Preclinical Studies
Due to ethical considerations, no controlled human efficacy studies have been performed
29
- While the results of animal studies cannot be extrapolated to humans with certainty, the extrapolation is supported by the understanding of the pathophysiologic mechanisms of the toxicity of cyanide (CN) and the mechanisms of the protective effect of hydroxocobalamin in dogs
- The results of the animal study help establish that hydroxocobalamin is likely to produce clinical benefit in humans
Survival rates (at day 14) in a controlled animal study of adult dogs treated with hydroxocobalamin
29,34
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The effectiveness of hydroxocobalamin was examined in a randomized, placebo-controlled, blinded study in CN-poisoned adult dogs assigned to treatment with vehicle (0.9% saline) or 75 mg/kg or 150 mg/kg hydroxocobalamin.
Survival at day 14 was reported
- There was a 100% survival rate at day 14 of animal subjects that received the 150 mg/kg dose (n=18)29,34
- 18% survival with saline vehicle (n=17)
- 79% at 75 mg/kg dose (n=19)
- The 75-mg/kg and 150-mg/kg doses are approximately equivalent to 5 g and 10 g of hydroxocobalamin in humans29,34
Clinical Studies
73% survival rate in a smoke inhalation study of 69 patients treated with hydroxocobalamin—
50 survived
29,40
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A prospective, open-label study included 69 subjects who had been exposed to smoke inhalation from fires. Subjects were over 15 years of age, presented with soot in the mouth and expectoration, and had altered neurological states. The median hydroxocobalamin dose was 5 g, with a range from 4 g to 15 g.29,40
- The majority (50 of 69; 72.5%) of subjects survived, following treatment with hydroxocobalamin29,40
- Forty-two patients had confirmed CN poisoning (≥39 µmol/L) of which 28 (67%) survived after treatment with hydroxocobalamin
71% survival rate in a retrospective study of patients ingesting or inhaling CN
and then treated with hydroxocobalamin — 10 of 14 survived
29,41
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Hospital records were retrospectively reviewed for all admissions to the toxicological intensive care unit with diagnoses of CN poisoning by ingestion or inhalation from 1988 through 2003. Analysis included 14 adult subjects who were treated with 5 g to 20 g of hydroxocobalamin.41
- Blood CN concentrations before administration of hydroxocobalamin exceeded the lethal threshold of 100 mmol/L (2.6 mg/L) in 11 of the 12 patients with available data41
- Of the 14 patients, 10 (71.4%) survived and were discharged41
- Of the 4 patients who died, all were in cardiac or respiratory arrest before treatment with hydroxocobalamin41
Experience in healthy subjects
A double-blinded, randomized, placebo-controlled, single-ascending-dose (2.5 g, 5 g, 7.5 g, and 10 g) study was conducted to assess the safety and tolerability of hydroxocobalamin in 136 healthy adults.
Incidence of adverse reactions occurring in >5% of subjects in 5 g dose group and corresponding incidence in 10 g dose group29
| Adverse Reaction |
5 g Dose Group |
10 g Dose Group |
Hydroxocobalamin
N=66
n(%) |
Hydroxocobalamin
N=18
n(%) |
| Chromaturia (red colored urine) |
66 (100) |
18 (100) |
| Erythema |
62 (94) |
18 (100) |
| Rasha |
13 (20) |
8 (44) |
| Blood pressure increasedb |
12 (18) |
5 (28) |
| Nausea |
4 (6) |
2 (11) |
| Headache |
4 (6) |
6 (33) |
| Lymphocyte percent decreased |
5 (8) |
3 (17) |
| Infusion site reaction |
4 (6) |
7 (39) |
a Rashes were predominantly acneiform.
b Increases in blood pressure peaked toward the end of the hydroxocobalamin infusion and typically returned to baseline levels by 4 hours postinfusion.
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