Month: September 2019

Diphacinone Toxicity

by empharmd, posted in EM PharmD Core

Daniel Hu, PharmD, BCCCP

Critical Care and Emergency Medicine Pharmacist

Providence St. Peter Hospital

Diphacinone (2-diphenylacetyl-1,3-indanedione, CAS Number 82-66-6) is an indandione-type anticoagulant.1,2 It falls into a class of compounds known as long-acting anticoagulant rodenticides, along with brodifacoum, bromadiolone, chlorophacinone, and difenacoum, which inhibit the synthesis of clotting factors II, VII, IX, and X. These compounds were developed to replace warfarin in rodenticides and many available mouse and rat baits today contain these superwarfarins.1 Diphacinone was patented in 1954 and brought to use three years later.2 

Diphacinone poisoning does not appear to be widely reported. The 2017 Annual Report of the American Association of Poison Control Centers’ National Poison Data System did not contain any specific reports of diphacinone.3 There are little to no clinical data regarding toxic ingestions of diphacinone in the literature. What literature are available date back to diphacinone’s development many decades ago, and are published in reference to the drug going by multiple names including dipaxin, diphenadione, diphacin, and diphenacin.2 Many of the data appear to be published in pesticide and rodenticide reports. Recommendations for these patients depend on extrapolation of treatments for other long-acting anticoagulant rodenticide superwarfarins. Pharmacokinetic data include a description of diphacinone as having an “ultraslow” fall from peak plasma levels (<15% per day) representing slow clearance.4

A loading dose of 20-60 mg and a maintenance dose of 3-15 mg have been reported in older literature, with an interval to maximum effect of 48-84 hours.4,5 Diphacinone has been reported to have a therapeutic duration and half-life of 15-20 days in humans.6 During its development as Dipaxin in the 1950s, it was stated to be “certainly one of the most potent hypoprothrombinemic agents known for man.”7 While a dose of 0.5-1 mg did not result in a significant change in protime, a dose of 20 mg resulted in a prothrombin concentration reduction by 55% by the second day which lasted until the fifth day in one study.7 Another study showed that a single dose of 30 mg could result in a 60% reduction in prothrombin complex percentage at 139 hours.8 A third study showed that after a prolonged period of administration, prothrombin levels took 15-20 days to recover to normal or near-normal.9

Regarding treatment of diphacinone toxicity, Hayes’ Handbook of Pesticide Toxicology: “Treatment is the same as for warfarin, but based on experimental data from animals it would seem advisable to increase the dose of vitamin K as well as the duration of the corrective treatment.”10 Caravati et al published a consensus guideline for out-of-hospital management of long-acting anticoagulant rodenticide poisoning in 2007 which contains expert recommendations that could perhaps be used to inform inpatient decision-making as well.1 Other recommendations can be found in the Handbook of Toxicology of Chemical Warfare Agents (Superwarfarins chapter) and Micromedex.11,12 As with any acute toxic exposure, Poison Center consultation is recommended.

To date there appear to be only two published case reports involving toxic exposure to diphacinone. The first case report was published in 1969 involving a five year old boy with a near-fatal hemorrhage due to ingestion of diphacinone who was administered 250 mL fresh blood, 250 mL fresh plasma, and 10 mg of intramuscular vitamin K. The boy was reported as having confessed that his purpose in ingesting the tablets was that “he wished to annoy his mother who had given him a “hiding” and had locked him in his stepfather’s room for a mischievous act he had committed”.13 The second was a dermal exposure in which an 18 year old man spilled 50 mL of a 0.106% diphacinone liquid into his boot, later presenting with hematuria and flank pain after 7 days, with PT and PTT elevations, reported in 2003. The patient was treated with intramuscular vitamin K and discharged on oral vitamin K.14 Interestingly, the former case report does not appear to be widely referenced, likely due to diphacinone being referred to as “diphenadione” and “Didandin” in the text.13

While case reports are sparse in the literature, the National Institute for Occupational Safety and Health (NIOSH) National Occupational Exposure Survey (NOES) conducted from 1981-1983 estimated that “8,704 workers (561 of these are female) are potentially exposed to diphacinone in the US” (not including farm workers). Additionally, diphacinone is easily found in many common anticoagulant products including Assassin, Tomcat, Ditrac, and Exterminator’s Choice.16 Thus, while published cases are rare, there are likely many instances that have gone unreported, and there remains a high potential for patients to experience toxic exposures with diphacinone.

References

  1. Caravati EM, Erdman AR, Scharman EJ, et al. Long-acting anticoagulant rodenticide poisoning: An evidence-based consensus guideline for out-of-hospital management. Clin Toxicol. 2007;45(1):1-22. 
  2. Pitt WC, Higashi M, Primus TM. The effect of cooking on diphacinone residues related to human consumption of feral pig tissues. Food Chem Toxicol. 2011;49(9):2030-2034. 
  3. Rumack BH, Bronstein AC, Spyker DA, Cantilena LR, Green JL, Dart RC. 2017 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 35th Annual Report. Clin Toxicol. 2011;49(10):910-941.
  4. Coon WW, Willis PW. Some aspects of the pharmacology of oral anticoagulants. Clin Pharmacol Ther. 1970;11(3):312-336. 
  5. [No authors listed]. Anticoagulant drugs. Br Med J. 1969 Feb 8;1(5640):365-7.
  6. Mount ME, Feldman BF. Mechanism of diphacinone rodenticide toxicosis in the dog and its therapeutic implications. Am J Vet Res. 1983;44(11):2009-2017. 
  7. Field JB, Goldfarb MS, Ware AG, Griffith GC. Dipaxin: 2-diphenylacetyl-1,3-indandione; clinical evaluation of a new anticoagulant. Circulation 1955; 11: 576–583
  8. Katz R, Ducci H, Roeschmann W, Toriello L. Clinical experience with dipaxin and with the combined use of prothrombopenic agents. Circulation. 1954;10(5):685-690. 
  9. Pascale LR, Olwin JH. Experience with a new anticoagulant, Dipaxin (2-diphenylacetyl-l,3-indandione). Circulation. 1954;9:230-237.
  10. Pelfrene AF. Rodenticides. In: Krieger R, ed. Hayes’ Handbook of Pesticide Toxicology. 3rd ed. Cambridge, MA: Academic Press; 2010.
  11. Murphy MJ, Lugo AM. Superwarfarins. In: Gupta RC, ed. Handbook of Toxicology of Chemical Warfare Agents. 2nd ed. Cambridge, MA: Academic Press; 2015.
  12. Diphacinone. Micromedex. https://www.micromedexsolutions.com/. Accessed June 30, 2019.
  13. Katz J, Metz J. Hemorrhages in a young boy due to unsuspected diphenadione (Didandin) intoxication. Kluwer Acad Publ. 1989;18:145-165. 
  14. Spiller H, Gallenstein G, Murphy M. Dermal absorption of a liquid diphacinone rodenticide causing coagulaopathy. Vet Hum Toxicol. 2003;45(313-314).
  15. Hazardous Substances Data Bank [Internet]. Bethesda (MD): National Library of Medicine (US); [Last Revision Date September 4, 2001; cited 2019 September 14]. Diphacinone; Hazardous Substances Databank Number: 82-66-6; [about 37 p]. Available from: https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?./temp/~C4CXQr:2.
  16. Merola V. Anticoagulant rodenticides: deadly for pests, dangerous for pets. Vet Med 2002;97:716-727.