Revised: September 2000 (3rd version of new form)Standard Commodity Classification No. of Japan
872431
THYRADIN -S Tablets 25
THYRADIN -S Tablets 50
THYRADIN -S Tablets 100
<Levothyroxine Sodium>
Powerful drug, designated drug and presctiption-only drug
Caution: Use only pursuant to the prescription or direction of a physician,
etc.
Storage2550100
Approval No.21000AMZ0017000021000AMZ0021900021000AMZ00171000 The product should be stored
in a light-resistant container at room temperature.Date of listing in the NHI
reimbursement price
July 1998November 1965July 2000
Expiration date Date of initial marketing in
Japan
September 1998July 1998
September 2000
Date of latest reevaluation March 1978
Do not use after the
expiration date indicated on
the package.
CONTRAINDICATIONS (THYRADIN-S Tablets
are contraindicated in the following patients.)
Patients with fresh myocardial infarction [Due to increase
in basal metabolism, cardiac load may increase, and the
condition of patients may be deteriorated.]
DESCRIPTION
1.Composition and dosage form
THYRADIN-S Tablets 25:
Each tablet contains 25 µg of levothyroxine sodium (The
Japanese Pharmacopoeia: dried material). Light red plain
tablet (scored).
THYRADIN-S Tablets 50:
Each tablet contains 50 µg of levothyroxine sodium (The
Japanese Pharmacopoeia: dried material). White plain
tablet (scored).
THYRADIN-S Tablets 100:
Each tablet contains 100 µg of levothyroxine sodium (The
Japanese Pharmacopoeia: dried material). Yellow tablet.
2.Product description
Brand name THYRADIN-S
Tablets 25
THYRADIN-S
Tablets 50
THYRADIN-S
Tablets 100
Appearance
Diameter  6.5 mm  6.5 mm  6.5 mm
Thickness  2.4 mm  2.4 mm  2.4 mm
Weight100 mg100 mg100 mg
Identification
code
TZ214TZ224TZ234
INDICATIONS
Myxedema, cretinism, hypothyroidism (primary or pituitary)
and goiter.
DOSAGE AND ADMINISTRATION
Usually for adults, administer orally 25-400 µg as
levothyroxine sodium once daily. Generally in many cases, 25-
100 µg is administered as a starting dose, and 100-400 µg is
administered for maintenance therapy. The dose may be
increased or decreased according to age and symptoms.
PRECAUTIONS
1.Careful Administration (THYRADIN-S Tablets should
be administered with care in the following patients.)
(1)Patients with severe cardiovascular disorders such as
angina pectoris, old myocardial infarction,
arteriosclerosis and hypertension
[Since the condition of patients may deteriorate due to
the cardiac load induced by an increase in basal
metabolism, the administration should be initiated with
a small amount, and the dose should be gradually
increased by taking longer time than usual. Maintenance
dosage should be kept at minimum.]
(2)Patients with adrenal cortical insufficiency or pituitary
insufficiency
[Since adrenal crisis with the symptoms of shock, etc.,
may be induced, the drug should be administered after
adequate treatment for adreanal cortical insufficiency
(administration of adreno-cortical hormones).]
(3)Patients with diabetes mellitus
[Since the condition of control of blood glucose may be
changed, sufficient care should be taken when the drug
is administered.] (refer to "Drug Interactions")
(4)Elderly patients (refer to "Use in the Elderly")
2.Important Precautions
To patients with hypothyroidism and myxedema, the
administration should be initiated with a small amount, and the dose shall be gradually increased up to the
maintenance dosage with sufficient observation.
3.Drug Interactions
[Precautions for coadministration] (THYRADIN-S
Tablets should be administered with care when
coadministered with the following drugs.)
Drugs Signs, Symptoms and
Treatment Mechanism and Risk Factors
Coumarin-type anticoagulant1) (warfarin potassium, etc.)Since the drug may increase
the action of coumarin-type anticoagulants, in case of coadminitsration, special
attention should be paid
such as by measuring
prothrombin time, etc., and
by adjusting the dose of
anticoagulants, etc.
It is considered that
thyroid hormones
may promote the
catabolism of
Vitamin K-
dependent
anticoagulant
factors.
Sympathomimetic drugs (epinephrine, norepinephrine, drugs containing ephedrine or methylephedrine)The drug may increase the
action of sympathomimetic
drugs. Since the risk of
coronary failure may
increase when the drugs are
coadministered to the
patients with coronary
artery diseases, special
attention should be paid in
case of coadiministration.
It is considered that
thyroid hormones
may increase the
sensitivity of
receptors for
catecholamines.
Cardiac grycosides (digoxin, digitoxin, etc.)Since it is reported that
serum digoxin
concentration decreases at
hyperthyroid condition and
increases at hypothyroid
condition, larger amount
(under hyperthyroid
condition) or smaller
amount (under hypothyroid
condition) of cardiac
glycosides than usual may
be required. In case of
coadministration, special
attention should be paid
(e.g., with monitoring blood
It is considered that
the absorption rate,
distribution volume,
hepatic metabolism,
renal excretion rate,
etc., of cardiac
glycosides may be
attributable to the
phenomenon.
concentration of cardiac
glycosides).
Hypoglycemic
agents
(insulin
preparations,
sulfonyl urea
preparations)
In the patients to whom
hypoglycemic agents are
administered, the drug-S
may change the condition
of control of blood glucose.
In case of coadministration,
the drugs should be
administered carefully by
observing the blood glucose
level and the condition of
patients, and by adjusting
the doses of drugs.
It is considered that
the drug may affect
whole glucose
metabolism and
change glucose
level.
Colestyramine2),
iron
preparations3),
antacids
containing
alminum4,5)
Since the absorption of the
drug may be retarded or
reduced by
coadministration, sufficient
care should be taken such
as providing sufficient dose
interval of the drug in case
of coadministration.
It is considered that
the drugs bind to the
drug in the
gastrointestinal tract
and suppress the
absorption of the
drug.
Phenitoin
preparations6)
Since phenitoin may
decrease the blood
concentration of the drug,
sufficient care should be
taken such as increasing the
dose of the drug in case of
coadministration.
It is considered that
phenitoin may
promote the
catabolism of
thyroid hormones.
4.Adverse Reactions
Post-marketing surveirances that will clarify the incidence
of adverse reactions have not been performed.
(THYRADIN-S Tablets are not classified as the drugs
which are subject to reexamination.)
(1)Clinically significant adverse reactions (incidence
unknown)
Angina pectoris may occur. In such case, overdosage
may be considered, and, appropriate measures, such as
reduction of dose, discontinuation, etc., should be
taken.
(2)Clinically significant adverse reactions (by similar
drugs) (incidence unknown)
1)The occurrence of shock in the treatment with similar
drug (liothyronine sodium) has been reported.
2)The occurrence of congestive heart failure in the
treatment with similar drug (liothyronine sodium) has
been reported. In such case, overdosage may be
considered, and, appropriate measures, such as
reduction of dose, discontinuation, etc., should be
taken.
(3)Other adverse reactions
Incidence unknown
Hypersensitivity†1)Symptoms of hypersensitivity
Hepatic†2)
Hepatic dysfunctions (fever, malaise, abnormal
findings in hepatic function test, etc.)
Cardiovascular†3)Palpitation, increase in pulse rate, arrhythmia
Psychoneurologic†3)Tremor, insomnia, headache, dizziness, diaphoresis, psychoneurologic symptoms such as nervousness, excitement, anxiety, psychosis, etc.
Gastrointestinal†3)Anorexia, vomiting, diarrhea
Others†3)Muscle pain, menstrual disturbance, weight decrease, weakness, hot flushes of skin
[Note]
†1)In such cases, the treatment with the drug should be discontinued.
†2)In such cases, appropriate measures, such as reduction of dose, discontinuation, etc., should be taken.
†3)In such case, overdosage may be considered, and, appropriate measures, such as reduction of do
se,
discontinuation, etc., should be taken.
5.Use in the Elderly
To elderly patients, the administration of THYRADIN-S
Tablets should be initiated with a small amount and
performed carefully such as by prolonging administration interval, etc., under close observation of patients.
[Since elderly patients may have reduced renal function, the administration of THYRADIN-S Tablets may induce
angina pectoris due to cardiac load by increased basal
metabolism.]
6.Overdosage
Symptoms: Refer to "Adverse Reactions."
Measures: In case of overdosage, treatments such as inhibition of absorption of THYRADIN-S Tablets from
gastrointestinal tract (e.g., induction of vomiting,
gastrolavage, administration of cholestylamine and
activated carbon, etc., in accordance with situation) or
symptomatic treatments (oxygen supplement for
maintenance of ventilation, administration of β-blockers
such as propranolol for sympathetic irritation,
administration of cardiac glycosides against congestive
heart failure, treatment for fever, hypoglycosism and
humoral loss, etc.) should be performed.
7.Precautions concerning Use
At dispensing drugs
For drugs that are dispensed in a press-through package
(PTP), instruct the patient to remove the drug from the
package prior to use. (It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may
puncture the esophageal mucosa, resulting in severe
complications such as mediastinitis.)
CLINICAL STUDIES
When THYRADIN-S Tablets were administered to 8 patients with primary hypothyroidism initiating with a dose of 50
µg/day and continuously administered with increasing the dose by 50 µg/day of each in every 2 weeks,
T3, rT3, T4 levels in blood are as shown in the following table, and the ratio (rT3/T3) increased in accordance with the increase in dose.
PHARMACOLOGY
1.Levothyroxine sodium enhances oxygen consumption of
the tissues and increases basal metabolism (Patients with
hypothyroidism8,9), Rats10-12)).
2.Levothyroxine sodium promotes growth but suppresses it at
a high dose (Rats12,13))
3.Levothyroxine sodium promotes protein anabolism but
induces protein catabolism at a high dose (Patients with
hypothyroidism14), Rats15,16)).
4.Levothyroxine sodium decreases lipids, especially,
reportedcholesterol (Patients with hypothyroidism9), Rats17),
Dogs18)).
5.Levothyroxine sodium promotes glycogenolysis in the liver
(Rats19)).
6.Levothyroxine sodium increases excretion of water and
electrolytes (Patients with hypothyroidism, Healthy
adults20)).
PHYSICOCHEMISTRY
Nonproprietary name:
Levothyroxine sodium (JAN)
Chemical name:
Monosodium O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-L-tyrosinate hydrate*
Molecular formula:
C15H10I4NNaO4 x H2O
Structural formula:
Molecular weight:
798.86 (anhydrous)
Description:
Levothyroxine sodium occurs as a pale yellowish white to light yellow-brown powder. It is odorless. It is slightly
soluble in ethanol, and practically insoluble in water and in ether. It dissolves in sodium hydroxide. It is gradually
colored by light.
PACKAGING
THYRADIN-S Tablets 25:
Boxes of 100 tablets (10 tab. × 10)
Boxes of 500 tablets (10 tab. × 50)
Bottles of 500 tablets
THYRADIN-S Tablets 50:
Boxes of 100 tablets (10 tab. × 10)
Boxes of 500 tablets (10 tab. × 50)
Bottles of 500 tablets
Boxes of 1,000 tablets (10 tab. × 100)
THYRADIN-S Tablets 100:
Boxes of 100 tablets (10 tab. × 10)
Boxes of 500 tablets (10 tab. × 50)
Bottles of 500 tablets
REFERENCES
1)Hansten, P.D.: Drug Intel. Clin. Pharm., 14, 331, 1980.
2)Northcutt, R.C., et al.: J. Am. Med. Assoc., 208, 1857,
1969.
3)Campbell, N.R.C., et al.: Ann. Intern. Med., 117, 1010,
1992.
4)Sherman, S.I., et al.: Am. J. Med., 96, 531, 1994.
5)Liel, Y., et al.: ibid., 97, 363, 1994.
6)Blackshear, J.L., et al.: Ann. Intern. Med., 99, 341, 1983.
7)Nihei, N., et al.: Igaku no Ayumi (J. Clinical and
Experimental Medicine), 104, 100, 1978.
8)Burack, R., et al.: J. Pharmacol. Exptl. Therap., 176, 212,
1971.
9)Hart, F.D., et al.: Brit. Med. J., 1, 512, 1950.
10)Barker, S.B., et al.: Proc. Soc. Exptl. Biol. Med., 83, 500,
1953.
11)Tata, J.R., et al.: Biochem. J., 86, 408, 1963.
12)Hsieh, A.C.L.: J. Endocrinol., 26, 55, 1963.
13)Tapp, E.: J. Bone & Joint Surg., 48, 526, 1966.
14)Rawson, R.W., et al.: Am. J. Med. Sci., 226, 405, 1953.
15)Farthing, C.P., et al.: J. Endocrinol., 21, 83, 1960.
16)Michels, R., et al.: Science, 140, 1417, 1963.
17)Ellefson, R.D., et al.: Endocrinol., 71, 425, 1962.
18)Grande, F., et al.: J. Nutr., 94, 60, 1968.
19)Sokoloff, L., et al.: J. Biol. Chem., 236, 795, 1961.
20)Byrom, F.B.: Clin. Sci., 1, 273, 1933.
REQUEST FOR LITERATURE SHOULD BE MADE TO:
Medical Service Department
Teikoku Hormone Mfg. Co., Ltd.
5-1, Akasaka 2-chome, Minato-ku, Tokyo, 107-8522 Japan. INFORMATION ON LONG-TERM ADMINISTRATION
The product may be dispensed by prescription for 90 days at one time in accordance with Notification No.73, issued on March 17, 2000 by the Ministry of Health and Welfare of Japan.
Manufactured by:
Teikoku Hormone Mfg.Co., Ltd.
5-1, Akasaka 2-chome, Minato-ku, Tokyo, 107-8522 Japan

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