Hydroxocobalamin

Why this drug is interesting

Cyanide poisoning is diagnosed on the history and the picture, never on a test. The SmPC says so outright: "There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and/or signs and symptoms of cyanide intoxication."¹ Every cyanide antidote is therefore given to a population that mostly does not have the diagnosis confirmed and sometimes does not have it at all.

That single fact is why hydroxocobalamin displaced the older regimens. It has no contraindications, does not induce methaemoglobinaemia, and does not cause the dose-dependent vasodilator hypotension that nitrite does — so the cost of giving it to someone who turns out not to be cyanide-poisoned is low. The alternative, sodium nitrite with sodium thiosulphate, deliberately creates methaemoglobin and has killed at doses less than twice therapeutic.

Pharmacology

Mechanism

Cyanide kills by binding the ferric iron of cytochrome c oxidase (complex IV), halting oxidative phosphorylation. Cells cannot use oxygen despite normal delivery, so metabolism becomes anaerobic and lactate climbs steeply while the venous oxygen saturation stays high.

Hydroxocobalamin carries a cobalt(III) centre with a free coordination site. Cyanide binds it with higher affinity than it holds cytochrome oxidase, forming cyanocobalamin — vitamin B₁₂ — which is stable, non-toxic and renally excreted. The reaction is stoichiometric, which is why the dose is large: 5 g of hydroxocobalamin is needed to sequester a clinically relevant cyanide burden.

Excretion and colour

Hydroxocobalamin is deep red. It produces red discolouration of skin, plasma and urine which is harmless, persists for days, and causes a great deal of downstream confusion — see the laboratory section below.

Dosing

Adults

• Initial dose 5 g — 2 × 100 mL — as an intravenous infusion over 15 minutes.¹
• Second dose 5 g if needed, depending on severity and clinical response, infused over 15 minutes to 2 hours according to how unstable the patient is.¹
• Maximum total recommended dose 10 g.¹

Children (0–18 years)

• Initial dose 70 mg/kg, not exceeding 5 g.¹
• Second dose 70 mg/kg, not exceeding 5 g.¹
• Maximum total 140 mg/kg, not exceeding 10 g.¹

Contraindications

None.¹ Known hypersensitivity to hydroxocobalamin or vitamin B₁₂ must be weighed in the benefit–risk assessment, but it is not listed as a contraindication.

Who to give it to

Cyanide poisoning may follow exposure to hydrogen cyanide and its salts, cyanogens including cyanogenic plants, aliphatic nitriles, or prolonged sodium nitroprusside infusion — as well as smoke from closed-space fires.¹

General signs

Nausea, vomiting, headache, altered mental status (confusion, disorientation), chest tightness, dyspnoea, tachypnoea or hyperpnoea early and bradypnoea or apnoea late, hypertension early and hypotension late, cardiovascular collapse, seizures or coma, mydriasis, and plasma lactate >8 mmol/L.¹

Smoke inhalation — the specific triad

Not all smoke inhalation victims have cyanide poisoning; many have burns, trauma and other toxic exposures. Before giving Cyanokit, the label recommends checking for:¹

• Exposure to fire smoke in an enclosed area
• Soot around the mouth, nose and/or oropharynx
• Altered mental status

In that setting, hypotension and/or a plasma lactate ≥10 mmol/L are highly suggestive of cyanide poisoning. Where those signs are present, treatment must not be delayed to obtain a lactate.¹

Whatever else happens, hydroxocobalamin does not substitute for oxygen therapy and must not delay airway management, oxygenation, hydration, cardiovascular support, seizure control or decontamination.¹

Adverse effects and monitoring

Oxalate nephropathy

This is easy to miss, because the patient is usually transferred to a burns unit or ICU where the antidote given in the resuscitation room is a line in the handover. It belongs in the referral.

Blood pressure

A transient, generally asymptomatic increase in blood pressure may occur, maximal towards the end of the infusion.¹ In a hypotensive fire victim this is usually welcome; it is the opposite of the nitrite problem.

Hypersensitivity

Hypersensitivity reactions may occur and known hypersensitivity to hydroxocobalamin or vitamin B₁₂ should be weighed against benefit before administration.¹

Interference with burn assessment

The deep red colour can induce red discolouration of the skin and may interfere with burn assessment — though skin lesions, oedema and pain remain highly suggestive of burns.¹ Estimate the burn area before you give it if you reasonably can.

Laboratory interference — the part nobody warns the receiving team about

Because of its colour, hydroxocobalamin interferes with colorimetric laboratory assays for up to several days. The SmPC tabulates the effect of a 5 g dose; interference after 10 g lasts longer.¹

Haemodialysis machines

Cyanide assay

Hydroxocobalamin lowers blood cyanide concentrations. Measurement is not required and must not delay treatment, but if a level is planned for documentation, draw the sample before treatment starts.¹

Using it with other cyanide antidotes

The safety of giving other cyanide antidotes simultaneously with Cyanokit has not been established. If the decision is made to give another antidote, the two must not be administered concurrently in the same intravenous line.¹

The reason is chemical, and all three labels say so. Cyanokit's own section 6.2 lists chemical incompatibility with sodium thiosulfate and sodium nitrite (among adrenaline, lidocaine, adenosine, atropine, midazolam, ketamine, suxamethonium, amiodarone, sodium bicarbonate and ascorbic acid), and the Nithiodote and sodium thiosulphate labels record the same incompatibility from their side.¹²³ Sequential sodium thiosulphate and sodium nitrite through one line is explicitly fine. For hydroxocobalamin the labels prohibit simultaneous same-line administration and are silent on sequential use with a flush — so use a separate line.

Physical incompatibility with particle formation has also been observed between reconstituted hydroxocobalamin and several other drugs including diazepam and dobutamine.¹ Give it through a dedicated line.

The other hydroxocobalamin — nitrous oxide and vitamin B₁₂

What nitrous oxide does

Nitrous oxide oxidises the cobalt ion at the centre of cobalamin, irreversibly inactivating it as a cofactor. Methionine synthase stops working. The consequence is a functional vitamin B₁₂ deficiency: the serum B₁₂ concentration is often normal, because the vitamin is present but inactivated. Homocysteine and methylmalonic acid rise, and after weeks to months of recreational use the patient develops subacute combined degeneration of the cord — dorsal column signs, a positive Lhermitte's, myeloneuropathy that may not fully recover.

The preparation and dose

The relevant UK product is Neo-Cytamen 1000 microgram/mL hydroxocobalamin solution for injection, licensed for pernicious anaemia and other B₁₂-deficiency macrocytic anaemias, and given by intramuscular injection.⁴ Its regimen for deficiency with neurological involvement — which is the closest licensed analogue to nitrous oxide myelopathy — is:

• Initially 1,000 micrograms on alternate days for as long as improvement is occurring⁴
• Maintenance 1,000 micrograms every two months⁴
• Without neurological involvement: 250–1,000 micrograms on alternate days for one to two weeks, then 250 micrograms weekly until the blood count is normal, then 1,000 micrograms every two to three months⁴

What else the deficiency label tells you

• Monitor plasma potassium during initial therapy — cardiac arrhythmias secondary to hypokalaemia have been reported as haematopoiesis resumes.⁴
• Monitor the platelet count in the first weeks — reactive thrombocytosis can occur.⁴
• Investigate folate if a megaloblastic anaemia fails to respond; doses above 10 micrograms daily can produce a haematological response in folate deficiency and mask the true diagnosis.⁴ Nitrous oxide also traps folate, so both may need replacing — see folinic acid.
• Contraindicated in hypersensitivity, and should not be used for megaloblastic anaemia of pregnancy unless B₁₂ deficiency has been demonstrated.⁴

Evidence and critical appraisal

There is no randomised controlled trial of hydroxocobalamin in human cyanide poisoning and there cannot be one. The only controlled efficacy data in the SmPC come from a dog model: survival at 4 hours of 41% with saline versus 95% at 75 mg/kg and 100% at 150 mg/kg, and at day 14 of 18% versus 79% and 100%.¹ The label also carries uncontrolled human data — 245 patients, with survival in 58% of the 213 whose outcome was known, 82% (118/144) of those not in cardiac arrest at presentation, and 62% (21/34) of those with blood cyanide above the accepted lethal threshold, plus 54 paediatric patients.¹

The practical case for it rests on the asymmetry. Give hydroxocobalamin to a smoke-inhalation victim who did not have cyanide poisoning and you have caused red urine, a week of uninterpretable creatinine values and a small risk of oxalate nephropathy. Give nitrite to the same patient and you have added methaemoglobin to carboxyhaemoglobin in someone whose oxygen-carrying capacity is already compromised.

The genuine criticism is cost and stocking. A 5 g kit is expensive, the shelf life is finite, and the departments most likely to need it — those near industry, or receiving from enclosed-space fires — are not always the ones that hold it. The stocking decision is a service question, and the answer should be made before the fire, not during it.

References

1. 1
   Cyanokit 5 g powder for solution for infusion (hydroxocobalamin) — Summary of Product Characteristics. electronic Medicines Compendium, product 4786. Sections 4.1–4.9, 5.1, 6.2. Source of all doses, the absence of contraindications, the smoke-inhalation triad and lactate thresholds, the 7-day renal monitoring requirement, the laboratory interference table, the haemodialysis blood-leak warning, the same-line prohibition and the canine survival figures. Verified 31 Aug 2026.
2. 2
   Nithiodote (sodium nitrite and sodium thiosulfate) — Summary of Product Characteristics, Hope Pharmaceuticals Ltd. electronic Medicines Compendium, product 7355. Section 6.2 for the chemical incompatibility with hydroxocobalamin.
3. 3
   Sodium Thiosulfate Solution for Injection — Summary of Product Characteristics, Hope Pharmaceuticals Ltd. electronic Medicines Compendium, product 7354. Section 4.2 for the labelled hydroxocobalamin-then-thiosulphate sequence.
4. 4
   Neo-Cytamen 1000 micrograms/1 mL solution for injection (hydroxocobalamin) — Summary of Product Characteristics. electronic Medicines Compendium, product 9746. Sections 4.1–4.4. The vitamin B₁₂ replacement product, distinct from Cyanokit. Source of the licensed indications, the 1,000 microgram alternate-day neurological regimen and its maintenance, the intramuscular route, the hypokalaemia and reactive thrombocytosis warnings and the folate-masking caution. Nitrous oxide toxicity is not a licensed indication. Verified 4 September 2026.