Peripheral neuropathies.

Megaloblastic anemia caused by vitamin B₁₂ deficiency

Adults

Peripheral neuropathies

The usual dose for adults is 1 ampule (500 µg of mecobalamin) daily, administered intramuscularly or intravenously 3 times a week.

The dose may be adjusted depending on the patient’s age and symptoms.

Megaloblastic anemia

The usual dose for adults is 1 ampoule (500 µg of mecobalamin) daily, administered intramuscularly or intravenously 3 times a week. After about 2 months of medication, the dose should be reduced to a single administration of 1 ampule at 1 to 3 months intervals for maintenance therapy.

Method of administration

Intramuscular or intravenous.

Intramuscular administration

In intramuscular administration, caution should be exercised by following the instructions mentioned below to avoid adverse effects on tissue or nerves.

Avoid repeated injection at the same site. Particular caution should be exercised when administering Methycobal to prematures, neonates, nursing infants and children.

Do not inject in densely innervated site.

If insertion of the injection needles causes intense pain or if blood flows back into the syringe, withdraw the needle immediately and inject at a different site.

Methycobal is susceptible to photolysis. It should be used promptly after the package is opened, and caution

should be taken not to expose the ampules to direct light.

Methycobal is supplied in one-point-cut ampules. The cut point of the ampoules should be wiped with an alcohol swab before opening.

It is not known whether Methycobal Injection can cause clinically significant interactions with other drugs.

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. Methycobal with the approved dosage can be used during pregnancy. It has been shown that mecobalamin is excreted in the milk of lactating rats.

Based on the pharmacodynamic properties and adverse event profile, it is unlikely that Methycobal would cause an impairment of driving performance or compromise the ability to use machinery.

Adverse reactions were reported in 13 of 2,872 patients (0.45%). (At the end of the reexamination period)

(1)  Clinically significant adverse reactions (incidence unknown)

Anaphylaxis

Anaphylaxis, such as decrease in blood pressure or dyspnea, may occur. Patients should be carefully observed. In the event of such symptoms, treatment should be discontinued immediately and appropriate measures taken.

(2)   Other adverse reactions

Note:     In the event of such symptoms, Methycobal should be discontinued.

If there are any undesirable effects, please contact to authority as below:

 Saudi Arabia:

 The National Pharmacovigilance and Drug Safety Centre (NPC)

Fax: +966-11-205-7662

Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

Toll free phone: 8002490000

E-mail: npc.drug@sfda.gov.sa

Website: www.sfda.gov.sa/npc

 Other GCC States:

 Please contact the relevant competent authority

Not applicable

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 organelle 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 in 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 cobalamide does.

Mecobalamin restores delayed synaptic transmission and diminished neurotransmitters to normal. Mecobalamin restores end-plate potential induction early by increasing never 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, haemoglobin, and haematocrit in vitamin B₁₂-deficient rats.

Clinical efficacy and safety

Mecobalamin was administered intramuscularly to patients with peripheral neuropathies at a single dose of 500 µg and 100 µg (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 µg group aggravation of symptoms was significantly suppressed compared to the low-dose group and this dose was thus demonstrated to be useful.

In placebo-controlled double-blind clinical trial, mecobalamin was administered intravenously or intramuscularly to patients with peripheral neuropathies at a single dose of 500 µg 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 megaloblastic anemia due to vitamin B₁₂ deficiency, their haematological parameters and symptoms improved in 3 weeks to 2 months after starting administration.

Single-dose administration

Mecobalamin was administered intramuscularly or intravenously to 12 healthy adult male volunteers at a single dose of 500 µg. the time to reach peak serum total vitamin B₁₂ (abbreviated to B₁₂) concentration (t_max) was 0.9 hr after intramuscular administration and immediately 3 min after intravenous administration, and the increment (except endogenous serum total B₁₂) in peak serum total vitamin B₁₂ concentration (ΔC_max) 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 (ΔAUC) 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 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.

Repeated-dose administration

Mecobalamin was administered intravenously to 6 healthy adult male volunteers at a single dose of 500 µg 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±1.5 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.

Preclinical safety data, including safety pharmacology, single and repeated dose toxicity, genotoxicity, reproductive and developmental toxicity, and antigenicity studies revealed no special findings relevant to humans.

D-mannitol

Water for injection

Glutathione injection showed a significant (up to 30% decrease) in the content in 6 hours.

Methycobal should be stored in LPE pack (Light Protect Easy open pack) below 25°C. If ampules are not kept in the LPE pack, mecobalamin decomposes by light and decreases the content

Boxes of 10 brown ampules (one-pint-cut type).

Methycobal should be used before the expiration date indicated on the package or label.

Use only as directed by a physician

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Methycobal is packaged in the LPE pack (Light Protect Easy open pack) to ensure the quality during storage. The LPE pack should be opened just before use.