan
0.140 g0.350 g
L-Valine
1.780 g4.450 g
L-Alanine
1.680 g4.200 g
L-Arginine
3.074 g7.685 g
L-Aspartic acid
0.040 g0.100 g
L-Histidine
0.620 g1.550 gL-Proline
1.060 g2.650 g
L-Serine
0.520 g1.300 g
L-Tyrosine
0.080 g0.200 gGlycine1.080 g2.700 gTotal amino acids
15.170 g
37.925 g
Total concentration of amino acids
7.585 w/v%
Inactive ingredients
L-Cysteine
Sodium Bisulfite
Glacial Acetic Acid (pH regulator)

Content per
200mL bag
0.050 g0.050 gq.s.

Content per
500mL bag
0.125 g0.125 gq.s.

Concentration of total nitrogen: 13.18 mg/mL
Concentration of free amino acids: 7.470 w/v%
Concentration of branched-chain amino acids: 2.755 w/v%
Fischer’s ratio : 54.13
Branched-chain amino acids / (phenylalanine + tyrosine) [molar ratio]
Concentration of electrolytes
Na+: Approx. 3 mEq/L
CH3COO−: Approx. 100 mEq/L
2. Product description
MORIHEPAMIN is a clear and colorless aqueous solution for injection. The pH
and the osmotic pressure ratio are as follows:
pHOsmotic pressure ratio
6.6 - 7.6
Approx. 3
3. Description of Containers (plastic bag)
The specification of the plastic bag used for this product is as follows:
Reserve capacity of the plastic bag
200mL plastic bag
Approx. 250 mL
500mL plastic bag
Approx. 220 mL(When the solution is poured from a height of 45 cm)
DOSAGE FORM
I.V. Infusion
PACKAGING
Bag of 200 mL
Bag of 500 mL
INDICATIONSMORIHEPAMIN is indicated for supportive treatment for hepatic encephalopathy
syndrome in patients with chronic liver disorder.
DOSAGE AND ADMINISTRATIONMORIHEPAMIN is usually intravenously drip-infused at a single dose of 500 mL
in adult patients. The standard infusion rate in adults is 180 minutes or longer per
500 mL.
If MORIHEPAMIN is administrated via a central venous line, a 500 mL ofMORIHEPAMIN should be mixed with a carbohydrate-containing solution
and be infused continuously via a central vein for 24 hours. The dosage may beadjusted according to the patient’s age, symptoms and body weight.
CONTRAINDICATIONS (MORIHEPAMIN is contraindicated in thefollowing patients.)
1. Patients with serious renal disorder [The symptoms may be aggravated due tooverload of nitrogen compounds.]
2. Patients with amino acid metabolism abnormality other than liver disorder[Imbalance of amino acids may be aggravated.]

PRECAUTIONS
1. Careful Administration (MORIHEPAMIN should be administered with carein the following patients)(1) Patients with severe acidosis [The high doses of the product may aggravateacidosis.](2) Patients with congestive cardiac failure [An increase in the circulating blood
volume may worsen cardiac stress in such patients.]
2. Important Precautions
If blood ammonia level increases and psychoneurotic symptoms aggravatefollowing administration of MORIHEPAMIN, MORIHEPAMIN should beinterrupted or changed to another therapy.
3. Use in the Elderly
In general, since physiological function is decreased in the elderly,MORIHEPAMIN should be carefully administered and taking measures such as
dose reduction.
4. Pediatric Use
The safety of MORIHEPAMIN in children has not been established. (No clinicalexperience)
5. Use in pregnancy and lactation
The safety of MORIHEPAMIN in pregnant woman and nursing mothers has notbeen established. Therefore, the product should not be used in pregnant woman,woman suspected of being pregnant, and nursing mothers unless the expected
benefit outweigh the potential risks.
6. Precautions for Use(1) Before administration
1) If crystal formation appears in the solution, it should be heated at atemperature of 50 to 60°C and dissolved, followed by being cooled down
to around body temperature before use.
2) Do not use the solution if it is absolutely not clear.
3) The solution should be immediately used after opening the package, andall residual solution must be discarded.
(2) During administration
MORIHEPAMIN contains approximately 100 mEq/L of acetate ions. Ifa large dose or a concomitant electrolyte solution is used, the patient’selectrolyte balance should be monitored carefully.
(3) Dosing rate
MORIHEPAMIN should be injected slowly into a vein.
7. Precautions for Handling
1. MORIHEPAMIN can be injected without using an air vent needle.
2. Do not open the outer wrap until use to prevent discoloration of the solution(a deoxidizer is included inside the outer wrap to maintain stability of theproduct).
3. Do not use the product if any discoloration or leakage of the solution is noted,
or droplets are present inside the outer wrap.
4. Do not use the product if the seal covering the rubber plug of a plastic bag ispeeled off.
5. A needle should be vertically inserted at the needle insertion (concave) portionof the rubber plug. If the needle is obliquely inserted, the drug solution may
be contaminated with a broken piece of rubber plug or outlet inner wall, or
the needle may penetrate through the plastic bag, resulting in leakage of thesolution. In addition, a needle should not be inserted repeatedly at the samesite.
6. Caution should be exercised not to damage the outer wrap. If the outer wrap
was damaged, the solution may be discolored.
7. The scale printed on a plastic bag should be used only as a guide.
8. MORIHEPAMIN can not be infused by the tandem system using a connecting
tube (U-shaped tube). If two plastic bags are infused at the same time orsequentially, a Y-shaped infusion set must be used.
8. Effects on ability to drive and use machine
Need to use with precaution because this drug can cause tremor, hypoglycaemia,
fever, headache, chest discomfort, palpitations.
INTERACTION
There is no report to indicate the interaction with other drug.
ADVERSE REACTIONS
Among 243 cases studied prior to the time of approval, 9 adverse reactions (3.7%)
were reported in 9 cases (3.7%). The commonly reported adverse reactions by thetime of approval included nausea/queasy (0.8% each), sweaty, transient increased
blood ammonia level, vascular pain, urticaria, tremor limb by hypoglycaemia(0.4% each).

Incidence unknown
Hypersensitivity
Gastrointestinal
Cadiovascular
Glucosemetabolism
Large dose or
Acidosisbolus infusion
Others0.1 to <5%Rash, etc.
Nausea/queasy, etc.
Chest discomfort, Palpitations, etc.
Hypoglycaemia
Transient increased blood ammonia
levelChills, Fever, Headache, Vascularpain, Sweaty

OVERDOSE
Acetate ion is contained by about 100 mEq/L, therefore in the case of large-dose
administration or combined use with electrolyte, due attention should be paid tothe electrolyte balance.
PHARMACOKINETICS1)
After 500 mL or 1,000 mL of MORIHEPAMIN was administered intravenously
in healthy male volunteers, plasma amino acids level and urinary amino acids
excretion were assessed. Plasma total amino acids concentration reached thepeak soon after completion of administration. And then the concentration rapidly
decreased and returned to the baseline value 24 hours after administration. Thepattern of plasma amino acids level was considered to reflect the compositionof amino acids in MORIHEPAMIN. Urinary excretion of the amino acids(i.e., threonine, serine, glycine, histidine, and lysine), higher levels of which
are contained in the urine, increased in proportion to dosage amount ofMORIHEPAMIN.
PHARMACOLOGY
1. Improvement of nervous symptoms3,4)
In rats with carbon tetrachloride-induced chronic liver dysfunction,
MORIHEPAMIN improved nervous symptoms, decreased plasma ammonia
levels and suppressed ammonia-induced coma. Similar results were obtained indogs with anastomosis of the portal vein and the inferior vena cava.
2. Improvement of electroencephalogram, free amino acids levels in plasma andbrain, and amine metabolism in brain5,6)
In rats with anastomosis of the portal vein and the inferior vena cava,
MORIHEPAMIN decreased ammonia-induced abnormal electroencephalogram.
MORIHEPAMIN also improved indoleamine metabolism in the plasma and brain
by decreasing blood ammonia levels and improving the plasma Fischer’s ratio.
3. Mechanism of promoting ammonia metabolism7)
It was considered that MORIHEPAMIN rapidly promoted ammonia metabolism
by increasing renal ammonia excretion in addition to activating urea cycle in theliver and upregulating glutamine synthesis in the brain and muscule.
CLINICAL STUDIES
1. General Clinical Studies
The results of general clinical studies of MORIHEPAMIN conducted in patientsof chronic hepatic failure with hepatic encephalopathy or hyperammonaemia
were as follows:
Improvement rate
Usefullness rate
(defined as(defined as“improved” or“useful” or “better”)“better”)
Hepatic encephalopathy
78.2% (68/87)
63.2% (55/87)
Hyperammonaemia
64.7% (11/17)
52.9% (9/17)
2. Controlled Studies2)
When the controlled study by using 500 mL of MORIHEPAMIN was conductedin patients of chronic hepatic failure with hepatic encephalopathy, the result
showed that the improvement rate, defined as the percentage of patients witha response rated as “improved” or better, was 77.2% (34/44 cases) and theusefulness rate, defined as the percentage of patients in whom treatment was rated
as “useful” or better, was 63.6% (28/44 cases). The effect indicated that bloodammonia level rapidly decreased.
Storage
Store below 30°C
Expiration date
36 months from date of manufacturing. Use before date of expiry shown on thelabel.
Manufactured by:
AY PHARMACEUTICALS CO., LTD.
Head Office: 31-1, Nihonbashi-hamacho 2-chome, Chuo-ku, Tokyo, Japan.
Plant: 235, Miyakami, Shimizu-ku, Shizuoka-shi, Shizuoka, Japan
REFERENCES
1) Sanjo, T., et al.: Jpn Pharmacol Ther, 19(1), 175, 1991
2) Sanjo, T., et al.: Jpn Pharmacol Ther, 19(1), 269, 1991
3) Kokuba, Y., et al.: Jpn Pharmacol Ther, 18(11), 4293, 1990
4) AY PHARMACEUTICALS CO., LTD.: In-house data (Effects ofMORIHEPAMIN to alleviate nervous symptoms)
5) Matsuda, A., et al.: Jpn Pharmacol Ther, 18(11), 4307, 1990
6) Chaki, H., et al.: Jpn Pharmacol Ther, 18(11), 4313, 1990
7) Kokuba, Y., et al.: Jpn Pharmacol Ther, 18(11), 4323, 1990
REQUESTS FOR LITERATURE (INCLUDING IN-HOUSE DATA) SHOULD
BE MADE TO:Drug Information
EA Pharma Co., Ltd.
1-1, Irifune 2-chome, Chuo-ku, Tokyo, Japan
Toll-free phone: 0120-917-719
Fax: 03-6280-9930