Hydroxocobalamin for Vitamin B12 Deficiency

Hydroxocobalamin is the natural, injectable form of vitamin B12 and the preferred intramuscular cobalamin where it is available, because it binds plasma proteins and is retained longer than cyanocobalamin, allowing injections every 2 to 3 months. It treats pernicious anaemia, other causes of cobalamin deficiency and their neurological complications.

Classification. Haematinic; water-soluble vitamin.

Mechanism. Converted intracellularly to methylcobalamin and adenosylcobalamin, cofactors for methionine synthase and methylmalonyl-CoA mutase, which are needed for DNA synthesis, homocysteine metabolism and myelin maintenance.

Pharmacokinetics. Intramuscular absorption is complete, with peak plasma levels in 1 to 2 hours. Binding to transcobalamin and plasma proteins gives prolonged retention. Excess is excreted in urine over days to weeks; total body stores last 2 to 4 years.

Cobalamin deficiency without neurological involvement (adults).

• Loading dose: 1000 µg intramuscularly on alternate days for 2 weeks (six doses).
• Maintenance: 1000 µg intramuscularly every 2 to 3 months, for life in pernicious anaemia and other irreversible causes.
• Maximum: 1000 µg each dose; higher doses add no benefit.

Deficiency with neurological involvement. 1000 µg intramuscularly on alternate days until no further improvement (can take 3 weeks or longer), then 1000 µg every 2 months.

Dietary deficiency. 1000 µg intramuscularly every 3 months, or oral cobalamin 1000 to 2000 µg daily if absorption is intact.

Children. 1 month to 11 years: 250 to 1000 µg intramuscularly on alternate days for 2 weeks, then 250 µg weekly until blood counts are normal, then 1000 µg every 3 months. 12 to 17 years: adult dosing.

Other licensed use. In cyanide poisoning, hydroxocobalamin is given in much larger intravenous doses (5 g in adults); this is a different regimen from that for deficiency.

Adjustments. Kidney: no reduction; preferred over cyanocobalamin in chronic kidney disease. Liver: none. Pregnancy and breastfeeding: dose unchanged.

Contraindications. Hypersensitivity to cobalamin or cobalt. Use caution in Leber hereditary optic neuropathy, where optic atrophy can progress.

Warnings. Early treatment of severe megaloblastic anaemia can cause sudden hypokalaemia and thrombocytosis. Folate deficiency often coexists and needs treating together.

Adverse effects. Common: red discolouration of urine and skin (harmless), injection-site pain, headache, nausea, acne. Serious: anaphylaxis (rare), hypokalaemia, hypertension (high-dose intravenous use).

Interactions. Chloramphenicol may blunt the haematological response. Metformin and long-term proton pump inhibitors cause deficiency. Red discolouration of plasma and urine can interfere with colorimetric laboratory tests.

Pregnancy and breastfeeding. Safe in both; requirements rise.

Common errors. Giving folic acid alone; stopping injections in pernicious anaemia; failing to check potassium in severe anaemia; delaying intramuscular dosing when neurological signs are present.

Administration. Deep intramuscular injection only; oral cobalamin is used for dietary deficiency. Intravenous use for deficiency is avoided because most of the dose is excreted.

Baseline. Full blood count, blood film, serum cobalamin (under 148 pmol/L, about 200 ng/L, is deficient; up to 250 pmol/L is borderline and needs methylmalonic acid or homocysteine), folate, ferritin, potassium and anti-intrinsic-factor antibodies.

Monitoring. Reticulocytosis appears at 3 to 8 days; haemoglobin rises steadily over 8 weeks. Check potassium in the first 48 hours in severe anaemia. Neurological recovery can take 6 to 12 months and may be incomplete.

Referral and escalation. Refer to haematology for pancytopenia, haemolysis or neurological deficit. Neurological signs need injections started the same day.