AMIPAREN

10% Amino Acid

AMIPAREN® is a new sterile infusion solution of total amino acids intended for use in
hyperalimentation and general parenteral nutrition.

AMIPAREN® contains relatively larger amounts of branched-chain amino acids (L-Leucine,

L-Isoleucine and L-Valine), which suppress protein breakdown and promote protein synthesis
in the muscle and smaller amounts of aromatic and acidic amino acids. A series of preclinical
and clinical studies established that AMIPAREN® was effective in sparing protein in various
types of insults and malnutritional state.

AMIPAREN® was also carefully formulated to contain no chloride ions and minimum sodium
ions to facilitate easy supplementation of electrolytes.

COMPOSITION
Each 500 mL of AMIPAREN® contains following ingredients:
L-Leucine 7.00 g L-Tyrosine 0.25 g
L-Isoleucine 4.00 g L-Arginine 5.25 g
L-Valine 4.00 g L-Histidine 2.50 g
Lysine Acetate 7.40 g L-Alanine 4.00 g
(L-Lysine equivalent) (5.25 g) L-Proline 2.50 g
L-Threonine 2.85 g L-Serine 1.50 g
L-Tryptophan 1.00 g Aminoacetic acid 2.95 g
L-Methionine 1.95 g L-Aspartic acid 0.50 g
L-Phenylalanine 3.50 g L-Glutamic acid 0.50 g
L-Cysteine 0.50 g Water for Injection ad 500 mL

Total free amino acids 50 g E/N ratio 1.44

Essential amino acids (E) 29.55 g Branched-chain amino acids 30.0 w/w%
Non-essential amino acids(N) 20.45 g Na+ 2 mEq/L
Total nitrogen 7.85 g Acetate- 120 mEq/L
Sodium bisulfite is added as a stabilizer

INDICATIONS
AMIPAREN® is indicated for amino acid supply in the following instances: hypoproteinemia,
malnutrition and pre and/or postoperative condition.

DOSAGE AND ADMINISTRATION

Central vein infusion:
The usual adult dosage is 400-800 mL per day by drip infusion via the central vein. The dosage
may be increased or decreased depending on the patient's age, symptoms and body weight.

Peripheral vein infusion:

The usual adult dosage is 200-400 mL per dose by drip infusion via the peripheral vein. The
usual peripheral infusion rate is such a rate as to provide about 10 g of amino acids over 60
minutes of infusion in order to achieve optimal physiological utilization of amino acids. A
typical infusion rate in adults is 100 mL over 60 minutes (about 25 drops per minute) and the
rate should be adjusted downward in the case of children, elderly patients and severely ill
patients.
The dosage may be increased or decreased depending on the patient's age, symptoms and body
weight.
Combination of AMIPAREN® with a carbohydrate solution is highly recommended for
efficient utilization of amino acids in the body.

PRECAUTIONS
1. Use is contraindicated in the following instances:
1. Patients with hepatic coma or risk of hepatic coma.
2. Patients with serious renal disorder or azotemia (for both, patients on dialysis or
hemofiltration are excluded).
3. Patients with abnormal amino acid metabolism.

2. The solution should be infused with care in the following instances:

1) Patients with severe acidosis.
2) Patients with congestive heart failure.
3) Patients with hyponatremia.
4) Patients on dialysis or hemofiltration with serious renal disorder or azotemia.

3. Important precautions:
The volume of urea, etc. removed and accumulated in patients on dialysis or hemofiltration
with serious renal disorder or azotemia varies depending on the dialysis method and patients’
conditions. Initiation and continuation of administration should be determined after the
patient’s conditions are carefully checked based on assessment of blood biochemistry, acid-
base equilibrium, and body-fluid balance, etc.

4. Adverse reactions:
1) Hypersensitivity: Rare eruption or other hypersensitive reactions were reported, if
such reactions occur, the solution should be discontinued.
2) Cardiovascular: Occasional chest discomfort and palpitation were reported.
3) Gastrointestinal: Occasional nausea and vomiting were reported.
4) Hepatic: An occasional increase in GOT, GPT and total bilirubin levels was reported.
5) Renal: An occasional increase in blood urea nitrogen was reported.
6) Large and acute administration: Acidosis was reported after large and acute
administration of the solution.
7) Other: Occasional chills, fever, hot flush, headache and vascular pain were reported.

5. Use in immature infants, newborns and infants:

The safety of the solution in immature infants, newborns and infants has not been
established yet.

6. Precautions in use:
(1) Acetate is formulated in an amount of about 120 mEq/L. Concomitant use of the solution
with electrolyte solutions and administration of the solution in large doses require careful
supervision of electrolyte balance.
(2) Infusion should be slow.
PHARMACOLOGY
The value of AMIPAREN® as a source of amino acids in the nutritional support was assessed
in hyperalimentation therapy using normal rats and insulted rats.
1. AMIPAREN® promptly improved and maintained nitrogen balance and exhibited a
pronounced nitrogen sparing effect in these models.
2. The solution promoted synthesis of plasma total protein and albumin.
3. The urinary 3-methylhistidine/creatinine ratio, an indicator of protein catabolism in the
muscle under insult, was low after infusion treatment, indicating a very potent
inhibitory effect of the solution on muscle protein breakdown.
4. The plasma concentration of free amino acids including branched-chain amino acids
showed minor fluctuation during infusion treatment. Amino acid metabolism was
judged to be steady during AMIPAREN® therapy.

CLINICAL STUDIES
Clinical studies of AMIPAREN® were conducted in a total of 546 patients undergoing central
or peripheral venous nutritional management.
These studies provided evidence of the high clinical value of the solution as a source of amino
acids in terms of major protein metabolism-related indexes including nitrogen balance, serum
total protein and albumin levels, rapid turnover protein level and urinary 3-
methylhistidine/creatinine ratio.

Adverse Reactions and Abnormal Laboratory Values

In 546 patients treated, 17 cases of side effects were reported. Complaints included
vascular pain (0.4%) and nausea and vomiting (0.4%). Abnormal laboratory tests showed
an increase in GOT and/or GPT (0.7%), an increase in BUN (0.5%) and an increase in
total bilirubin (0.4%).

PRECLINICAL STUDIES
1. Pharmacokinetics
14
C-Amino acids formulated in AMIPAREN® were readily taken up into plasma protein
fractions after intravenous infusion in all normal rats at 3, 7 and 57 weeks of age. The
radioactivity was distributed in higher concentrations to protein fractions of the pancreas
liver and kidneys as well as muscles. Respiratory excretion accounted for 37.1%-44.2%
over 72 hours postinfusion. As other major routes of elimination, 3.9%-5.2% and 1.2%-
3.1% of the radioactivity were recovered from the urine and feces, respectively.
Amino acid fractions in the urine contained only 1.1 %-1.5% of the amino acids given. The
overall retention of amino acids in the body amounted to more than 98.5% of the dose.

2. Toxicity
(1) Acute toxicity: LD50 values (intravenous, infusion rate: 4 mL/minute)
107 mL/kg male rabbits
120 mL/kg female rabbits
(2) Long term toxicity studies (rabbits, intravenous, 13 weeks and 26 weeks, an antigenicity
study and a local irritation study did not reveal any AMIPAREN® related specific toxic
symptoms.
DESCRIPTION
AMIPAREN® is a sterile, clear, colorless aqueous solution for infusion.
pH: about 6.9 (average immediately after manufacture) and 6.5 – 7.5 (specification).
Specific gravity (20oC): 1.032
Osmolarity: Approx. 900 mOsm/L

PRECAUTION AND HANDLING

1. A crystalline precipitate may form due to temperature changes during storage. Shake the
solution at temperature of 15-25oC to dissolve precipitate before use.
2. Do not use the product if the solution is discolored or a precipitate that cannot be dissolved
by shaking has formed.
3. Open the outer wrap just before use.
4. Do not use if bag is leaking, solution cloudy or contains foreign matters.

STORAGE
Store below 30oC, protected from light.

PACKAGE
Box, 1 soft bag of 500 mL
REG. NO.: DKL9218703649A1