FDA Approves Hydroxocobalamin for Cyanide Poisoning
By Eric Toner, M.D., January 2, 2007
On December 15, 2006 the Food and Drug Administration (FDA) approved intravenous hydroxocobalamin for the treatment of known or suspected cyanide poisoning . Cyanide has long been used as a weapon by the military and terrorists, has caused mass casualties in industrial accidents, and is a hazard to firefighters and victims of smoke inhalation.
The New Drug: Hydroxocobalamin
Hydroxocobalamin, also known as vitamin B12a, is a precursor of cyanocobalamin (vitamin B12) and has been used for 10 years in France as the treatment of choice for cyanide poisoning. Hydroxocobalamin binds cyanide in both the intracellular and intravascular space to form cyanocobalamin (vitamin B12), which is then excreted in the urine. Hydroxocobalamin has long been available in the U.S. as a food supplement, but not as a medication.
The FDA approved the drug as Cyanokit®. It is manufactured by Merck Sante s.a.s. in France and packaged by Dey Laboratories for EMD Pharmaceuticals, Inc. The kit contains an unreconstituted form of hydroxocobalamin and the supplies needed to reconstitute the drug and administer it intravenously. Cyanokit® was approved under the Animal Efficacy Rule, which allows use of animal data for evidence of a drug's effectiveness for certain conditions when the drug cannot be ethically or feasibly tested in humans.
According to the FDA: . . . in a controlled study in cyanide-poisoned adult dogs, the use of Cyanokit reduced whole blood cyanide concentration by approximately 55% by the end of the infusion, and significantly improved survival of the Cyanokit -treated dogs compared with dogs receiving placebo. The safety, metabolism and excretion of Cyanokit were evaluated in 136 healthy adult humans. At the proposed starting dose of 5 grams, the drug was found to be generally well tolerated with side effects that were mild to moderate. The most frequently reported adverse reactions in the trial were red urine, skin redness (both from the drug's coloration itself), a temporary increase in blood pressure, headache, nausea and injection site reactions. Allergic reactions were observed in a small number of individuals but were relatively mild and responded quickly to treatment.1
Cyanide exerts its toxic effects by binding reversibly to cytochrome oxidase, thereby inhibiting mitochondrial oxidative phosphorylation. This interruption of aerobic metabolism produces profound metabolic acidosis and rapid death. To be effective, an antidote must be administered before there is irreversible cell damage, often within minutes of exposure.2 This has been a major challenge because it necessitates empiric treatment of cyanide poisoning (there is no time for a definitive diagnosis), and the standard treatment itself is quite toxic. Therefore, until now, definitive treatment could only be administered in a hospital because of safety concerns and the time needed to transport the patient to the hospital usually precluded its effective use.
Problems with the Standard Treatment
Previously, the standard treatment for cyanide poisoning involved the administration of amyl and/or sodium nitrite. Those substances combine with hemoglobin to produce methemoglobin, which, in turn, has a strong affinity for cyanide. Sodium thiosulfate is then administered to scavenge the cyanide from the methemoglobin, producing thiocyanate, which is excreted in the urine.
There are several problems with this approach, however, because the nitrites can cause significant hypotension, and methemoglobinemia is itself toxic. This is particularly true if there is coexisting carboxyhemoglobinemia, such as occurs with smoke inhalation. Cyanide is a common component of the smoke produced from burning synthetic materials, and carboxyhemoglobin results from inhalation of carbon monoxide in smoke. By one estimate, a third of smoke inhalation victims have significant cyanide levels. The combination of met- and carboxy-hemoglobinemia can result in profound loss of oxygen-carrying capacity. Because of this toxicity, the hitherto standard regimen is not appropriate for administration outside of a hospital. Consequently, the regimen is rarely used because, paradoxically, those patients who need the treatment the most (those with lethal levels of exposure) do not survive long enough to get to a hospital where they can be treated. And those who do survive long enough to get to a hospital probably need it the least. Because it is used so infrequently, few hospitals maintain enough of a stock of amyl or sodium nitrite to treat more than a few cyanide victims. As a result, even if patients could be transported to the hospital in time, few hospitals could treat multiple victims of cyanide exposure.
New Drug Promises Effective Treatment for Mass Casualty Cyanide Poisoning
In contrast, because of its good safety profile, hydroxocobalamin can be used in the prehospital setting. In France, it is routinely given to smoke inhalation victims at the scene of a fire. In 2005, there were 1,602,000 fires reported in the U.S. resulting in 3,675 civilian deaths, 17,925 civilian injuries, and 87 firefighter deaths. It is estimated that 80% of fire related deaths are due to smoke inhalation. In 2005, more than 4000 U.S. firefighters were injured by smoke inhalation.3 If American EMS units adopt the French practice of routine empirical use of hydroxocobalamin for smoke inhalation, this would represent a significant step forward in readiness for a mass casualty event involving cyanide. Not only would there be an effective medication for cyanide poisoning that can be administered safely by paramedics in time to be helpful, but such routine use would also mandate maintenance of local stockpiles that would be available in the case of a large scale disaster.
FDA press release 12/15/06. Available online at http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=129360§ionID=&isEPVantage=no. Accessed 12/20/06.
Sauer S, Keim M. Hydroxycobalamin: Improved public health readiness for cyanide disasters. Ann Em Med 2001;37:635-641
National Fire Protection Association, Research and Reports, Fire Statistics 2005.
Uhl W, Nolting A, Golor G, Rost KL, Kovar A. Safety of hydroxocobalamin in healthy volunteers in a randomized, placebo-controlled study. Clin Toxicol (Phila) 2006;44 Suppl 1:17-28.
Borron SW, Stonerook M, Reid F. Efficacy of hydroxocobalamin for the treatment of acute cyanide poisoning in adult beagle dogs. Clin Toxicol (Phila) 2006;44 Suppl 1:5-15.