Eisai Co., Ltd. 1
Standard Commodity Classification No. of Japan Revid: April 2005 (4th version, Revisions associated with the amend-
ment of the Pharmaceutical Affairs Law) 873136
- Drug for peripheral neuropathies -
Methycobal injection 500 µg
<Mecobalamin preparation>
Prescription drug
幽默哲理故事Caution: See “PRECAUTION FOR HANDLING” ction.
Caution : U only as directed by a physician.
DESCRIPTION
METHYCOBAL is a clear, red injection containing the fol-
lowing ingredients, and contained in brown ample
(one-point-cut type).
Ingredients Content per ampule (1 mL)
Active ingredient Mecobalamin500 µg
Inactive ingredient D-Mannitol 50 mg
Product description Methycobal is a clear, red liquid
pH 5.3 - 7.3
Osmotic pressure ratio about 1 (ratio relative to isotonic sodium chloride solution)
INDICATIONS
Peripheral neuropathies
Megaloblastic anemia caud by vitamin B12 deficiency <Precautions>
METHYCOBAL should not be ud aimlessly for more than one month unless it is effective.
DOSAGE AND ADMINISTRATION
• Peripheral neurophathiesjust so so
The usual dosage for adults is 1 ampule (500 µg of meco-balamin) daily, administered intramuscularly or intrave-nously 3 times a week. The dosage may be adjusted de-pending on the patient’s age and symptoms.
• Megaloblastic anemia
The usual dosage for adults is 1 ampule (500 µg of meco-balamin) daily, administered intramuscularly or intrave-nously 3 times a week. After about 2 months of medica-tion, the do should be reduced to a single administration of 1 ampule at 1 to 3 months intervals for maintenance therapy.
PRECAUTIONS
1. Adver Reactions
Adver reactions were reported in 13 of 2,872 patients
(0.45 %). (At the end of the reexamination period)
(1) Clinically significant adver reactions (incidence
unknown)
Anaphylactoid reaction
Anaphylactoid reaction such as decrea in blood pres-
sure or dyspnea, may occur. Patients should be care-
fully obrved. In the event of such symptoms, treat-
ment should be discontinued immediately and appro-
priate measures taken.
(2) Other adver reactions
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Incidence
unknown Hypernsitivity note) Rash
otdrOthers Headache
and
hot nsation
Diaphoresis and pain/induration at
the site of intramuscular injection
Note: In the event of such symptoms, treatment should be
discontinued.
2. Precautions concerning U
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(1) Administration
METHYCOBAL is susceptible to photolysis. It should
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be ud promptly after the package is opened, and cau-
tion should be taken so as not to expo the ampules to
direct light.
(2) Intramuscular administration
In intramuscular administration, caution should be ex-
ercid by following the instructions mentioned below
to avoid adver effects on tissues or nerves.
wsc是什么意思1) Avoid repeated injection at the same site. Particular
caution should be exercid when administering
METHYCOBAL to prematures, neonates, nursing
infants and children.
2) Do not inject in denly innervated site.
3) If inrtion of the injection needle caus inten pain
or if blood flows back into the syringe, withdraw the
needle immediately and inject at a different site.
Storage
METHYCOBAL should be stored in LPE pack (Light Protect Easy open pack) at room temperature. (If ampules are not kept in the LPE pack, mecobalamin decompos by light and decreas the content).
Expiration date
METHYCOBAL should be ud before the expiration date indicated on the package or label. Approv
al No. 57AM-1221 Date of listing in the NHI reimburment price Jun 1984 Date of initial marketing in Japan Jun 1984 Date of latest reexamination Mar 1998 Date of latest approval of indications Jul 1983
2 Eisai Co., Ltd.
(3) Opening the ampule
METHYCOBAL is supplied in one-point-cut ampules.
The cut point of the ampules should be wiped with an
alcohol swab before opening. PHARMACOKINETICS
1. Single-do administration
Mecobalamin was administered intramuscularly or intra-venously to 12 healthy adult male volunteers at a single do of 500 µg. The time to reach peak rum total vitamin B12 (abbreviated to B12) concentration (t max) was 0.9 hr af-ter intramuscular administration and immediately to 3 min after intravenous administration, and the increment (except endogenous rum total B12) in peak rum t
otal vitamin B12 concentration (∆C max) was 22.4 ng/mL after intramus-cular administration and 85.0 ng/mL after intravenous ad-ministration.
The area under the rum total B12 concentration-time curve (∆AUC) calculated by increment of the actual values at 144 hr after administration was 204.1 ng ⋅ hr/mL after intramuscular administration and 358.6 ng ⋅ hr/mL after in-travenous administration.
On the other hand, the rate of binding saturation showed a similar increa in both groups of subjects for 144 hr after administration. 1)
Serum total vitamin B12 concentration after single
administration of METHYCOBAL Injection 500 µg
Pharmacokinetic parameters after a single do
administration of Methycobal Injection 500 µg
t max(hr) ∆C
max
(ng/mL) ∆AUC1440(ng⋅hr/mL) t1/2 (hr)
I.V. 0-
3
min 85.0±8.9 358.6±34.4 27.1
I.M. 0.9±0.1 22.4±1.1 204.1±12.9 29.0
Mean ± S.E., n=12 2. Repeated-do administration
Mecobalamin was administered intravenously to 6 healthy adult male volunteers at a single do of 500 µg daily for
10 concutive days. Serum total B12 concentration deter-
mined before each administration incread from day to day. After 2 days of administration, the rum total B12 concentration was 5.3±1.8 ng/mL, about 1.4 times the 24 hr value (3.9±1.2 ng/mL) after administration. At 3 days of administration it had incread to 6.8±1.5 ng/mL, about 1.7 times the 24 hr value, and this concentration was main-tained until the last dosing. 1)CLINICAL STUDIES
Clinical efficacy
Mecobalamin was administered intramuscularly to patients with peripheral neuropathies at a single dos of 500 µg and 100 µg (low-do group) daily 3 times a week for 4 concu-tive weeks in a double-blind clinical trial. In the chronic stage and fixed stage of peripheral neuropathies in the 500 µg group aggravation of symptoms was significantly suppresd com-pared to the low-do group and this do was thus demon-strated to be uful. 2)
In a placebo-controlled double-blind clinical trial, mecobala-min was administered intravenously or intramuscularly to pa-tients with peripheral neuropathies at a single do of 500 µg daily 3 times a week for 4 concutive weeks. The improve-ment rate for intravenous administration was 38.7% (24/62) for moderately to remarkably improved and 74.2% (46/62) for fairly to remarkably improved. The improvement rate for in-tramuscular administration was 46.3% (25/54) for moderately to remarkably improved and 81.5% (44/54) for fairly to re-markably improved. The equivalence of mecobalamin efficacy for both administration routes was thus demonstrated. The dis-eas of subjects in the trial were diabetic neuropathy, poly-neuritis, cervical spondylosis, sciatica, alcoholic neuropathy, facial paralysis and mononeuritis, etc. 3)
When mecobalamin was administered to patients with mega-loblastic anemia due to vitamin B12 deficiency, their hemo-grams and symptoms improved in 3 weeks to 2 months after starting administration.
PHARMACOLOGY
1. Mecobalamin is a kind of endogenous coenzyme B12
Mecobalamin plays an important role in transmethylation as a coenzyme of methionine syntheta in
the synthesis of methionine from homocysteine.
2. Mecobalamin is well transported to nerve cell organ-
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elles, and promotes nucleic acid and protein synthesis.
Mecobalamin is better transported to nerve cell organelles than cyanocobalamin in rats. It has been shown in experi-ments with cells from the brain origin and spinal nerve cells in rats to be involved in the synthesis of thymidine from deoxyuridine, promotion of deposited folic acid utili-zation and metabolism of nucleic acid.Also, mecobalamin promotes nucleic acid and protein synthesis in rats more than cobamamide does. 4 - 6)
3. Mecobalamin promotes axonal transport and axonal
regeneration.
Mecobalamin normalizes axonal skeletal protein transport in sciatic nerve cells from rat models with streptozoto-cin-induced diabetes mellitus. It exhibits neuropathologi-cally and electrophysiologically inhibitory effects on nerve degeneration in neuropathies induced by drugs, such as adriamycin, acrylamide, and vincristine (in rats and rab-bits), models of axonal degeneration in mice and neurop
a-thies in rats with spontaneous diabetes mellitus. 7 - 12)
4. Mecobalamin promotes myelination (phospholipid syn-
thesis).
Mecobalamin promotes the synthesis of lecithin, the main constituent of medullary sheath lipid and increas myeli-nation of neurons in rat tissue culture more than cobama-mide does. 13, 14)
Eisai Co., Ltd. 3
5. Mecobalamin restores delayed synaptic transmission
and diminished neurotransmitters to normal.
Mecobalamin restores end-plate potential induction early by increasing nerve fiber excitability in the crushed sciatic nerve in rats. In addition, mecobalamin normalizes dimin-ished brain tissue levels of acetylcholine in rats fed a cho-line-deficient diet. 15, 16)
6. Mecobalamin promotes the maturation and division of
erythroblasts, thereby alleviating anemia.
It is well known that vitamin B 12-deficiency may cau specific megaloblastic anemia. Mecobalamin promotes nu-cleic acid synthesis in bone marrow and promotes the maturation and division of erythroblasts, thereby increasing erythrocyte production. Mecobalamin brings about a rapid recovery of diminished red blood cell, hemoglobin, and hematocrit in vitamin B 12-deficient rats.
PHYSICOCHEMISTRY
Nonproprietary name: Mecobalamin (JAN, INN) Chemical name:
散曲Co α-[α-(5,6-Dimethylbenz-1H -imidazolyl)]-Co β- methylcobamide
Molecular formula: C 63H 91CoN 13O 14P Molecular weight: 1,344.38
Structural formula:
Description:
Mecobalamin occurs as dark red crystals or crystalline powder. It is sparingly soluble in water, slightly soluble in ethanol (99.5), and practically insoluble in acetonitrile. It is affected by light.
PRECAUTION FOR HANDLING
METHYCOBAL is packaged in the LPE pack (Light Protect Easy open pack) to ensure quality during storage.
The LPE pack should be opened immediately before using.
PACKAGING
METHYCOBAL Injection 500 µg (1mL) Boxes of 10 and 50 ampules
REFERENCES
1) Ogawa T. et al.: Vitamin, 63, 123, 1989. 2) Kameyama M. et al.: Jpn. J. Clin. Exp. Med.,
49, 1967, 1972.
3) Maruyama S. et al.: ibid ., 66, 995, 1989.
4) Inada M. et al.: Nervous systems and Methyl B 12
(Kyowa kikaku tsuushin), 23, 1981.
5) Nakazawa T. et al.: Vitamin, 42, 193, 1970. 6) Nakazawa T. et al.: ibid ., 42, 275, 1970.
7) Takenaka T. et al.: Prog. Med., 2, 1759, 1982. 8) Ohnishi A. et al.: Jpn. J. Clin. Pharmacol. Ther.,
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18, 387, 1987.
9) Watanabe T. et al.: J. Neurol. Sci., 122, 140, 1994. 10) Saitoh T. et al.: Nervous Systems and Methyl B 12
(Kyowa kikaku tsuushin), 75, 1981.
11) Yamazaki K. et al.: Neurosci. Lett., 170, 195, 1994. 12) Yagihashi S. et al.: Jpn. J. Clin. Pharmacol. Ther.,
19, 437, 1988.
13) Nakagawa T. et al.: Nervous Systems and Methyl B 12
(Kyowa kikaku tsuushin), 54, 1981. 14) Yonezawa T. et al.: ibid ., 49, 1981. 15) Shibuya T. et al.: ibid ., 134, 1981.
16) Sasaki H. et al.: Pharmacol. Biochem. Behav.,
43, 635,1992.
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5-5, Koishikawa 5-chome, Bunkyo-ku, Tokyo, 112-8088
REQUEST FOR DRUG INFORMATION SHOULD BE MADE TO:
Customer Information Services Section Free Dial: 0120-419-497 Eisai Co., Ltd.
Manufactured and marketed by: Eisai Co., Ltd.
6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo, 112-8088
