METHYCOBAL Mecobalamin 500mcg Tablet 1's

Experience to date with deliberate or accidental overdose is limited. No specific antidote is known. As in any case of overdose, treatment should be symptomatic and general supportive measure should be utilised.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy. Clinical studies have been done on pregnant women and no harmful effects have been reported. Mecobalamin with the approved dosage can be used during pregnancy. It has been shown that Mecobalamin is excreted in the milk of lactating rats.

Injection: Precautions concerning Use: Administration: Mecobalamin (METHYCOBAL) is susceptible to photolysis. It should be used promptly after the package is opened, and caution should be taken so as not to expose the ampoules to direct light.
Intramuscular administration: In intramuscular administration, caution should be exercised by following the instructions mentioned as follows to avoid adverse effects on tissues or nerves: Avoid repeated injection at the same site. Particular caution should be exercised when administering Mecobalamin (METHYCOBAL) to premature infants, neonates, nursing infants and children.
Do not inject in densely innervated site.
If insertion of the injection needle causes intense pain or if blood flows back into the syringe, withdraw the needle immediately and inject at a different site.
Opening the ampoule: Mecobalamin (METHYCOBAL) is supplied in one-point-cut ampoules. The cut point of the ampoules should be wiped with an alcohol swab before opening.
Precaution for Handling: Mecobalamin (METHYCOBAL) is packaged in the LPE (Light Protect Easy open pack) to ensure quality during storage. The LPE pack should be opened immediately before using.

Tablet: Mecobalamin (METHYCOBAL) should be stored at temperatures not exceeding 30°C.
Sugar-coated tablets should be protected from light and moisture after opening package. (Light decreases the content and tablet may turn reddish with exposure to moisture.)
Injection: Mecobalamin (METHYCOBAL) should be stored in LPE (Light-Protect-Easy open pack) package at temperatures not exceeding 25°C. (If ampoules are not kept in the LPE pack, mecobalamin decomposes by light and decreases the content.)

Pharmacology: Pharmacodynamics: Mecobalamin is a kind of endogenous coenzyme B12: Mecobalamin plays an important role in transmethylation as a coenzyme of methionine synthetase in the synthesis of methionine from homocysteine.
Mecobalamin is well transported to nerve cell organelles, and promotes nucleic acid and protein synthesis: Mecobalamin is better transported to nerve cell organelles than cyanocobalamin in rats. It has been shown in experiments 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 utilization and metabolism of nucleic acid. Also, mecobalamin promotes nucleic acid and protein synthesis in rats more than cobamamide does.
Mecobalamin promotes axonal transport and axonal regeneration: Mecobalamin normalizes axonal skeletal protein transport in sciatic nerve cells from rat models with streptozotocin-induced diabetes mellitus. It exhibits neuropathologically and electrophysiologically inhibitory effects on nerve degeneration neuropathies induced by drugs, such as adriamycin, acrylamide, and vincristine (in rats and rabbits), models of axonal degeneration in mice and neuropathies in rats with spontaneous diabetes mellitus.
Mecobalamin promotes myelination (phospholipid synthesis): Mecobalamin promotes the synthesis of lecithin, the main constituent of medullary sheath lipid and increases myelination of neurons in rat tissue culture more than cobamamide does.
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 diminished brain tissue levels of acetylcholine in rats fed a choline-deficient diet.
Mecobalamin promotes the maturation and division of erythroblasts, thereby alleviating anemia: It is well known that vitamin B12-deficiency may cause specific megaloblastic anemia. Mecobalamin promotes nucleic 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 B12-deficient rats.
Clinical efficacy: Tablet: Mecobalamin was administered orally to patients with peripheral neuropathies at doses of 1,500 mcg and 120 mcg (low-dose group) daily divided into three doses for 4 consecutive weeks in a double-blind clinical trial. In the chronic stage and fixed stage in peripheral neuropathies, the improvement rate for moderately to remarkably improved was 17.6% (6/34) in 1,500 mcg group and 9.7% (3/31) in 120 mcg group. The improvement rate for fairly to remarkably improved was 64.7% (22/34) in the 1,500 mcg group and 41.9% (13/31) in the 120 mcg group. The dose of 1,500 mcg/day was thus demonstrated to be useful.
In a placebo-controlled double-blind clinical trial, mecobalamin and cobamamide were administered orally to patients with peripheral neuropathies at doses of 1,500 mcg daily for 4 consecutive weeks. The rates for moderately to remarkably improved for peripheral neuropathies were 38.6% (17/44) for mecobalamin, 22.2% (10/45) for cobamamide and 26.7% (12/45) for placebo. Mecobalamin was thus demonstrated to be useful.
Injection: Mecobalamin was administered intramuscularly to patients with peripheral neuropathies at a single dose of 500 mcg and 100 mcg (low-dose group) daily 3 times a week for 4 consecutive weeks in a double-blind clinical trial. In the chronic stage and fixed stage of peripheral neuropathies in the 500 mcg group aggravation of symptoms was significantly suppressed compared to the low-dose group and this dose was thus demonstrated to be useful.
In a placebo-controlled double-blind clinical trial, mecobalamin was administered intravenously or intramuscularly to patients with peripheral neuropathies at a single dose of 500 mcg daily 3 times a week for 4 consecutive weeks. The improvement 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 intramuscular administration was 46.3% (25/54) for moderately to remarkably improved and 81.5% (44.54) for fairly to remarkably improved. The equivalence of mecobalamin efficacy for both administration routes was thus demonstrated. The diseases of subjects in the trial were diabetic neuropathy, polyneuritis, cervical spondylosis, sciatica, alcoholic neuropathy, facial paralysis and mononeuritis, etc.
When mecobalamin was administered to patients with megalobalstic anemia due to vitamin B12 deficiency, their hemograms and symptoms improved in 3 weeks to 2 months after starting administration.
Pharmacokinetics: Single-dose administration: Tablet: When Mecobalamin (METHYCOBAL) was administered orally to healthy adult male volunteers at single doses of 120 mcg and 1,500 mcg, the peak serum total vitamin B12 (abbreviated to B12) concentration was reached after 3 hrs. for both doses, and this was dose-dependent. The half-life, increment in the serum total B12 concentration and ∆AUC0 but 12 hrs after administration are shown in the following figure and table. 40 to 90 percent of the cumulative amount of total B12 excreted in the urine by 24 hrs after administration was excreted within the first 8 hrs.
(Note) A single dose of 1,500 mcg is unapproved. (See Figure 1 and Table 3.)

Injection: Mecobalamin was administered intramuscularly or intravenously to 12 healthy adult male volunteers at a single dose of 500 mcg. The time to reach peak serum total vitamin B12 (abbreviated to B12) concentration (tmax) was 0.9 hr after intramuscular administration and immediately to 3 mins. after intravenous administration, and the increment (except endogenous serum total B12) in peak serum total vitamin B12 concentration (∆Cmax) was 22.4 ng/mL after intramuscular administration and 85.0 ng/mL after intravenous administration.
The area under the serum 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 intravenous administration. On the other hand, the rate of binding saturation showed a similar increase in both groups of subjects for 144 hr. after administration. (See Figure 2 and Table 4.)

Repeated-dose administration: Tablet: Mecobalamin (METHYCOBAL) was administered orally to healthy adult male volunteers at a dose of 1,500 mcg daily for 12 consecutive weeks and changes in the serum total B12 concentration were determined until 4 weeks after the last administration. The serum concentration increased for the first 4 weeks after administration, rising to about twice as high as the initial value. Thereafter, there was a gradual increase which peaked at about 2.8 times the initial value at the 12th week of dosing. The serum concentration declined after the last administration (12 weeks), but was stil about 1.8 times the initial value 4 weeks after the last administration. (See Figure 3.)




Injection: Mecobalamin was administered intravenously to 6 healthy adult male volunteers at a single dose of 500 mcg daily for 10 consecutive days. Serum total B12 concentration determined before each administration increased from day to day. After 2 days of administration, the serum 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 increased to 6.8±1.5 ng/mL, about 1.7 times the 24 hr value, and this concentration was maintained until the last dosing.